Abnormal Glucose Tolerance, Cystic Fibrosis, Diabetes, Pancreatic Insufficiency
Conditions
Keywords
Cystic Fibrosis Related Diabetes, Glucose Intolerance, Insulin Secretion, Glucagon-Like Peptide-1 (GLP-1)
Brief summary
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
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.
Interventions
Randomized, open-label, cross-over study of 6 weeks exposure to dulaglutide 0.75 mg subcutaneous weekly or observation.
Sponsors
University of Pennsylvania
Children's Hospital of Philadelphia
Children's Hospital Colorado
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 OGTT criteria for EGI, IGT, or CFRD, or diagnosed CFRD. 1. There will be no restriction on enrollment of individuals with CFRD but without fasting hyperglycemia (fasting hyperglycemia is defined as fasting glucose ≥126 mg/dL) 2. Individuals with CFRD and fasting hyperglycemia (defined as above or by the use of basal insulin therapy) must also have a HbA1c ≤8% and a random (non-fasting) C-peptide ≥1.2 ng/mL17; enrollment of this subgroup will be limited to n =10. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early-phase insulin secretion | 18 weeks | The primary outcome measure is the insulin secretory rate during the first 30-min during a mixed meal tolerance test (ISR-AUC30). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early-phase insulin secretion adjusted for glucose excursion | 18 weeks | 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) |
| Glucose tolerance | 18 weeks | This secondary outcome measure is mixed meal tolerance test-related glucose area under the curve over 180 min (Glc-AUC180). |
Countries
United States
Contacts
CONTACTPaola Alvarado, MS
CONTACTCornelia Dalton-Bakes
PRINCIPAL_INVESTIGATORMichael R Rickels, MD, MS
University of Pennsylvania
PRINCIPAL_INVESTIGATORAndrea Kelly, MD, MSCE
Children's Hospital of Philadelphia
Outcome results
None listed