Effect of Chronic Incretin-based Therapy in Cystic Fibrosis

Study Overview
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Brief Summary
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In recent years, diabetes has emerged as one of the most significant co-diseases that many Cystic Fibrosis (CF) patients develop. Type 1 and Type 2 diabetes results when either the body does not make enough insulin or the body does not respond correctly to this insulin. Insulin is a hormone which is made by cells in the pancreas and helps carry glucose (sugar) from the food we eat to the cells of the body for energy. While cystic fibrosis related diabetes (CFRD) has many features similar to both Type 1 and Type 2 diabetes, it is very different; therefore, treatment and care of CFRD is not the same. The purpose of this research study is to examine and understand the various mechanisms that contribute to CFRD and gain a better understanding of potential means to treat CFRD. The primary objective is to determine effectiveness of chronic incretin-based therapy vs. placebo on insulin secretion in CF patients with indeterminate glucose tolerance, impaired glucose tolerance, or CFRD.

Detailed Description
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Insufficient incretin action has been associated with T2D. To study the possible link between insufficient incretin action and impaired insulin secretion in CFRD as in T2D, the present study will determine whether early intervention with incretin-based therapy using the DPP-4 inhibitor sitagliptin (Januvia®) to raise endogenous levels of the incretin hormones--i.e.--glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) for a 6-month period will improve insulin secretion in CF patients with indeterminate glucose tolerance, impaired glucose tolerance or early CFRD.

Official Title
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A Randomized, Double-blind, Placebo Controlled Study of the Effectiveness of Chronic Incretin-based Therapy on Insulin Secretion in Cystic Fibrosis

Conditions
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Cystic Fibrosis, Pancreatic Insufficiency

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CF, defined by positive sweat test or CFTR mutation analysis according to CFF diagnostic criteria Age ≥ 18y on date of consent Pancreatic insufficiency Recent OGTT consistent with Indeterminate-GT, IGT, CFRD w/o fasting hyperglycemia, or an established diagnosis of CFRD without fasting hyperglycemia For female subjects, negative urine pregnancy test at enrollment. Exclusion Criteria: Established diagnosis of non-CF diabetes (i.e. T1D) or CFRD with fasting hyperglycemia, (fasting glucose > 126 mg/dL) History of clinically symptomatic pancreatitis within last year, Prior lung or liver transplant, Severe CF liver disease, as defined by portal hypertension, Fundoplication-related dumping syndrome, Medical co-morbidities that are not CF-related or are unstable per investigator opinion (i.e. history of bleeding disorders, immunodeficiency), Acute illness or changes in therapy (including antibiotics) within 6 weeks prior to enrollment, Treatment with oral or intravenous corticosteroids within 6 weeks of enrollment, Hemoglobin <10g/dL, within 90 days of Visit 1 or at Screening, Abnormal renal function, within 90 days of Visit 1 or at Screening; defined as Creatinine clearance < 50 mL/min (based on the Cockcroft-Gault formula) or potassium > 5.5mEq/L on non-hemolyzed specimen, A history of anaphylaxis, angioedema or Stevens-Johnson syndrome, Inability to perform study specific procedures (MMTT, GPA), Subjects, who in study team opinion, may be non-compliant with study procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin<br>The dose of sitagliptin (Januvia®) 100 mg tablet will be taken orally each morning for 6 months. | Drug: Sitagliptin<br>* The GPA test as described in the primary outcome section will be performed at baseline and after 6 months of therapy in the Sitagliptin and placebo arms. Furthermore, evaluation of endogenous GLP-1 levels will be assessed by a mixed meal tolerance test compared at baseline and 6 months.<br>* Other names: Januvia;|
| Placebo Comparator: Placebo<br>Placebo tablet will be taken orally each morning for 6 months. | Drug: Placebo<br>* The GPA test as described in the primary outcome section will be performed at baseline and after 6 months of therapy in the Sitagliptin and placebo arms. Furthermore, evaluation of endogenous GLP-1 levels will be assessed by a mixed meal tolerance test compared at baseline and 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Second-phase Insulin Response Derived From the Glucose-potentiated Arginine Test as a Measure of β-cell Sensitivity to Glucose at Baseline and at 6 Months | The key endpoint of interest will be the change in second phase insulin response derived from the Glucose-Potentiated Arginine (GPA) test. The GPA test will measure insulin, which will be a measure of pancreatic endocrine function in response to the injection of arginine. Arginine is a naturally occurring amino acid (substance) in the body. It will be given in the veins to make the pancreas secrete insulin. After the first injection of arginine, a glucose infusion will be started in order to raise the level of sugar in the blood to 230 mg/dl. Once the level is achieved, arginine will be injected again and blood samples are measured. After a 2 hour break, the glucose infusion will be started to achieve a blood sugar of 340 mg/dl and the arginine injection will be repeated. Comparison of responses at baseline and after 6 months of incretin-based therapy (Sitagliptin) or placebo will be performed using statistical methods. | Baseline and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, Diabetes, Pancreatic Insufficiency