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Randomized Controlled Trial
. 2021 Nov;20(6):1010-1017.
doi: 10.1016/j.jcf.2021.05.013. Epub 2021 Jun 16.

Long-term amikacin liposome inhalation suspension in cystic fibrosis patients with chronic P. aeruginosa infection

Diana Bilton  1 , Isabelle Fajac  2 , Tacjana Pressler  3 , John Paul Clancy  4 , Dorota Sands  5 , Predrag Minic  6 , Marco Cipolli  7 , Ivanka Galeva  8 , Amparo Solé  9 , Alexandra L Quittner  10 , Zhanna Jumadilova  11 , Monika Ciesielska  11 , Michael W Konstan  12 ; CLEAR-110 Study Group
Affiliations
Randomized Controlled Trial

Long-term amikacin liposome inhalation suspension in cystic fibrosis patients with chronic P. aeruginosa infection

Diana Bilton et al. J Cyst Fibros. 2021 Nov.

Abstract

Background: . In CLEAR-108-a phase 3, randomised, open-label study-once-daily amikacin liposome inhalation suspension (ALIS) was noninferior to twice-daily tobramycin inhalation solution (TIS) in improving lung function in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection after 3 treatment cycles (28 days on/28 days off). The CLEAR-110 extension study (ClinicalTrials.gov: NCT01316276; EudraCT: 2011-000443-24) assessed long-term safety, tolerability, and efficacy of ALIS in eligible patients who completed CLEAR-108.

Methods: . Patients received once-daily ALIS 590 mg for 12 treatment cycles (96 weeks). Patients were grouped by prior treatment: the "prior-ALIS" cohort received ALIS in CLEAR-108, and the "ALIS-naive" cohort received TIS in CLEAR-108.

Results: . Overall, 206 patients (prior-ALIS, n=92; ALIS-naive, n=114) entered CLEAR-110 and received ≥1 dose of ALIS. Most patients (88.8%) experienced ≥1 treatment-emergent adverse event (TEAE) through day 672 (end of year 2). Most TEAEs (72.3%) were mild or moderate in severity. Severe TEAEs were reported in 31 patients (15.0%). Two life-threatening TEAEs (haemoptysis; intestinal obstruction) and 1 death (cardiac failure) were reported. Twenty-one patients (10.2%) discontinued treatment due to a TEAE (mostly infective pulmonary exacerbation of CF). Mean change from baseline in forced expiratory volume in 1 second percent predicted at day 672 was -3.1% (prior-ALIS, -4.0%; ALIS-naive, -2.3%). Mean change from baseline in sputum density of P. aeruginosa at day 672 was 0.02 (prior-ALIS, -0.16; ALIS-naive, 0.19) log CFU/g.

Conclusions: . Long-term treatment with ALIS was well tolerated with a favourable adverse event profile and demonstrated continued antibacterial activity in CF patients with chronic P. aeruginosa infection.

Keywords: ALIS; Amikacin; Cystic fibrosis; Liposomal; Pseudomonas aeruginosa.

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Conflict of interest statement

Declaration of Competing Interest D. Bilton: National Institute for Health Research funding support through the Imperial College, Royal Brompton Hospital, Specialist Respiratory Bio-Medical Research Unit; has received research contract support from Insmed Incorporated. I. Fajac: Received research contract support from Insmed Incorporated, has received a research grant from Actelion, and has served on advisory boards for Gilead Sciences and Vertex. T. Pressler: Received research contract support from Insmed Incorporated. J. P. Clancy: Serves on the Scientific Advisory Board and has received clinical trial support for phase II studies of ALIS in CF for Insmed Incorporated. D. Sands: Received research contract support from Insmed Incorporated. P. Minic: Received research contract support from Insmed Incorporated. M. Cipolli: Received research contract support from Insmed Incorporated, a grant from Vertex Pharmaceuticals, and served on advisory boards for Chiesi and Vertex. I. Galeva: Received research contract support from Insmed Incorporated. A. Solé: Has served on the advisory board for Gilead Sciences and Vertex. A. L. Quittner: Consulting for AbbVie, Aradigm, Insmed Incorporated, and Vertex; investigator-initiated studies for the Cystic Fibrosis Foundation. Z. Jumadilova: Employee of Insmed Incorporated. M. Ciesielska: Employee of Insmed Incorporated. M. Konstan: Has served on the Arikayce Clinical Program Steering Committee; has received grants and personal fees from Insmed Incorporated, Laurent Pharmaceuticals, Anthera, the Cystic Fibrosis Foundation, and AzurRX; has received personal fees from Chiesi, Celtazsys, Ionis Pharmaceuticals, Merck, Paranta Biosciences, Santhera, Ph Pharma, and Kala Pharmaceuticals; and has received nonfinancial support from Insmed Incorportated.

Figures

Figure 1.
Figure 1.
Change from baseline in predose FEV1% predicted (mITT population). FEV1% predicted increased at all on-treatment periods (shaded) among patients in the prior-ALIS cohort and at most on-treatment periods for patients in the ALIS-naive cohort; missing values were excluded. Note: In the CLEAR-110 study, all patients received ALIS 590 mg QD. The prior-ALIS cohort comprised patients who received ALIS 590 mg QD during the previous CLEAR-108 study, while the ALIS-naive cohort comprised patients who received TIS 300 mg BID in CLEAR-108. ALIS, amikacin liposome inhalation suspension; FEV1, forced expiratory volume in 1 second; mITT, modified intent-to-treat; QD, once daily; TIS, tobramycin inhaled solution.
Figure 2.
Figure 2.
Change from baseline in sputum density of Pseudomonas aeruginosa (mITT population). Pseudomonas aeruginosa sputum density decreased within each cycle during the on-treatment period (shaded) compared with the off-treatment period; missing values were excluded. Note: In the CLEAR-110 study, all patients received ALIS 590 mg QD. The prior-ALIS cohort comprised patients who received ALIS 590 mg QD during the previous CLEAR-108 study, while the ALIS-naive cohort comprised patients who received TIS 300 mg BID in CLEAR-108. ALIS, amikacin liposome inhalation suspension; CFU, colony forming units; mITT, modified intent-to-treat; QD, once daily; TIS, tobramycin inhaled solution.
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References

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