Clinical trial NCT02712983: Dose-finding Study to Assess the Efficacy, Safety and Tolerability of Tobramycin Inhalation Powder in Patients With Non-Cystic Fibrosis Bronchiectasis and Pulmonary P. Aeruginosa Infection
Official title: A Randomized, Blinded, Parallel Group, Multi-center Dose-finding Study, to Assess the Efficacy, Safety and Tolerability of Different Doses of Tobramycin Inhalation Powder in Patients With Non-Cystic Fibrosis Bronchiectasis and Pulmonary P. Aeruginosa Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-cystic Fibrosis Bronchiectasis
Keywords: Inhaled tobramycin
tobramycin inhalation powder
bronchiectasis
pulmonary Pseudomonas aeruginosa infection
dose-finding study
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Queen's University, Belfast
name: University Hospital, Antwerp
name: University of Milan
name: Fundacion Clinic per a la Recerca Biomédica
name: Erasmus Medical Center
name: Papworth Hospital NHS Foundation Trust
name: Royal Brompton & Harefield NHS Foundation Trust
name: University of Dundee
name: University of Edinburgh
First posted: 2016-03-18
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to support the selection of a safe and tolerable tobramycin inhalation powder (TIP) dose, and regimen that exhibits effective bacterial reduction of P. aeruginosa in non-cystic fibrosis bronchiectasis (BE) patients with P. aeruginosa colonization.

Detailed description: This was a blinded, randomized, dose and regimen finding trial utilizing a three treatment cohort design where active TIP and TIP/Placebo cyclical (3 capsules o.d \[Cohort A\], 5 capsules o.d. \[Cohort B\] or 4 capsules b.i.d. \[Cohort C\]) versus Placebo were administered for a total of 112 days.

Novartis decided to close the recruitment of new subjects into this study earlier than scheduled. Subjects who had a signed informed consent form and entered screening by 10-Sep-2018 still participated in the study. The latest possible randomization was on 08-Oct-2018. All subjects enrolled in the study (107 enrolled subjects out of 180 planned) continued as planned through to their last scheduled visit. The early recruitment halt of the study was not due to safety or lack of efficacy.

Eligibility criteria: Key Inclusion Criteria:

* Written informed consent must be obtained before any assessment is performed.
* Male and female patients of ≥ 18 years of age at screening (Visit 1).
* Proven diagnosis of non-CF BE as documented by computed tomography or high-resolution computed tomography
* At least 2 or more exacerbations treated with oral antibiotics OR 1 or more exacerbation requiring intravenous antibiotic treatment within 12 months prior to screening.
* FEV1 ≥ 30% predicted at screening (Visit 1).
* P. aeruginosa, must be documented in a respiratory sample at least 1 time within 12 months and also present in the expectorated sputum culture at Visit 1.

Key Exclusion Criteria:

* Patients with a history of cystic fibrosis.
* Patients with a primary diagnosis of bronchial asthma.
* Patients with a primary diagnosis of COPD associated with at least a 20 pack year smoking history.
* Any significant medical condition that is either recently diagnosed or was not stable during the last 3 months, other than pulmonary exacerbations, and that in the opinion of the investigator makes participation in the trial against the patients' best interests.
* Clinically significant (in the opinion of the investigator) hearing loss that interferes with patients' daily activities (such as normal conversations) or chronic tinnitus. Patients with a past history of clinically significant hearing loss in the opinion of the investigator may be eligible only if their hearing threshold at screening audiometry is 25dB or lower at frequencies 0.5-4 kHz. The use of a hearing device is reflective of a clinically significant hearing loss; hence patients using hearing aids at screening are not eligible.
* Patients with active pulmonary tuberculosis.
* Patients currently receiving treatment for nontuberculous mycobacterial (NTM) pulmonary disease.
* Patients who are regularly receiving inhaled anti-pseudomonal antibiotic (during the study inhaled anti-pseudomonal antibiotics are not allowed other than the study drug).

