The Impact of Insulin Therapy on Protein Turnover in Pre-Diabetic Cystic Fibrosis Patients
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Prediabetic State; Fibrosis
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Insulin replacement therapy may be effective in breaking the cycle of protein catabolism,
      undernutrition and overall clinical deterioration in pre-diabetic, insulin insufficient CF
      youth because of its potent anabolic effect. A significant number of CF patients might
      benefit from this therapeutic approach with a substantial impact on morbidity and mortality.
    

Detailed description: 
      Insulin insufficiency related to pancreatic fibrosis and β-cell dysfunction is present in
      almost every cystic fibrosis (CF) patient. Progressive abnormalities in insulin secretion
      begin in childhood, and, in adults, CF related diabetes (CFRD) is eventually present in more
      than half of the CF population. CFRD is associated with weight loss, protein catabolism, loss
      of lean body mass (LBM), and early death from lung disease and malnutrition. The negative
      consequences of diabetes are just the "tip of the iceberg", since clinical deterioration has
      been documented to begin in the pre-diabetic period. Non-diabetic glucose tolerance
      abnormalities in CF are associated with protein catabolism, weight loss and lung function
      decline, all of which correlate with the severity of insulin secretory defects, suggesting a
      key pathologic role for insulin insufficiency. Insulin is a potent anabolic hormone, critical
      for maintenance of body weight and muscle mass. In a placebo-controlled clinical trial,
      insulin therapy improved body mass index (BMI) and LBM in patients with very early CFRD (CFRD
      without fasting hyperglycemia), and this is now standard care for these patients. There is
      growing preliminary evidence that insulin therapy is beneficial even earlier, in CF patients
      with pre-diabetes due to insulin insufficiency. Given the universal prevalence of insulin
      insufficiency in CF, the high lifetime risk of developing diabetes, the clinical impact of
      insulin insufficiency on protein catabolism and survival in CF, and the critical importance
      of maintaining body weight and LBM in this population, there is an urgent need to determine
      whether insulin replacement therapy should be instituted for anabolic purposes prior to the
      actual onset of diabetes and, if so, to ascertain the optimal regimen. The current protocol
      describes a double-blind, placebo-controlled trial to determine whether insulin therapy
      improves protein catabolism in youth with CF and abnormal glucose tolerance, and to explore
      differences in efficacy between multiple daily pre-meal insulin dosing (as is currently
      standard for early CFRD) versus a more convenient once daily basal insulin dose (as has been
      used in small uncontrolled pilot studies). The findings of this study will provide a
      mechanistic rationale for instituting insulin in youth with CF and pre-diabetes, and will
      inform both research studies and clinical practice as to the best regimen for insulin
      delivery in this population.
    

Intervention name(s): novolog insulin; levemir insulin; placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 3x daily rapid-acting insulin; basal insulin once a day; once or 3x daily
Other intervention name(s): apart; detemir; insulin diluent
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin Detemir
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment