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Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial

Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial
Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial
Background: Use of maintenance antibiotic therapy with the macrolide azithromycin is increasing in different chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD. Methods: The BESTCILIA (Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia) trial was a multi-centre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial at 6 European PCD clinics at tertiary paediatric level and university hospitals (Denmark, Germany, Netherlands, Switzerland, and United Kingdom). Patients with a confirmed diagnosis of PCD, aged 7-50 years, and FEV1 >40% predicted, were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 or 500 mg as tablets according to body weight (</≥ 40 kg) or identical placebo, three times a week for 6 months. The random allocation sequence was a permuted block randomisation, with a block size of four, generated by an external consultancy. Participants, investigators, and care providers were masked to treatment allocation. The primary endpoint was the number of respiratory system exacerbations over 6 months. Analysis was by intention-to-treat. This study is registered in the European Union Clinical Trials Register, number 2013-004664-58. Findings: Between June 24, 2014, and August 23, 2016, 102 patients were screened, of whom 90 were randomly assigned to either azithromycin (n=49) or placebo (n=41). The study was ended without having included the planned number of participants due to recruitment difficulties. The mean (SD) number of respiratory system exacerbations over 6 months was 0·75 (SD 1·12) in the azithromycin group compared to 1·62 (1·64) in the placebo group, and participants receiving azithromycin had significantly lower rate of exacerbations during the individual treatment periods (rate ratio [95% CI 0·26-0·78], p=0·004). In total, four serious adverse events were reported, occurring in one (2%) of 47 participants in the azithromycin group and in three (7%) of 41 participants in the placebo group. Loose stools or diarrhoea were more common in the azithromycin group than in the placebo group (11 [23%] vs two [5%]). Interpretation: This first multi-national randomised controlled trial on pharmacotherapy in PCD showed that azithromycin maintenance therapy for 6 months was well tolerated and halved the rate of respiratory exacerbations. Azithromycin maintenance therapy is an option for PCD patients with frequent exacerbations potentially leading to reduced need for additional antibiotic treatments and preventing irreversible lung damage.
2213-2600
493-505
Kobbernagel, Helene E.
194e2202-c935-4462-a73a-e69dd776cdea
Buchvald, Frederik F.
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Haarman, Eric G.
953b1ca1-3218-435c-9a0e-32e7b2d95798
Casaulta, Carmen
0a57a56c-3780-4fd4-a616-2e1348742348
Collins, Samuel
02ee5d8a-03c4-453d-9f09-35905137e9dd
Hogg, Claire
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Kuehni, Claudia E.
ac67c925-ee32-429d-a3b5-c244daa314b4
Lucas, Jane S
5cb3546c-87b2-4e59-af48-402076e25313
Moser, Claus E
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Quittner, Alexandra L.
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Raidt, Johanna
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Rosthøj, Susanne
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Sørensen, Anne L
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Thomsen, Kim
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Werner, Claudius
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Omran, Heymut
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Neilsen, Kim G
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Kobbernagel, Helene E.
194e2202-c935-4462-a73a-e69dd776cdea
Buchvald, Frederik F.
8059843a-30a8-4d79-8b99-a8f476d3fa57
Haarman, Eric G.
953b1ca1-3218-435c-9a0e-32e7b2d95798
Casaulta, Carmen
0a57a56c-3780-4fd4-a616-2e1348742348
Collins, Samuel
02ee5d8a-03c4-453d-9f09-35905137e9dd
Hogg, Claire
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Kuehni, Claudia E.
ac67c925-ee32-429d-a3b5-c244daa314b4
Lucas, Jane S
5cb3546c-87b2-4e59-af48-402076e25313
Moser, Claus E
b5092ab3-7a34-4b4c-94f0-95d90bc83db1
Quittner, Alexandra L.
c0f8318e-574d-4766-8154-6f055eba45ea
Raidt, Johanna
56220321-ca45-4c3a-b0f4-ed89e56de406
Rosthøj, Susanne
fd438428-0e5c-46df-baab-199f98698125
Sørensen, Anne L
aad552aa-2305-441a-905b-3c69940172be
Thomsen, Kim
bad4d892-a199-4c73-96c0-a5fc82f89a4c
Werner, Claudius
4179e6c9-6cf3-4e9a-802f-de64cf1fbd72
Omran, Heymut
49c453b0-2ce2-4925-b5d4-7beffe2bae8d
Neilsen, Kim G
658f479a-af9c-4759-a825-89e64876d415

