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14-09-2023 | Congenital Lung Disease | Editor's Choice | News

ERS 2023

Inhaled idrevloride in hypertonic saline may benefit patients with primary ciliary dyskinesia

Author: Laura Cowen

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medwireNews: Treatment with inhaled idrevloride in hypertonic saline is associated with improved lung function relative to hypertonic saline alone in people with primary ciliary dyskinesia, show results from the phase 2 CLEAN-PCD trial.

Idrevloride is an epithelial sodium channel (ENaC) blocker that has been shown to inhibit sodium ion transport and increase the apical surface liquid volume on airway epithelial cells in vitro, explain Felix Ringshausen (Hanover Medical School, Germany) and co-authors in The Lancet Respiratory Medicine.

They add that the effect was magnified by co-administering idrevloride with hypertonic saline and could benefit patients with primary ciliary dyskinesia by restoring mucus hydration. This in turn could “improve mucus clearance, reduce airway obstruction, and improve lung function in affected individuals,” they say.

To test their hypothesis, Ringshausen and team initiated the international CLEAN-PCD trial which included four treatment sequences in a crossover design and involved participants aged 12 years or older (mean age 27.8 years) with primary ciliary dyskinesia and a percentage of predicted forced expiratory volume in 1 second (ppFEV1) of 40–90%.

In group 1, 43 participants were randomly assigned to receive idrevloride 85 µg in 3 mL hypertonic saline (4.2% sodium chloride [NaCl]) nebulized twice daily for 28 days, followed by a 28-day washout period then hypertonic saline alone for 28 days.

The second group comprised 41 patients who received the same two treatments but in the reverse order, while groups 3 (n=21) and 4 (n=18) were given idrevloride in hypotonic saline (0.17% NaCl) followed by placebo (0.17% NaCl) and vice versa.

At baseline, the mean ppFEV1 across all participants was 66.1. After 28 days of treatment with idrevloride in hypertonic saline there was a 1.0 percentage point absolute increase in the least squares mean ppFEV1. This was significantly greater than the 0.5 percentage points decrease relative to baseline observed after 28 days of treatment with hypertonic saline alone.

Furthermore, a responder analysis showed that significantly more patients had a 3.0 percentage point or greater improvement in ppFEV1 after idrevloride in hypertonic saline than after hypertonic saline alone, at 37% versus 23%, with a corresponding odds ratio of 2.9.

Conversely, there were no significant differences in ppFEV1 when idrevloride in hypertonic saline was compared with idrevloride alone or placebo. These treatments were associated with absolute decreases in the least squares mean ppFEV1 of 0.5 and 1.3 percentage points, respectively.

Ringshausen et al report that they observed a similar pattern of results for absolute FEV1, forced vital capacity (FVC), and ppFVC but there was no improvement in the percentage of predicted mid-maximal expiratory flow rates for any treatment, and none of the treatments were consistently associated with quality-of-life improvements.

Adverse event rates were similar across treatments, ranging from 57% with hypertonic saline alone to 65% with idrevloride plus hypertonic saline. Cough was more common during treatments containing idrevloride or hypertonic saline compared with placebo, and oropharyngeal pain occurred in a greater proportion of participants during idrevloride treatments than during treatment with hypertonic saline alone or placebo, whereas chest discomfort was more common during treatments that included hypertonic saline.

The researchers also carried out a small extension study (part B) in which patients were given the option of an additional 28 days of treatment with the CFTR-targeted potentiator ivacaftor in combination with each of the study treatments.

This showed that ppFEV1 increased further (by 4.7 percentage points versus baseline) in the group given ivacaftor plus idrevloride in hypertonic saline.

“We cannot exclude the possibility that ivacaftor provided some beneficial effects in part B with idrevloride in hypertonic saline, although the placebo aerosol plus ivacaftor yielded no improvement in lung function,” Ringshausen and co-authors remark. Rather, they suggest that “the effect of idrevloride in hypertonic saline after 56 days of dosing was greater than after 28 days.”

They add: “The total improvement from baseline for idrevloride in hypertonic saline reflected an equal contribution from both the part A and part B intervals, with the part B 28-day change being 2.5 percentage points.”

The team concludes that their data “support the hypothesis that hydration of mucus in primary ciliary dyskinesia airways improves mucus clearance, reduces airway mucus obstruction, and can improve lung function.”

In an accompanying comment, Francesca Santamaria (Federico II University, Naples, Italy) and co-authors write: “Despite the promising findings of the CLEAN-PCD study, further evidence is needed before formal recommendations for treatment are made; however, these data offer the opportunity to rethink primary ciliary dyskinesia treatment and emphasise the relevance of testing new therapeutic approaches that might act at a deeper level, targeting the mechanisms of disease, than those currently applied.”

These findings were simultaneously presented at the ERS International Congress 2023, held in Milan, Italy.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group

Lancet Respir Med 2023; doi:10.1016/S2213-2600(23)00226-6
Lancet Respir Med 2023; doi:10.1016/S2213-2600(23)00236-9
Ringshausen F, Shapiro A, Nielsen K, et al. Safety and efficacy of idrevloride in people with primary ciliary dyskinesia: a double-blind, randomized, placebo-controlled crossover trial (CLEAN-PCD). ERS 2023. Clinical trials session, abstract RCT801.

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