Cystic Fibrosis Related Diabetes, Pancreatic Insufficiency
Conditions
Keywords
Cystic Fibrosis, Diabetes, Cystic Fibrosis Related Diabetes, Pre-diabetes, oral hypoglycemic agents, Repaglinide, treatment, inflammatory markers, Lung function, nutrition
Brief summary
The purpose of this study is to provide the necessary data and experience to design a larger, full scale clinical trial to determine if a certain medicine (repaglinide), which increases the amount of insulin secreted by the pancreas, can improve the nutritional status and pulmonary function of adolescents and young adults with cystic fibrosis and prediabetes by improving blood glucose control. The investigators are also trying to determine the relationship between systemic inflammatory factors and glucose impairment.
Detailed description
As people with Cystic Fibrosis (CF) are living well into adulthood new complications are arising. CF-Related Diabetes (CFRD) has emerged as a major complication. Years prior to the diagnosis of CFRD, patients have decreasing insulin secretion, glucose intolerance, deteriorating pulmonary function, and nutritional impairment. There are no current standard recommendations for the treatment of CF patients with prediabetes, and there is little evidence that treatment of this prediabetic state in CF patients will prevent the deterioration of the lung function, nutritional status and potentially slow the progression to manifest CFRD. To determine the feasibility of testing this hypothesis, we will perform a pilot, double-blinded, randomized controlled trial in 20 CF pancreatic insufficient patients ages of 12 to 24 years old with impaired glucose tolerance test (IGT) or CFRD without fasting hyperglycemia (CFRD-No FH) and assign them to either placebo or Repaglinide 0.5 mg PO 3 - 4 times a day before meals for two years. Patients will monitor their blood glucose daily and will be followed every 3 months for 2 years to determine changes in nutritional status by BMI and DEXA, lung function tests, frequency of hospitalizations, antibiotic courses, and degree of glucose tolerance, insulin secretion and insulin sensitivity. In addition, based on the evidence of increased inflammation in type 2 diabetes, correlation of systemic inflammatory response at different degrees of glucose tolerance and after treatment, will be assessed in these subjects, as well as in another 20 CF pancreatic insufficient matched patients with normal glucose tolerance who will be studied once without intervention
Interventions
DRUGplacebo
CF pancreatic insufficient patients with impaired glucose tolerance (IGT) or CFRD without fasting hyperglycemia (CFRD-No FH) by OGTT will be treated with placebo by taking 1 pill before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
DRUGrepaglinide
CF pancreatic insufficient patients with impaired glucose tolerance (IGT) or CFRD without fasting hyperglycemia (CFRD-No FH) by OGTT will be treated with repaglinide 0.5 mg before each meal that contains more than 20 grams of carbohydrate 3-4 times a day for 2 years.
Sponsors
Washington University School of Medicine
National Institutes of Health (NIH)
Novo Nordisk A/S
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Arbelaez, Ana Maria
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 24 Years
Healthy volunteers
No
Inclusion criteria
* Male or females 12 -24 years old * Diagnosis of Cystic Fibrosis by sweat test with exocrine pancreatic insufficiency * Must have a glucose pattern by Oral Glucose Tolerance Test with fasting blood glucose \<126 mg/dl and 2 hour: 140 - 199 mg/dl or \>200 mg/dl. * Weight must be stable within 5% for 3 months prior to initiation visit * Must be able to reproducibly perform spirometry based on American Thoracic Society guidelines
Exclusion criteria
* Patients receiving growth hormone therapy or taking insulin * Patients with evidence of liver dysfunction * Patients who are status-post lung or liver transplantation * Patients who have received systemic steroids for more than 28 days during the 6 months prior to the study * Patients with active ABPA on steroids * Patients taking medications that affect glucose metabolism or contraindicated with repaglinide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| BMI | 2 year/end of study | — |
| Body Composition | 2 year/end of study | Reporting % of Fat and Lean body mass |
| CRP | 2 year/end of study | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| C-Peptide | 2 year | — |
| Glucose Tolerance | 2-year | We completed the OGTT at the 2 year/end of study visit. |
| Inflammatory Markers | 2 year/end of study | — |
| Wt Z Score | 2 year/end of study | — |
| Tanner Stage | 2 year/end of study | Puberty scale measuring 1-5, 1 being least development, 5 being most development. |
| FEV 1 | 2 year/end of study | % of lung function |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients Who Received Placebo All participants were receiving ADEK vitamins and pancreatic enzyme replacement. Patients were required to be clinically stable, without evidence of deterioration from previous pulmonary function tests (PFTs) for 3-months prior to the study and without CF exacerbation or hospitalization for 2-months prior to the study. Additionally, patients were required to have maintained stable weight within 5% variance for 3-months prior to participation. Exclusion criteria included fasting blood glucose levels \>126 mg/dL on study day, IV antibiotic or systemic steroid use within two months, oral corticosteroid usage for more than 28-days over the past 6-months, history of lung or liver transplant, elevated transaminases, allergic bronchopulmonary aspergillosis, or the inability to perform spirometry. | 4 |
