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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 a number of chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD. Methods: The Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial was a multicentre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial done at 6 European PCD clinics (tertiary paediatric care centres and university hospitals in Denmark, Germany, Netherlands, Switzerland, and UK). Patients with a confirmed diagnosis of PCD, aged 7–50 years old, and predicted FEV 1 greater than 40% were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 mg or 500 mg as tablets according to bodyweight (</≥ 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 exacerbations over 6 months. Analysis was by intention to treat. This study is registered in the EU Clinical Trials Register, EudraCT number 2013-004664-58. Findings: Between June 24, 2014, and Aug 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 number of respiratory exacerbations over 6 months was 0·75 (SD 1·12) in the azithromycin group compared with 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 0·45 [95% CI 0·26–0·78]; p=0·004). 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 multinational 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 patients with PCD with frequent exacerbations potentially leading to reduced need for additional antibiotic treatments and preventing irreversible lung damage. Funding: European Commission Seventh Framework Programme and Children's Lung Foundation (Denmark).

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
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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
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Collins, Samuel
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Hogg, Claire
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Kuehni, Claudia E.
ac67c925-ee32-429d-a3b5-c244daa314b4
Lucas, Jane S
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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
bad4d892-a199-4c73-96c0-a5fc82f89a4c
Werner, Claudius
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Omran, Heymut
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Neilsen, Kim G
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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 a number of chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD. Methods: The Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial was a multicentre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial done at 6 European PCD clinics (tertiary paediatric care centres and university hospitals in Denmark, Germany, Netherlands, Switzerland, and UK). Patients with a confirmed diagnosis of PCD, aged 7–50 years old, and predicted FEV 1 greater than 40% were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 mg or 500 mg as tablets according to bodyweight (</≥ 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 exacerbations over 6 months. Analysis was by intention to treat. This study is registered in the EU Clinical Trials Register, EudraCT number 2013-004664-58. Findings: Between June 24, 2014, and Aug 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 number of respiratory exacerbations over 6 months was 0·75 (SD 1·12) in the azithromycin group compared with 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 0·45 [95% CI 0·26–0·78]; p=0·004). 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 multinational 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 patients with PCD with frequent exacerbations potentially leading to reduced need for additional antibiotic treatments and preventing irreversible lung damage. Funding: European Commission Seventh Framework Programme and Children's Lung Foundation (Denmark).

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More information

Accepted/In Press date: 29 January 2020
e-pub ahead of print date: 4 May 2020
Published date: 4 May 2020
Additional Information: Funding Information: The BESTCILIA study (Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia) was funded by the European Commission Seventh Framework Programme (grant agreement number 305404 ). The Children's Lung Foundation (Denmark) supported the final data processing and analysis of the trial. The Swiss National Science Foundation (SNF grant no 320030_173044) contributed to the Swiss arm of the study. Work in the laboratory of HO was in part funded by the DFG (OM6/7, -8, -10, -11 [CRU326]), Interdisziplinaeres Zentrum für Klinische Forschung Muenster IZKF (Om2/009/12, Om2/015/16), Care-for-Rare Foundation, Eva Luise und Horst Köhler Stiftung and REGISTRY WAREHOUSE (HORIZON2020, grant agreement no 777295 ). HEK, FFB, EGH, CH, CEK, JSL, HO, and KGN are participants in BEAT-PCD (COST Action 1407), and the affiliated departments of HEK, FFB, EGH, CH, JSL, HO, and KGN are part of the European Reference Network on respiratory diseases (ERN-LUNG). We thank the patients and their families for participating in the study and all the research staffs for facilitating the study. We thank Simone Helms and Sandra Diepenhorst for excellent work as study nurses. Psychologist Anika Gross and N W P Rutjes for their work with questionnaire (QOL–PCD) and Jörg Große-Onnebrink for doing Multiple breath wash out. Publisher Copyright: © 2020 Elsevier Ltd

Identifiers

Local EPrints ID: 438687
URI: http://eprints.soton.ac.uk/id/eprint/438687
ISSN: 2213-2600
PURE UUID: b22d725f-9ddd-40b4-be8a-b781021fea77
ORCID for Jane S Lucas: ORCID iD orcid.org/0000-0001-8701-9975

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Date deposited: 20 Mar 2020 17:37
Last modified: 17 Mar 2024 05:18

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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 ORCID iD
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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