Kate Johnson

October 28, 2016

LOS ANGELES — For patients with non–cystic fibrosis bronchiectasis, an investigational inhaled powder form of ciprofloxacin can significantly reduce the frequency of exacerbations, results from the phase 3 RESPIRE 1 trial show.

"This is the first large, double-blind, randomized inhaled antibiotic trial to suggest efficacy in non–cystic fibrosis bronchiectasis," said lead investigator Kevin Winthrop, MD, from Oregon Health & Science University in Portland. "I am very encouraged."

"There is a tremendous unmet need for this an orphan disease because there are no approved therapies for its treatment," he said here at CHEST 2016: American College of Chest Physicians Annual Meeting.

"Many of these patients develop resistant bacteria over time that make the outpatient treatment of exacerbations difficult," said Neil Freedman, MD, from the NorthShore University Health System in Evanston, Illinois, who is chair of the CHEST scientific program committee.

"At the present time, there are only a few inhaled antibiotics, and availability is limited by cost. An additional inhaled antibiotic would be very helpful to clinicians treating this patient population," he said.

Dr Winthrop and his colleagues randomized 416 adults to one of three groups for 48 weeks: twice-daily inhaled ciprofloxacin administered in 12 cycles of 14 days on, 14 days off; twice-daily ciprofloxacin administered in six cycles of 28 days on, 28 days off; and placebo.

All study participants had been treated for at least two exacerbations in the previous 12 months, and all had a positive culture for one of seven organisms: Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Streptococcus pneumoniae, Stenotrophomonas maltophilia, and Burkholderia cepacia.

Exacerbation endpoints were a composite of three criteria: fever; need for systemic antibiotics; and worsening of three signs and symptoms, such as dyspnea, cough, and wheezing.

During the 48-week study period, the number of exacerbations was significantly lower with the 14-day regimen than with placebo (adjusted hazard ratio [aHR], 0.53; P = .0005). The number was also lower with the 28-day regimen than with placebo, but the difference was not significant (aHR, 0.73; P = .0650).

Exacerbations were 39% less frequent with the 14-day regimen than with placebo (P = .0061), but the difference in frequency between the 28-day regimen and placebo was not significant.

"In terms of safety and tolerability, we are very happy," Dr Winthrop reported. "Sometimes these therapies can be difficult to tolerate, but that didn't seem to be the case in RESPIRE 1."

Rates of serious treatment-emergent adverse events were similar with the 14-day regimen, the 28-day regimen, and placebo (16.9% vs 19.9% vs 23.4%). Discontinuation rates related to these events were low and evenly distributed among the three groups.

Data on respiratory adverse events — including bronchospasm and hemoptysis — were also encouraging, he said. Rates of discontinuation because of respiratory adverse events were similar: 6% for the pooled ciprofloxacin groups and about 8% for placebo.

"There were no cases of tendonitis or tendon rupture that we thought were related to treatment," said Dr Winthrop.

"This is a specially formulated version of ciprofloxacin," he explained. "About 40% of it, once inhaled, reaches the alveolar space and there is very little systemic absorption. I wouldn't expect to see this, and we haven't seen it to date."

A 'Very Needed' Treatment Option

"RESPIRE 1, a large randomized controlled trial, demonstrates the clinical efficacy and tolerability of inhaled ciprofloxacin," said Charlotte Suppli Ulrik, MD, from Hvidovre Hospital and University of Copenhagen, Denmark.

"The management of frequent exacerbations in non–[cystic fibrosis] bronchiectasis is a challenge, with very limited evidence for the various treatment options," said Dr Ulrik, who was involved in a recent systematic review of antibiotic therapy for stable non–cystic fibrosis bronchiectasis (Chron Respir Dis. Published online August 9, 2016).

Studies that add to these very promising findings could lead "to the implementation of a very needed treatment option in clinical practice for this relatively large group of patients," she told Medscape Medical News.

Several previous trials have failed to show benefit for patients with non–cystic fibrosis bronchiectasis, "so this is exciting," Dr Winthrop told Medscape Medical News. Results from the phase 3 RESPIRE 2 trial are expected soon, he reported.

The study was sponsored by Bayer. Dr Winthrop reports receiving consultancy fees from Bayer and Raptor. Dr Ulrik has disclosed no relevant financial relationships.

CHEST 2016: American College of Chest Physicians Annual Meeting. Presented October 24, 2016.

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