Primary outcomes:
measure: Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs)
timeFrame: Baseline (Visit 101/Day 1), Visit 102 (Day 8), Visit 103 (Day 29)
Secondary outcomes:
measure: Change From Baseline to Each Post-baseline Visit in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs)
timeFrame: Baseline (Visit 101/Day 1), Visit 104 (Day 57), Visit 105 (Day 85), Visit 106 (Day 113), End of Treatment (EOT), Visit 201 (Day 141), Visit 202 (Day 169)
measure: Time to First Onset of Pulmonary Exacerbation by Exacerbation Category
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Duration of Pulmonary Exacerbation by Exacerbation Category
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Exposure Adjusted Rate of Pulmonary Exacerbations (PE) Over the Entire Study Period
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Percentage of Participants With at Least One Pulmonary Exacerbation by Exacerbation Category
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Percentage of Participants Who Permanently Discontinued Study Drug Due to Pulmonary Exacerbation
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Time to Permanent Study Drug Discontinuation Due to Pulmonary Exacerbation
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Time to First Use (Overall, Oral, and Parenteral) of Anti-pseudomonal Antibiotics Usage
timeFrame: From Baseline (Visit 101/Day 1) up to approximately Day 173
measure: Percentage of Participants Requiring Anti-pseudomonal Antibiotics
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Duration of Anti-pseudomonal Antibiotics Usage
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Percentage of Participants Requiring Hospitalization Due to Serious Respiratory-related Adverse Events
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Duration of Hospitalization Due to Serious Respiratory-related Adverse Events
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Number of Hospitalization Due to Serious Respiratory-related Adverse Events
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Time to First Hospitalization Due to Serious Respiratory-related Adverse Events
timeFrame: Baseline (Visit 101/Day 1) to Visit 202 (Day 169)
measure: Serum Tobramycin Concentration
timeFrame: Baseline (Visit 101/Day 1), Visit 102 (Day 8) and Visits 103 (Day 29): 0-1 hours and 1-2 hours post-dose.
measure: Sputum Tobramycin Concentration
timeFrame: Baseline (Visit 101/Day 1): 0-1 hours and 1-2 hours post-dose; Visit 102 (Day 8):0-2 hours and 5-6 hours post-dose; Visits 103 (Day 29): 5 to 6 hours post-dose, Visit 104 (Day 57) and Visit 105 (Day 85): 3-4 hours post-dose.
measure: Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning
timeFrame: Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)
measure: Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning
timeFrame: Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)
measure: Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality
timeFrame: Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)
measure: Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Emotional Functioning
timeFrame: Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)
measure: Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Social Functioning
timeFrame: Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)
measure: Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Treatment Burden
timeFrame: Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)
measure: Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Health Perceptions
timeFrame: Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)
measure: Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Respiratory Symptoms
timeFrame: Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)
Other outcomes:
Locations:
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Nice
country: France
facility: Novartis Investigative Site
state: Cedex1
city: Montpellier cedex 5
country: France
facility: Novartis Investigative Site
state: Herault
city: Grenoble
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
state: North Rhine-Westphalia
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Pordenone
country: Italy
facility: Novartis Investigative Site
state: PN
city: Milan
country: Italy
facility: Novartis Investigative Site
city: Pavia
country: Italy
facility: Novartis Investigative Site
city: Scafati
country: Italy
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunitat Valencia
city: Baracaldo - Vizcaya
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Valladolid
country: Spain
facility: Novartis Investigative Site
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
state: Cambridgeshire
city: Dundee
country: United Kingdom
facility: Novartis Investigative Site
state: Perthshire
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Edinburgh
country: United Kingdom
facility: Novartis Investigative Site
city: Lancaster
country: United Kingdom
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Novartis Investigative Site
city: Southampton
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharma
role: STUDY_DIRECTOR
References:
citation: Loebinger MR, Polverino E, Chalmers JD, Tiddens HAWM, Goossens H, Tunney M, Ringshausen FC, Hill AT, Pathan R, Angyalosi G, Blasi F, Elborn SJ, Haworth CS; iBEST-1 Trial Team. Efficacy and safety of TOBI Podhaler in Pseudomonas aeruginosa-infected bronchiectasis patients: iBEST study. Eur Respir J. 2021 Jan 5;57(1):2001451. doi: 10.1183/13993003.01451-2020. Print 2021 Jan.
citation: Loebinger MR, Polverino E, Blasi F, Elborn SJ, Chalmers JD, Tiddens HA, Goossens H, Tunney M, Zhou W, Angyalosi G, Hill AT, Haworth CS; iBEST-1 Trial Team. Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection: Design of a dose-finding study (iBEST-1). Pulm Pharmacol Ther. 2019 Oct;58:101834. doi: 10.1016/j.pupt.2019.101834. Epub 2019 Aug 18.