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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes; Cystic Fibrosis; Pancreatic Insufficiency; Abnormal Glucose Tolerance
• Intervention / Treatment: Drug: Dulaglutide 0.75Mg/0.5Ml Inj Pen

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Paola Alvarado, MS; Phone Number: 215-746-2081; Email: Paola.Alvarado@pennmedicine.upenn.edu
• Study Contact Backup: Name: Cornelia Dalton-Bakes; Phone Number: 215-746-2085; Email: corneliv@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Paola Alvarado, MS; Phone Number: 215-746-2081; Email: Paola.Alvarado@pennmedicine.upenn.edu
      • Contact: Cornelia Dalton-Bakes; Phone Number: 215-746-2085; Email: corneliv@pennmedicine.upenn.edu
      • Principal Investigator: Michael Rickels, MD, MS
      • Principal Investigator: Andrea Kelly, MD, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dulaglutide; 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; Randomized, open-label, cross-over study of 6 weeks exposure to dulaglutide 0.75 mg subcutaneous weekly or observation.
No Intervention: Observation; 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?

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

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Children's Hospital of Philadelphia
• Investigators: Principal Investigator: Michael R Rickels, MD, MS, University of Pennsylvania; Principal Investigator: Andrea Kelly, MD, MSCE, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2021
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: January 26, 2021
• First Submitted That Met QC Criteria: January 26, 2021
• First Posted (Actual): January 29, 2021

Study Record Updates

• Last Update Posted (Estimated): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Glucose Intolerance; Insulin Secretion; Cystic Fibrosis Related Diabetes; Glucagon-Like Peptide-1 (GLP-1)
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Hyperglycemia; Pancreatic Diseases; Fibrosis; Glucose Intolerance; Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Hypoglycemic Agents; Physiological Effects of Drugs; Dulaglutide
• Other Study ID Numbers: 848357

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Upon completion of enrollment.
• IPD Sharing Time Frame: Upon completion of enrollment.
• IPD Sharing Access Criteria: Consent will be uploaded to CT.gov
• IPD Sharing Supporting Information Type: ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes