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Effect of Chronic Incretin-based Therapy in Cystic Fibrosis

Primary Purpose

Cystic Fibrosis, Pancreatic Insufficiency

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Sitagliptin
Placebo
Sponsored by
University of Pennsylvania
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Cystic Fibrosis focused on measuring Cystic Fibrosis, Diabetes, Pancreatic Insufficiency

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Children's Hospital of Philadelphia and University of Pennsylvania

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Sitagliptin

Placebo

Arm Description

The dose of sitagliptin (Januvia®) 100 mg tablet will be taken orally each morning for 6 months.

Placebo tablet will be taken orally each morning for 6 months.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Full Information

First Posted
June 12, 2013
Last Updated
February 24, 2022
Sponsor
University of Pennsylvania
Collaborators
Children's Hospital of Philadelphia
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1. Study Identification

Unique Protocol Identification Number
NCT01879228
Brief Title
Effect of Chronic Incretin-based Therapy in Cystic Fibrosis
Official Title
A Randomized, Double-blind, Placebo Controlled Study of the Effectiveness of Chronic Incretin-based Therapy on Insulin Secretion in Cystic Fibrosis
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
June 2013 (undefined)
Primary Completion Date
December 2019 (Actual)
Study Completion Date
March 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Pennsylvania
Collaborators
Children's Hospital of Philadelphia

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis, Pancreatic Insufficiency
Keywords
Cystic Fibrosis, Diabetes, Pancreatic Insufficiency

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sitagliptin
Arm Type
Experimental
Arm Description
The dose of sitagliptin (Januvia®) 100 mg tablet will be taken orally each morning for 6 months.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo tablet will be taken orally each morning for 6 months.
Intervention Type
Drug
Intervention Name(s)
Sitagliptin
Other Intervention Name(s)
Januvia
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Baseline and 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael M Rickels, MD
Organizational Affiliation
University of Pennsylvania
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Philadelphia and University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19194
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34406395
Citation
Kelly A, Sheikh S, Stefanovski D, Peleckis AJ, Nyirjesy SC, Eiel JN, Sidhaye A, Localio R, Gallop R, De Leon DD, Hadjiliadis D, Rubenstein RC, Rickels MR. Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance. J Clin Endocrinol Metab. 2021 Aug 18;106(9):2617-2634. doi: 10.1210/clinem/dgab365. Epub 2021 May 22. Erratum In: J Clin Endocrinol Metab. 2021 Oct 15;: J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1778.
Results Reference
derived
Links:
URL
https://pubmed.ncbi.nlm.nih.gov/34406395/
Description
Published paper for this study titled: "Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance".

Learn more about this trial

Effect of Chronic Incretin-based Therapy in Cystic Fibrosis

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