Prevention of Cystic Fibrosis Diabetes (Prevent)

A Randomized, Double-blind, Placebo-controlled Study to Determine Whether Chronic Treatment of Cystic Fibrosis Subjects With Impaired Glucose Tolerance Using Sitagliptin (Januvia) Prevents the Development of Diabetes

Acute systemic hyperglycemia causes oxidative stress and a pro-inflammatory response. The pro-inflammatory cytokines induced by hyperglycemia are toxic to islet insulin producing cells, and thus worsen glucose intolerance. Patients with cystic fibrosis (CF) have a high prevalence of CF related diabetes (CFRD) and up to 40% of CF adults develop CFRD. During the prediabetic phase in CF, there is progression from normal glucose homeostasis to high risk prediabetes characterized by episodes of acute hyperglycemia after meals and during respiratory exacerbations. The mild hyperglycemia seen in CF patients with high risk prediabetes following a meal would be expected to induce a degree of systemic inflammation and oxidative stress. These repetitive episodes, if left unchecked, could lead to progression of glucose impairment, worsening severity of oxidative stress and inflammation, and ultimately the development of CFRD, all via hyperglycemia-induced toxicity to beta cells. Furthermore, this process may be accelerated in CF because lung disease and resultant respiratory exacerbations are associated with oxidative stress and inflammation and this will further contribute to beta cell damage.

Sitagliptin is a recently approved agent for type 2 diabetes and markedly enhances insulin secretion in the presence of hyperglycemia and has been shown to be effective in preventing postprandial hyperglycemia. The hypothesis to be tested in this project is that sitagliptin will prevent the development of CFRD in CF subjects with high risk prediabetes by blocking postprandial hyperglycemia. The investigators propose a randomized, double-blind, placebo-controlled, multicenter, 15-month longitudinal study in 118 CF subjects with high risk prediabetes to test this hypothesis. Specifically, the investigators aim to show that chronic treatment with sitagliptin: prevents the conversion to diabetes; results in preservation of beta cell function; reduces systemic measures of oxidative stress and inflammation; and slows the rate of progression of lung disease.

Funding Source - FDA Office of Orphan Products Development

Study Overview

• Status: Terminated
• Conditions: Cystic Fibrosis; Prediabetes
• Intervention / Treatment: Drug: Sitagliptin

Detailed Description

This was a double-blind, placebo-controlled, multicenter study intending to enroll 118 CF subjects aged 13 years of age or older who have high risk prediabetes. High risk prediabetes was defined during the screening visit by performing an oral glucose tolerance test (OGTT) and finding that the fasting plasma glucose level is between 110-125 mg/dl and/or the 2-hour plasma glucose level is between 140 and 199 mg/dl. Upon enrollment, subjects were randomized to receive either sitagliptin or placebo. Each subject was to be followed for 15 months to determine if sitagliptin prevented the conversion to frank diabetes.

The following was to be done at enrollment and every 6 months: an OGTT with collection of blood at 0, 1/2, and 2 hours for measurement of glucose and insulin in order to determine progression of glucose intolerance; collection of blood at time 0 and 2 hours during the OGTT and measurement of systemic redox status, oxidative stress, and degree of inflammation to determine the degree of basal oxidative stress and inflammation as well as the degree of hyperglycemia-induced oxidative stress and inflammation; collection of exhaled breath condensate in a subset of subjects at selected sites at time 0 and 2 hours during the OGTT and measurement of airway redox status, degree of inflammation, and glucose levels to determine basal respiratory tract redox status and inflammation, the degree of hyperglycemia-induced changes in redox status and inflammation, and correlation between plasma and airway glucose levels; collection of blood to determine safety of the study medication (liver and renal function, complete blood count, electrolyte concentrations); and determination of progression of lung disease as defined by the number of respiratory exacerbations severe enough to require hospitalization and the rate of decline in lung function.

The results of two OGTTs performed at least one week apart was used to determine whether the subject had converted from high risk prediabetes to frank diabetes (primary objective). Conversion to CFRD was defined when both OGTTs were abnormal (abnormal is defined as a fasting plasma glucose level greater than 125 mg/dl and/or a 2 hour glucose level greater than 199 mg/dl). The results of measures of redox balance, oxidant stress and inflammation (secondary objectives) would provide biologic plausibility to our concept on the mechanism of action of sitagliptin in preventing the development of CF diabetes.

Hemoglobin-specific A1c fraction (HbA1c) was to be measured half-way between the 6-monthly visits and a rise of more than 0.5% from the enrollment value would result in two OGTT tests done at least one week apart to determine if diabetes has developed. At these interval study visits, blood was also collected to assess the safety of the study drug and, if the subject was female, to determine if pregnancy had occurred.

In the event that diabetes did develop, the study drug (or placebo) was to be stopped and the subject would have completed the study.

