Clinical trial NCT04731272: GLP-1 Agonist Therapy in Cystic Fibrosis-Related Glucose Intolerance
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Cystic Fibrosis
Pancreatic Insufficiency
Abnormal Glucose Tolerance
Diabetes
Keywords: Cystic Fibrosis Related Diabetes
Glucose Intolerance
Insulin Secretion
Glucagon-Like Peptide-1 (GLP-1)
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Children's Hospital of Philadelphia
name: Children's Hospital Colorado
First posted: 2021-01-29
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Early-phase insulin secretion
timeFrame: 18 weeks
Secondary outcomes:
measure: Early-phase insulin secretion adjusted for glucose excursion
timeFrame: 18 weeks
measure: Glucose tolerance
timeFrame: 18 weeks
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital of Colorado
state: Colorado
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Michael R Rickels, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Philadelphia
name: Andrea Kelly, MD, MSCE
role: PRINCIPAL_INVESTIGATOR
References: