Prevention of Cystic Fibrosis Diabetes

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.

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.