Prevention of Cystic Fibrosis Diabetes — Prevent  

Cystic Fibrosis Clinical Trial

Official title: 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

Status Terminated

Clinical Trial Summary

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

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• Prediabetes
• Prediabetic State

• NCT number: NCT00967798
• Study type: Interventional
• Source: Emory University
• Status: Terminated
• Phase: Phase 3
• Start date: May 2010
• Completion date: December 31, 2017