GLP-1 Agonist Therapy in Cystic Fibrosis-Related Glucose Intolerance

Study Overview
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Brief Summary
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Diabetes is a major co-morbidity in pancreatic insufficient cystic fibrosis (PI-CF) and associated with worse outcomes. While reduced β-cell mass contributes to the insulin secretory defects that characterizes cystic fibrosis-related diabetes (CFRD), other modifiable determinants appear operative in the emergence and progression of abnormal glucose tolerance towards diabetes. Identifying interventions to preserve β-cell function are crucial for delaying and potentially preventing CFRD development. In this study, we hypothesize that weekly administration of the long-acting glucagon-like peptide-1 (GLP-1) agonist dulaglutide will improve defective early-phase insulin secretion and improve glucose tolerance during a mixed-meal tolerance test.

Detailed Description
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Diabetes is a major co-morbidity in pancreatic insufficient cystic fibrosis (PI-CF) and associated with worse outcomes. While reduced β-cell mass contributes to the insulin secretory defects that characterizes cystic fibrosis-related diabetes (CFRD), other modifiable determinants appear operative in the emergence and progression of abnormal glucose tolerance towards diabetes. Identifying interventions to preserve β-cell function are crucial for delaying and potentially preventing CFRD development. In this study, we hypothesize that weekly administration of the long-acting glucagon-like peptide-1 (GLP-1) agonist dulaglutide will improve defective early-phase insulin secretion and improve glucose tolerance during a mixed-meal tolerance test.

Official Title
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Effect of GLP-1 Agonist Therapy on Insulin Secretion in Adults With Pancreatic Insufficient Cystic Fibrosis and Abnormal Glucose Tolerance: a Randomized, Open-label, Cross-over Trial

Conditions
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Cystic Fibrosis, Pancreatic Insufficiency, Abnormal Glucose Tolerance, Diabetes

Intervention / Treatment
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* Drug: Dulaglutide 0.75Mg/0.5Ml Inj Pen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Male or female, aged ≥18 years on date of consent 2. Confirmed diagnosis of CF, defined by positive sweat test or Cystic Fibrosis transmembrane conductance regulator (CFTR) mutation analysis according to Cystic Fibrosis Foundation (CFF) diagnostic criteria. 3. Pancreatic insufficiency defined by clinical requirement for pancreatic enzyme replacement. 4. Abnormal glucose tolerance defined by oral glucose tolerance test (OGTT) criteria for early glucose intolerance (EGI), impaired glucose tolerance (IGT), or CFRD without fasting hyperglycemia (fasting hyperglycemia is defined as fasting glucose ≥126 mg/dL) 5. Ability to take subcutaneous medication and be willing to adhere to the weekly administration regimen and complete study specific procedures (MMTT) 6. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 6 weeks after the end of dulaglutide or observation administration; oral contraceptives, intra-uterine devices, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable Exclusion Criteria: 1. BMI <19 kg/m2 2. Presence of first-degree atrioventricular block or other evidence for cardiac conduction system or structural heart defects 3. Pregnancy or lactation; a negative urine pregnancy test will be required at enrollment 4. Known allergic reactions to any GLP-1 agonist, and any history of severe hypersensitivity reactions (anaphylaxis or angioedema) 5. Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2) 6. Pulmonary exacerbation requiring IV antibiotics or systemic glucocorticoids within 4 weeks prior to study procedures 7. Gastrointestinal symptom exacerbation defined by current nausea/vomiting or diarrhea 8. Established diagnosis of non-CF diabetes (e.g. type 1 diabetes) or CFRD with fasting hyperglycemia (fasting glucose ≥126 mg/dL [use of prandial insulin or repaglinide will be permitted]) 9. History of clinically symptomatic pancreatitis within the last year 10. Prior lung, liver or other solid organ transplant 11. Severe CF liver disease, as defined by the presence of portal hypertension 12. History of fundoplication-related dumping syndrome 13. Hemoglobin <10 g/dL, within 90 days of study procedures or at screening 14. Abnormal renal function, within 90 days of study procedures or at screening; defined as creatinine >2x upper limit of normal (ULN) or potassium >5.5mEq/L on non-hemolyzed specimen 15. History of any illness or condition that, in the opinion of the investigator might confound the results of the study or pose an additional risk to the subject

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dulaglutide<br>The Mixed Meal Tolerance Test as described in the primary outcome section will be performed at baseline and after 6 weeks of dulaglutide therapy in the intervention period. | Drug: Dulaglutide 0.75Mg/0.5Ml Inj Pen<br>* Randomized, open-label, cross-over study of 6 weeks exposure to dulaglutide 0.75 mg subcutaneous weekly or observation.<br>|
| No Intervention: Observation<br>The Mixed Meal Tolerance Test as described in the primary outcome section will be performed at baseline and after 6 weeks of no intervention in the observation period. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early-phase insulin secretion | The primary outcome measure is the insulin secretory rate during the first 30-min during a mixed meal tolerance test (ISR-AUC30). | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early-phase insulin secretion adjusted for glucose excursion | This secondary outcome measure is insulin secretory rate/glucose area under cure during the first 30-min during a mixed meal tolerance test (ISR-AUC30/ Glc-AUC30) | 18 weeks | 
| Glucose tolerance | This secondary outcome measure is mixed meal tolerance test-related glucose area under the curve over 180 min (Glc-AUC180). | 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis Related Diabetes, Glucose Intolerance, Insulin Secretion, Glucagon-Like Peptide-1 (GLP-1)