Prevention of Cystic Fibrosis Diabetes

• Preservation of beta cell function [ Time Frame: every 6 months for 2 years ] [ Designated as safety issue: No ]
• Reduction in airway redox imbalance, oxidative stress, and inflammation [ Time Frame: every 6 months for 2 years ] [ Designated as safety issue: No ]
  Only in a subset of subjects
• Reduction in systemic redox imbalance, oxidative stress, and inflammation [ Time Frame: every 6 months for 2 years ] [ Designated as safety issue: No ]
• Slow the rate of progression of lung disease [ Time Frame: every 3 months for 2 years ] [ Designated as safety issue: No ]

• Preservation of beta cell function [ Time Frame: baseline, 12 months, and 24 hours ] [ Designated as safety issue: No ]
• Reduction in airway oxidative stress and inflammation [ Time Frame: every 6 months for 2 years ] [ Designated as safety issue: No ]
• Reduction in systemic oxidative stress and inflammation [ Time Frame: every 6 months for 2 years ] [ Designated as safety issue: No ]
• Slow the rate of progression of lung disease [ Time Frame: every 3 months for 2 years ] [ Designated as safety issue: No ]

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, 27-month longitudinal study in 186 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

This is a double-blind, placebo-controlled, multicenter study of 186 CF subjects aged 13 years of age or older who have high risk prediabetes. High risk prediabetes is 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 will be randomized to receive either sitagliptin or placebo. Each subject will be followed for 27 months to determine if sitagliptin prevents the conversion to frank diabetes.

The following will 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 will be used to determine whether the subject has converted from high risk prediabetes to frank diabetes (primary objective). Conversion to CFRD will be defined when both OGTTs are 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) will 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) will be measured half-way between the 6-monthly visits and a rise of more than 0.5% from the enrollment value will result in two OGTT tests done at least one week apart to determine if diabetes has developed. At these interval study visits, blood will also be collected to assess the safety of the study drug and, if the subject is female, to determine if pregnancy has occurred.

As a further measure to assure that the conversion to CFRD is captured as soon as possible, subjects will monitor every two weeks home glucose levels by finger stick using a 5-point glucose profile (fasting, 2 hours after the beginning of meals at breakfast, lunch, and supper, and at bedtime). If the fasting glucose value is greater than or equal to 130 mg/dl or any of the 2 hour postprandial glucose values are greater than or equal to 180 mg/dl, the 5-point profile will be repeated the following day. Trigger for doing two OGTTs at least one week apart based on finger stick will be a fasting blood glucose greater than or equal to 130 mg/dl and/or 2 hour post prandial greater than or equal to 180 mg/dl on two successful days of home monitoring.

In the event that diabetes does develop, the study drug (or placebo) will be stopped and the subject will have completed the study.

In summary, this is 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.

• Cystic Fibrosis
• Prediabetes

• Experimental: Sitagliptin

  CF patients receiving Sitagliptin.

  Intervention: Dose is 100 mg taken orally once a day in the morning with breakfast. Duration is two years or until converted to CF diabetes, whichever comes sooner.

  Intervention: Drug: Sitagliptin
• Placebo Comparator: Sugar pill

  CF patients receiving placebo.

  Intervention: Placebo is taken orally once a day in the morning with breakfast. Duration is two years or until converted to CF diabetes, whichever comes sooner.

  Intervention: Drug: Sitagliptin

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 NYHA class III/IV, ejection fraction less than 25%, or receiving digoxin
• Liver disease as defined by ALT or 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.
• Using overnight enteral tube feedings in the previous six weeks.