| Patients Who Received Repaglinide All participants were receiving ADEK vitamins and pancreatic enzyme replacement. Patients were required to be clinically stable, without evidence of deterioration from previous pulmonary function tests (PFTs) for 3-months prior to the study and without CF exacerbation or hospitalization for 2-months prior to the study. Additionally, patients were required to have maintained stable weight within 5% variance for 3-months prior to participation. Exclusion criteria included fasting blood glucose levels \>126 mg/dL on study day, IV antibiotic or systemic steroid use within two months, oral corticosteroid usage for more than 28-days over the past 6-months, history of lung or liver transplant, elevated transaminases, allergic bronchopulmonary aspergillosis, or the inability to perform spirometry. | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Total | Patients Who Received Placebo | Patients Who Received Repaglinide |
|---|---|---|---|
| 2 hour c-peptide | 9.6 mg/dl | 9.7 mg/dl | 9.5 mg/dl |
| 2 hour glucose | 182.7 mg/dl | 182.4 mg/dl | 183 mg/dl |
| Age, Categorical <=18 years | 6 Participants | 3 Participants | 3 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 1 Participants |
| Age, Continuous | 15.5 years | 16 years | 15 years |
| BMI | 18.94 Kg/m^2 | 19.45 Kg/m^2 | 18.38 Kg/m^2 |
| CRP | 1.95 mg/L | 1.8 mg/L | 2.1 mg/L |
| Fasting C-Peptide | 1.45 mg/dl | 1.2 mg/dl | 1.7 mg/dl |
| Fasting Glucose | 99.6 mg/dl | 99.1 mg/dl | 100 mg/dl |
| Fat % | 21.2 % Fat mass | 20.34 % Fat mass | 22.06 % Fat mass |
| FEV 1 | 95.25 % of lung function | 97.75 % of lung function | 92.75 % of lung function |
| Inflammatory marker IL1 | 0.5 pg/ml | 0.1 pg/ml | 0.9 pg/ml |
| Inflammatory marker IL6 | 10.5 pg/ml | 8.3 pg/ml | 12.6 pg/ml |
| Inflammatory marker IL8 | 7.75 pg/ml | 7 pg/ml | 8.5 pg/ml |
| Inflammatory marker TNF Alpha | 5.9 pg/ml | 7.3 pg/ml | 4.5 pg/ml |
| Lean % | 75.9 % Lean mass | 76.71 % Lean mass | 75 % Lean mass |
| Region of Enrollment United States | 16 participants | 8 participants | 8 participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 1 Participants |
| Tanner stage | 3.5 units on a scale | 3.75 units on a scale | 3.25 units on a scale |
| Wt Z score | -0.7 Z score | -1.11 Z score | -0.29 Z score |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
BMI
Time frame: 2 year/end of study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 1 Placebo | BMI | 19.63 Kg/m^2 |
| 2. Repaglinide | BMI | 21.19 Kg/m^2 |
Primary
Body Composition
Reporting % of Fat and Lean body mass
Time frame: 2 year/end of study
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 1 Placebo | Body Composition | Lean | 77.15 % body mass |
| 1 Placebo | Body Composition | Fat | 19.82 % body mass |
| 2. Repaglinide | Body Composition | Lean | 70.83 % body mass |
| 2. Repaglinide | Body Composition | Fat | 26.21 % body mass |
Primary
CRP
Time frame: 2 year/end of study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 1 Placebo | CRP | 9.6 mg/L |
| 2. Repaglinide | CRP | 2 mg/L |
Secondary
C-Peptide
Time frame: 2 year
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 1 Placebo | C-Peptide | fasting | 1.5 pg/ml |
| 1 Placebo | C-Peptide | 2 hour | 7.5 pg/ml |
| 2. Repaglinide | C-Peptide | fasting | 1.6 pg/ml |
| 2. Repaglinide | C-Peptide | 2 hour | 7.7 pg/ml |
Secondary
FEV 1
% of lung function
Time frame: 2 year/end of study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 1 Placebo | FEV 1 | 90.5 % lung function |
| 2. Repaglinide | FEV 1 | 91.5 % lung function |
Secondary
Glucose Tolerance
We completed the OGTT at the 2 year/end of study visit.
Time frame: 2-year
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 1 Placebo | Glucose Tolerance | fasting glucose | 101.5 mg/dl |
| 1 Placebo | Glucose Tolerance | 2 hour glucose | 185.75 mg/dl |
| 2. Repaglinide | Glucose Tolerance | fasting glucose | 94.5 mg/dl |
| 2. Repaglinide | Glucose Tolerance | 2 hour glucose | 184 mg/dl |
Secondary
Inflammatory Markers
Time frame: 2 year/end of study
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 1 Placebo | Inflammatory Markers | IL1 | 0.14 pg/ml |
| 1 Placebo | Inflammatory Markers | IL6 | 10.4 pg/ml |
| 1 Placebo | Inflammatory Markers | IL8 | 5.8 pg/ml |
| 1 Placebo | Inflammatory Markers | TNF alpha | 5.1 pg/ml |
| 2. Repaglinide | Inflammatory Markers | TNF alpha | 3.6 pg/ml |
| 2. Repaglinide | Inflammatory Markers | IL1 | 0.34 pg/ml |
| 2. Repaglinide | Inflammatory Markers | IL8 | 5.2 pg/ml |
| 2. Repaglinide | Inflammatory Markers | IL6 | 6 pg/ml |
Secondary
Tanner Stage
Puberty scale measuring 1-5, 1 being least development, 5 being most development.
Time frame: 2 year/end of study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 1 Placebo | Tanner Stage | 4.25 units on a scale |
| 2. Repaglinide | Tanner Stage | 5 units on a scale |
Secondary
Wt Z Score
Time frame: 2 year/end of study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 1 Placebo | Wt Z Score | -1.21 Z score |
| 2. Repaglinide | Wt Z Score | -0.26 Z score |