Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial

Abstract

Background: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission.

Methods: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters.

Results: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group.

Conclusions: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Trial registration: ClinicalTrials.gov NCT02273661.

Conflict of interest statement

Conflict of interest: C. Godet reports having received speaker fees, travel support from Pfizer, MSD; fees for board memberships from SOS Oxygène and Pulmatrix; grant support from Ohre Pharma, Pfizer, MSD, SOS Oxygène, ISIS Medical and AstraZeneca. Conflict of interest: F. Couturaud reports having received research grant support from Bristol-Myers Squibb/Pfizer and fees for board memberships or symposia from Bayer, Bristol-Myers Squibb/Pfizer, Merck Sharp & Dohme and AstraZeneca, and having received travel support from Bayer, Bristol-Myers Squibb/Pfizer, Leo Pharma, Merck Sharp & Dohme and Actelion. Conflict of interest: S. Marchand-Adam reports having received consultancy for board membership, consultancy or speaker fees and travel support from AstraZeneca, Boehringer Ingelheim, Novartis and Roche. Conflict of interest: C. Pison reports having received, outside of the submitted work, consultancy for board membership, consultancy or speaker fees, travel support from AGIR à Dom, Chiesi, Boehringer Ingelheim, GSK, SOS Oxygène, AstraZeneca and Novartis. Conflict of interest: F. Gagnadoux reports having received grants and personal fees from Resmed; personal fees and non-financial support from Boehringer Ingelheim, Nyxoah, Sefam; personal fees from Actelion, Cidelec, Novartis, and non-financial support from Asten, unrelated to the submitted work. Conflict of interest: E. Blanchard reports having received consultancy or speaker fees, travel support from Pfizer, MSD, Novartis, Gilead, Roche, Boehringer Ingelheim, SOS Oxygene and ISIS Medical. Conflict of interest: C. Taillé reports having received consulting or advisory fees from Sanofi, GSK, AstraZeneca, Novartis and Chiesi, and research grants from Sanofi and GSK, outside the submitted work. Conflict of interest: B. Philippe reports having received speaker fees, travel support from Chiesi, Novartis and Oxyvie. Conflict of interest: S. Hirschi reports having received research grant support from CSL Behring and Adiral, and fees for board membership from Boehringer Ingelheim and Roche. Conflict of interest: C. Andréjak reports having received fees for board memberships or symposia and travel support from GSK, AstraZeneca, Zambon and Insmed. Conflict of interest: A. Bourdin reports having received grants from AstraZeneca, Boehringer Ingelheim, Cephalon/TEVA, GlaxoSmithKline, Novartis and Sanofi-Regeneron; has provided consultancy for Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MedinCell, Merck, Novartis, Roche and Sanofi-Regeneron; and has acted as an investigator or co-investigator for trials sponsored by Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, Galapagos, GlaxoSmithKline, Merck, Novartis, Roche, Sanofi-Regeneron and Vertex. Conflict of interest: C. Chenivesse reports having received grants from AstraZeneca and Santelys outside the submitted work, personal fees from ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKlein, Novartis, Sanofi-Regeneron and TEVA outside the submitted work and congress support from ALK-Abello, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pierre Fabre, Pfizer, Roche and TEVA. Conflict of interest: S. Dominique reports having received consultancy for board membership, speaker fees, travel support from Roche, Chiesi, Boehringer Ingelheim, AstraZeneca, Novartis and Actelion, outside the submitted work. Conflict of interest: L. Bassinet has nothing to disclose. Conflict of interest: M. Murris-Espin reports having received consultancy for board membership or speaker fees, or travel support, from Insmed, MSD, Pfizer, Asten, LVL, Vertex, Vivisol and Zambon. Conflict of interest: F. Rivière reports having received consultancy fees from Roche and Boehringer Ingelheim. Conflict of interest: G. Garcia reports having received grants from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi-Regeneron and Chiesi; has provided consultancy for AstraZeneca, GlaxoSmithKline, Novartis and Sanofi-Regeneron; and has acted as an investigator or co-investigator for trials sponsored by AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron. Conflict of interest: D. Caillaud reports having received consultancy or speaker fees, travel support from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini and Novartis. Conflict of interest: F-X. Blanc has nothing to disclose. Conflict of interest: F. Goupil reports having received travel support from Aliseo/Asten Santé, GSK, Chiesi, Novartis and Actelion. Conflict of interest: A. Bergeron reports having received consultancy or speaker fees, from Pfizer, Gilead, MSD, AstraZeneca and Takeda, and grants from SOS Oxygene. Conflict of interest: A. Gondouin reports having received consultancy or speaker fees, or travel support from Roche, Boehringer Ingelheim, Vitalaire, Actelion, LFB, GSK and Pfizer. Conflict of interest: J-P. Frat reports having received grants from the French Ministry of Health, outside the submitted work; grants, personal fees and non-financial support from Fisher & Paykel HealthCare, outside the submitted work; personal fees and non-financial support from SOS Oxygène, outside the submitted work. Conflict of interest: T. Flament has nothing to disclose. Conflict of interest: B. Camara reports having received outside of the submitted work, consultancy for speaker fees, travel supports from AGIR à Dom. Conflict of interest: P. Priou received travel support from Asten Santé. Conflict of interest: A-L. Brun has nothing to disclose. Conflict of interest: F. Laurent reports having received consultancy for board membership, consultancy or speaker fees, travel support from Bayer, Roche, Chiesi, Boehringer Ingelheim, SOS Oxygène, AstraZeneca, Basilea, Novartis and Actelion. Conflict of interest: S. Ragot has nothing to disclose. Conflict of interest: J. Cadranel reports having received speaker fees from MSD and Pfizer.

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