Ivacaftor (Kalydeco) and Insulin in Cystic Fibrosis (CF)

Cystic Fibrosis Related Diabetes (CFRD) is associated with worse nutritional status, greater
pulmonary function decline, and increased mortality, highlighting its relevance in Cystic
Fibrosis (CF). CFRD arises primarily from compromised insulin secretion - traditionally
considered a by-product of pancreatic exocrine tissue damage and fibrosis. Recent
developments in the field of diabetes are propelling a re-examination of this basic
explanation. The impact of the cystic fibrosis transmembrane conductance regulator (CFTR)
potentiator, ivacaftor, upon insulin secretion and glucose regulation has not been examined,
but improved glucose tolerance has been appreciated anecdotally. This study aims to
understand the impact of ivacaftor therapy upon blood glucose and insulin and incretin
secretion.

Inclusion Criteria:

- 6 yrs or older with cystic fibrosis

- at least one G551D CFTR mutation or other non-G551D gating mutation, or residual
function CFTR mutation such as, but not limited to, R117H mutation, for which
ivacaftor is to be initiated.

- Plan to initiate ivacaftor treatment for FDA approved indications by clinical care
team or as part of an ongoing study of ivacaftor for other CFTR mutations, including
gating mutations, or residual function mutations.

- not pregnant

Exclusion Criteria:

- established diagnosis of non-CF related diabetes (ie., Type I diabetes)

- history of clinically symptomatic pancreatitis in past year

- prior lung or liver transplant

- severe CF liver disease

- fundoplication-related dumping syndrome

- medical co-morbidities that are not CF-related or are unstable per the Investigator
opinion

- acute CF pulmonary exacerbation within 4 weeks prior to study procedures

- treatment with oral or intravenous corticosteroids within 4 weeks of study

- hemoglobin <10g/dL within 90 days of GPA test or at Screening

- abnormal renal function within 90 days of GPA test or at Screening

- long-standing CFRD with fasting hyperglycemia, elevated HbA1C (>8) beyond time
surrounding diagnosis of CFRD, significant basal insulin requirement

- inability to perform study specific procedures (MMTT, GPA).