In summary, this was a double-blind, placebo-controlled clinical trial to determine whether sitagliptin prevents the conversion of CF subjects with high-risk prediabetes to frank diabetes. If successful, this would be the first treatment modality available to prevent the development of CFRD, a serious and life shortening complication of CF. Unfortunately, the study sites were unable to achieve enrollment targets and the study was prematurely terminated March 31, 2017 because of low enrollment. For those subjects enrolled in the study, there was no safety concerns. Data are currently being analyzed for the subjects that were enrolled.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Healthcare of Atlanta at Scottish Rite
    • Atlanta, Georgia, United States, 30322
      • Emory University and Children's Healthcare of Atlanta at Egleston
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged 13 years of age or older at the time of enrollment
• Diagnosis of cystic fibrosis (CF) confirmed by pilocarpine iontophoresis sweat chloride measurements and/or genotyping
• Clinically stable with no lower respiratory tract exacerbation requiring intravenous antibiotics in the three weeks prior to enrollment
• On a stable clinical treatment regimen for at least three weeks prior to enrollment
• Male or female. If female, is not lactating and has a negative pregnancy test at screening. If female of child bearing potential, willing to practice effective birth control (i.e. a method known to decrease the risk of pregnancy to less than 1%)
• Able to understand and provide informed consent
• Willing and able to comply with the study schedule and testing
• High risk prediabetes as defined by high-risk impaired fasting glucose levels of 110-125 mg/dl and/or a 2-hour plasma glucose level of 140 to 199 mg/dl found on an Oral Glucose Tolerance Test performed at screening 8 weeks or less before enrollment
• Available by telephone
• Has literacy and language skills required to fill out study material

Exclusion Criteria:

• Diagnosed with CF related diabetes
• Chronic heart failure with New York Heart Association (NYHA) class III/IV, ejection fraction less than 25%, or receiving digoxin
• Liver disease as defined by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) three times above the upper limit of normal.
• Serum creatinine greater than 1.3 mg/dl for males and greater than 1.1 mg/dl for females or receiving chronic dialysis
• Taking chronic oral or intravenous glucocorticosteroids during the past month
• On insulin therapy during the past month
• CF lung disease severe enough to require daytime chronic oxygen therapy via nasal cannula during the past month
• Unable to perform pulmonary function testing
• History of any illness or condition that, in the opinion of the sponsor might confound the results of the study or pose an additional risk in administering study drug to the subject
• Post lung or liver transplant
• Listed and awaiting organ transplant
• Current drug or alcohol dependency
• Participating in another clinical drug trial or past participant within 30 days of enrollment
• Pancreatic sufficient
• History of acute pancreatitis as documented by characteristic clinical manifestations and elevation of serum amylase and lipase within the last 2 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sitagliptin; CF patients receiving Sitagliptin. Intervention: Dose is 100 mg taken orally once a day in the morning with breakfast. Duration is one year or until converted to CF diabetes, whichever comes sooner.	Drug: Sitagliptin; 100 mg of sitagliptin is taken orally each morning with breakfast. Duration is 12 months or conversion to CF diabetes, whichever comes first.; Other Names: Januvia
Placebo Comparator: Sugar pill; CF patients receiving placebo. Intervention: Placebo is taken orally once a day in the morning with breakfast. Duration is one year or until converted to CF diabetes, whichever comes sooner.	Drug: Sitagliptin; 100 mg of sitagliptin is taken orally each morning with breakfast. Duration is 12 months or conversion to CF diabetes, whichever comes first.; Other Names: Januvia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Conversion to Cystic Fibrosis Related Diabetes	The number of participants with conversion to cystic fibrosis related diabetes was determined.	Month 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Beta-cell Disposition Index	Preservation of beta-cell function was to be assessed with the disposition index, which is a measurement of beta-cell function adjusted for insensitivity to insulin.	Baseline through Month 15
Change in Redox Couples Glutathione/Glutathione Disulfide and Cysteine/Cystine	Cysteine (Cys)/cystine (CySS) and glutathione (GSH)/glutathione disulfide (GSSG) redox couples are biomarkers of oxidative stress.	Baseline through Month 12
Change in Inflammatory Cytokines	Hyperglycemia causes release of pro-inflammatory cytokines which can further compromise beta-cell function by increasing insulin resistance and by inducing beta-cell apoptosis. Inflammatory cytokines that have been shown to contribute to destruction of beta-cells include interleukin 1 beta (IL-1b), tumor necrosis factor alpha (TNFa), and interleukin 6 (IL-6).	Baseline through Month 12
Change in Percent Predicted FEV1	The decline of lung function was assessed with forced expiratory volume (FEV1), which measures how much air is exhaled during one second of a forced exhale. Change is described as the difference in FEV1 at baseline subtracted from FEV1 at the end of treatment study visit. A protocol change during the study reduced the treatment time from 24 months to 12 months. The end of treatment study visit for participants in the early part of the study occurred at 24 months, while the end of treatment visit was a 12 months for participants enrolling later. Negative values indicate a decline in lung function over the course of the study.	Baseline, end of treatment (Month 12 or Month 24)

Collaborators and Investigators

• Sponsor: Emory University
• Investigators: Principal Investigator: Arlene A Stecenko, MD, Emory University

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: August 27, 2009
• First Submitted That Met QC Criteria: August 27, 2009
• First Posted (Estimate): August 28, 2009

Study Record Updates

• Last Update Posted (Actual): June 25, 2018
• Last Update Submitted That Met QC Criteria: May 23, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: diabetes; inflammation; cystic fibrosis; oxidative stress; lung disease; redox balance
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate
• Other Study ID Numbers: IRB00012724; 1R01FD003527-01 (U.S. FDA Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No