Safety of aerosolized INS 365 in patients with mild to moderate cystic fibrosis: Results of a phase I multi-center study

Peadar G. Noone, Nicole Hamblett, Frank Accurso, Moira L. Aitken, Michael Boyle, Mark Dovey, Ron Gibson, Craig Johnson, Don Kellerman, Michael W. Konstan, Laura Milgram, Jean Mundahl, George Retsch-Bogort, David Rodman, Judy Williams-Warren, Robert W. Wilmott, Pam Zeitlin, Bonnie Ramsey

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Cystic fibrosis (CF) is characterized by defective cystic fibrosis transmembrane regulator (CFTR) expression and function, associated with abnormal ion transport and mucociliary clearance, and clinical lung disease. Triphosphate nucleotides such as uridine-5′triphosphate (UTP) and INS 365, may be useful for CF through actions, mediated via P2Y2 extracellular receptors, on chloride and liquid secretion, and ciliary beat frequency. INS 365 may offer chemical stability advantages over UTP. In a randomized, double-blind, multicenter phase I study, we studied the safety and maximally tolerated dose of escalating, single doses of aerosolized INS 365, in adult and pediatric patients with mild to moderate CF lung disease (FEV1 ≥ 45% predicted). In four successive dose cohorts of adult patients (n = 12 per cohort, age ≥ 18 years) and four successive pediatric dose cohorts (n = 12 per cohort, age 5-12 years), patients were randomized 3:1 active/placebo (0.9% saline) to evaluate doses of 20, 40, 80, and 100 mg INS 365 delivered by nebulizer (Pad Star™). Sputum was collected pre- and post-dosing to obtain preliminary results on clinical efficacy. After each dose cohort, a Data Safety Monitoring Committee (DSMC) reviewed the data. Forty-eight adult and 36 pediatric patients completed the protocol (up to 100 mg for adults, 80 mg for pediatric patients). The predominant adverse events were cough, wheezing, chest tightness, and a decrease in FEV1 (occurring in 8/48 adults, and 5/36 pediatric patients), which occurred predominantly in the 80-mg and 100-mg dose cohorts. Though a few adult patients had a tendency to increase sputum production, there was tittle consistent effect noted on sputum production in this acute, single-dose study. The data suggest that aerosolized INS 365 is safe when delivered at single doses of up to 40 mg in adults and children with CF, but that higher doses are unlikely to be tolerated.

Original languageEnglish (US)
Pages (from-to)122-128
Number of pages7
JournalPediatric pulmonology
Issue number2
StatePublished - 2001
Externally publishedYes


  • Cystic fibrosis
  • INS 365
  • New therapies
  • P2Y receptors
  • Triphosphate nucleotides
  • Uridine-5′-triphosphate

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pulmonary and Respiratory Medicine


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