Phase 2 randomized safety and efficacy trial of nebulized denufosol tetrasodium in cystic fibrosis.
BACKGROUND
Denufosol tetrasodium is a selective P2Y(2) agonist that enhances mucosal hydration and mucus clearance by activating Cl(-) secretion and inhibiting epithelial Na(+) transport through a non-cystic fibrosis transmembrane conductance regulator mechanism in the lung.


OBJECTIVE
To examine the safety and efficacy of 28 days of treatment with denufosol compared with placebo in patients with mild cystic fibrosis.


METHODS
The study was a randomized, double-blind, multi-center, 28-day, phase 2 clinical trial of denufosol tetrasodium inhalation solution (20, 40, or 60 mg) versus placebo (normal saline). Patients with screening FEV(1) >or= 75% of predicted normal value and not treated with inhaled antibiotics for the past 30 days were randomized to receive one of three doses of denufosol or placebo administered three times daily.


RESULTS
Eighty-nine patients were randomized and received the study drug, 94% completed the study, and 98% were compliant with dosing. All treatments were generally well tolerated, with no dose-response trends observed with respect to safety parameters. The most common adverse event was cough (52% of placebo patients and 47% of denufosol patients). Five patients discontinued early due to adverse events, two on placebo and three on denufosol. Denufosol patients (pooling active doses) had significantly higher changes from baseline in FEV(1) (P = 0.006), FEF(25%-75%) (P = 0.008), FVC (P = 0.022), and FEV(1)/FVC (P = 0.047) than placebo patients at the end of the study.


CONCLUSIONS
Denufosol administered three times daily for 28 days appeared to be safe and well tolerated in this population with mild cystic fibrosis and provided preliminary evidence of potential benefit in lung function.
Deterding
Robin R
RR
The Children's Hospital, 1056 East 19th Avenue, B395, Denver, CO 80218, USA. deterding.robin@tchden.org
Lavange
Lisa M
LM
Engels
Jean M
JM
Mathews
Dave W
DW
Coquillette
Sarah J
SJ
Brody
Alan S
AS
Millard
Steve P
SP
Ramsey
Bonnie W
BW
D000293:Adolescent; D000328:Adult; D002648:Child; D003371:Cough / Q000139:chemically induced; D003550:Cystic Fibrosis / Q000188:drug therapy*; D003845:Deoxycytosine Nucleotides / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008176:Lung Volume Measurements; D008297:Male; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D058910:Purinergic P2 Receptor Agonists; D016896:Treatment Outcome; D014529:Uridine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D003845:Deoxycytosine Nucleotides; D058910:Purinergic P2 Receptor Agonists; C465279:denufosol tetrasodium; D014529:Uridine