Kobbernagel, Helene E., Buchvald, Frederik F., Haarman, Eric G., Casaulta, Carmen, Collins, Samuel, Hogg, Claire, Kuehni, Claudia E., Lucas, Jane S, Moser, Claus E, Quittner, Alexandra L., Raidt, Johanna, Rosthøj, Susanne, Sørensen, Anne L, Thomsen, Kim, Werner, Claudius, Omran, Heymut and Neilsen, Kim G (2020) Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial. The Lancet Respiratory Medicine, 8 (5), 493-505. (doi:10.1016/S2213-2600(20)30058-8).

Record type: Article

Abstract

Background: Use of maintenance antibiotic therapy with the macrolide azithromycin is increasing in different chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD. Methods: The BESTCILIA (Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia) trial was a multi-centre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial at 6 European PCD clinics at tertiary paediatric level and university hospitals (Denmark, Germany, Netherlands, Switzerland, and United Kingdom). Patients with a confirmed diagnosis of PCD, aged 7-50 years, and FEV1 >40% predicted, were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 or 500 mg as tablets according to body weight (</≥ 40 kg) or identical placebo, three times a week for 6 months. The random allocation sequence was a permuted block randomisation, with a block size of four, generated by an external consultancy. Participants, investigators, and care providers were masked to treatment allocation. The primary endpoint was the number of respiratory system exacerbations over 6 months. Analysis was by intention-to-treat. This study is registered in the European Union Clinical Trials Register, number 2013-004664-58. Findings: Between June 24, 2014, and August 23, 2016, 102 patients were screened, of whom 90 were randomly assigned to either azithromycin (n=49) or placebo (n=41). The study was ended without having included the planned number of participants due to recruitment difficulties. The mean (SD) number of respiratory system exacerbations over 6 months was 0·75 (SD 1·12) in the azithromycin group compared to 1·62 (1·64) in the placebo group, and participants receiving azithromycin had significantly lower rate of exacerbations during the individual treatment periods (rate ratio [95% CI 0·26-0·78], p=0·004). In total, four serious adverse events were reported, occurring in one (2%) of 47 participants in the azithromycin group and in three (7%) of 41 participants in the placebo group. Loose stools or diarrhoea were more common in the azithromycin group than in the placebo group (11 [23%] vs two [5%]). Interpretation: This first multi-national randomised controlled trial on pharmacotherapy in PCD showed that azithromycin maintenance therapy for 6 months was well tolerated and halved the rate of respiratory exacerbations. Azithromycin maintenance therapy is an option for PCD patients with frequent exacerbations potentially leading to reduced need for additional antibiotic treatments and preventing irreversible lung damage.

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Accepted/In Press date: 29 January 2020
e-pub ahead of print date: 4 May 2020
Published date: 4 May 2020

Identifiers

Local EPrints ID: 438687
URI: http://eprints.soton.ac.uk/id/eprint/438687
ISSN: 2213-2600
PURE UUID: b22d725f-9ddd-40b4-be8a-b781021fea77

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Date deposited: 20 Mar 2020 17:37
Last modified: 13 Aug 2022 04:12

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Contributors

Author: Helene E. Kobbernagel
Author: Frederik F. Buchvald
Author: Eric G. Haarman
Author: Carmen Casaulta
Author: Samuel Collins
Author: Claire Hogg
Author: Claudia E. Kuehni
Author: Jane S Lucas
Author: Claus E Moser
Author: Alexandra L. Quittner
Author: Johanna Raidt
Author: Susanne Rosthøj
Author: Anne L Sørensen
Author: Kim Thomsen
Author: Claudius Werner
Author: Heymut Omran
Author: Kim G Neilsen

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