Phase 2 randomized safety and efficacy trial of nebulized denufosol tetrasodium in cystic fibrosis.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

MEASUREMENTS AND MAIN 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.

• Authors: Robin R Deterding, Lisa M Lavange, Jean M Engels, Dave W Mathews, Sarah J Coquillette, Alan S Brody, Steve P Millard, Bonnie W Ramsey, Cystic Fibrosis Therapeutics Development Network and the Inspire 08-103 Working Group
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 176 Issue 4 Pg. 362-9 (Aug 15 2007) ISSN: 1073-449X [Print] United States
• PMID: 17446337 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Deoxycytosine Nucleotides
• Purinergic P2 Receptor Agonists
• denufosol tetrasodium
• Uridine

Topics

• Adolescent
• Adult
• Child
• Cough (chemically induced)
• Cystic Fibrosis (drug therapy)
• Deoxycytosine Nucleotides (therapeutic use)
• Double-Blind Method
• Female
• Humans
• Lung Volume Measurements
• Male
• Middle Aged
• Nebulizers and Vaporizers
• Purinergic P2 Receptor Agonists
• Treatment Outcome
• Uridine (analogs & derivatives, therapeutic use)