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

Pg. Noone et al., Safety of aerosolized INS 365 in patients with mild to moderate cystic fibrosis: Results of a phase I multi-center study, PEDIAT PULM, 32(2), 2001, pp. 122-128
Citations number
Categorie Soggetti
Journal title
ISSN journal
8755-6863 → ACNP
Year of publication
122 - 128
SICI code
Cystic fibrosis (CF) is characterized by defective cystic fibrosis transmem brane regulator (CFTR) expression and function, associated with abnormal io n transport and mucociliary clearance, and clinical lung disease. Triphosph ate nucleotides such as uridine-5'-triphosphate (UTP) and INS 365, may be u seful for CF through actions, mediated via P2Y(2) extracellular receptors, on chloride and liquid secretion, and ciliary beat frequency. INS 365 may o ffer chemical stability advantages over UTP. In a randomized, double-blind, multicenter phase I study, we studied the safety and maximally tolerated d ose of escalating, single doses of aerosolized INS 365, in adult and pediat ric patients with mild to moderate CF lung disease (FEV1 greater than or eq ual to 45% predicted), In four successive dose cohorts of adult patients (n = 12 per cohort, age greater than or equal to 18 years) and four successiv e 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, 8 0, and 100 mg INS 365 delivered by nebulizer (Pari Star (TM)). Sputum was c ollected pre- and post-dosing to obtain preliminary results on clinical eff icacy. After each dose cohort, a Data Safety Monitoring Committee (DSMC) re viewed the data. Forty-eight adult and 36 pediatric patients completed the protocol (up to 1 00 mg for adults, 80 mg for pediatric patients). The predominant adverse ev ents were cough, wheezing, chest tightness, and a decrease in FEV1 (occurri ng in 8/48 adults, and 5/36 pediatric patients), which occurred predominant ly in the 80-mg and 100-mg dose cohorts. Though a few adult patients had a tendency to increase sputum production, there was little consistent effect noted on sputum production in this acute, single-dose study. The data sugge st 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 t o be tolerated. (C) 2001 Wiley-Liss, Inc.