Prevention of Cystic Fibrosis Diabetes
Condition: Cystic Fibrosis; Prediabetes
MeSH terms: Cystic Fibrosis; Fibrosis
Intervention: Sitagliptin
Intervention description: 100 mg of sitagliptin is taken orally each morning with breakfast. Duration is 12 months or conversion to CF diabetes, whichever comes first.
Intervention MeSH terms: Sitagliptin Phosphate
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 33.0
Sex: All
Minimum age: 13 Years
Healthy volunteers: No
Keywords: cystic fibrosis; diabetes; inflammation; oxidative stress; redox balance; lung disease

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
    

Eligibility criteria:

        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.