Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection

Design of a dose-finding study (iBEST-1)

Research output: Contribution to journalArticle

Abstract

In patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate. We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection. In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7-Save28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis. As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area.

Original languageEnglish
Article number101834
Number of pages29
JournalPulmonary Pharmacology & Therapeutics
Volume58
Early online date18 Aug 2019
DOIs
Publication statusPublished - Oct 2019

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Tobramycin
Bronchiectasis
Powders
Pseudomonas aeruginosa
Inhalation
Pseudomonas Infections
Safety
Lung
Infection
Sputum
Microbiota
Anti-Bacterial Agents
Biomarkers
Screening
Cystic Fibrosis
Sample Size
Disease Progression
Therapeutics
Placebos
Quality of Life

Cite this

@article{3c0416f103d5495daa7a2e38d3886701,
title = "Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection: Design of a dose-finding study (iBEST-1)",
abstract = "In patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate. We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection. In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7-Save28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis. As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area.",
author = "Loebinger, {Michael R} and Eva Polverino and Francesco Blasi and Elborn, {Stuart J} and Chalmers, {James D} and Tiddens, {Harm Awm} and Herman Goossens and Michael Tunney and Wenchun Zhou and Gerhild Angyalosi and Hill, {Adam T} and Haworth, {Charles S}",
note = "This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking iABC grant agreement n° 115721. The authors thank Mittal Makhija, Novartis Healthcare Pvt. Ltd, India, for providing medical writing and editorial support to draft the manuscript.Copyright {\circledC} 2019. Published by Elsevier Ltd.",
year = "2019",
month = "10",
doi = "10.1016/j.pupt.2019.101834",
language = "English",
volume = "58",
journal = "Pulmonary Pharmacology & Therapeutics",
issn = "1094-5539",
publisher = "Elsevier",

}

TY - JOUR

T1 - Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection

T2 - Design of a dose-finding study (iBEST-1)

AU - Loebinger, Michael R

AU - Polverino, Eva

AU - Blasi, Francesco

AU - Elborn, Stuart J

AU - Chalmers, James D

AU - Tiddens, Harm Awm

AU - Goossens, Herman

AU - Tunney, Michael

AU - Zhou, Wenchun

AU - Angyalosi, Gerhild

AU - Hill, Adam T

AU - Haworth, Charles S

N1 - This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking iABC grant agreement n° 115721. The authors thank Mittal Makhija, Novartis Healthcare Pvt. Ltd, India, for providing medical writing and editorial support to draft the manuscript.Copyright © 2019. Published by Elsevier Ltd.

PY - 2019/10

Y1 - 2019/10

N2 - In patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate. We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection. In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7-Save28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis. As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area.

AB - In patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate. We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection. In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7-Save28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis. As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area.

U2 - 10.1016/j.pupt.2019.101834

DO - 10.1016/j.pupt.2019.101834

M3 - Article

VL - 58

JO - Pulmonary Pharmacology & Therapeutics

JF - Pulmonary Pharmacology & Therapeutics

SN - 1094-5539

M1 - 101834

ER -