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

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.

• TIP (Drug): TIP dose regimen
• TIP and placebo (Drug): TIP and inhaled placebo dose regimen
• Placebo (Drug): Inhaled placebo dose regimen

Primary outcomes

• Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs) [Baseline (Visit 101/Day 1), Visit 102 (Day 8), Visit 103 (Day 29)]: Microbiological data was collected to understand the direct impact of the drug on the pathogens. Sputum samples were cultured for the presence of three Pseudomonas aeruginosa (P. aeruginosa) biotypes measured were mucoid, dry and small colony variant. Change was determined using the formula = (Post-baseline value - baseline value). If no P. aeruginosa was isolated for a visit, log10 colony forming units (CFU) was imputed with log10 (19) for all biotypes. Only values for all morphotypes presented.

Secondary outcomes

• Change From Baseline to Each Post-baseline Visit in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs) [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)]: Microbiological data was collected to understand the direct impact of the drug on the pathogens. Sputum samples were cultured for the presence of three Pseudomonas aeruginosa (P. aeruginosa) biotypes measured were mucoid, dry and small colony variant. Change was determined using the formula = (Post-baseline value - baseline value). If no P. aeruginosa was isolated for a visit, log10 colony forming units (CFU) was imputed with log10 (19) for all biotypes. Only values for all morphotypes are presented.
• Time to First Onset of Pulmonary Exacerbation by Exacerbation Category [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The time to first onset of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization. Participants were censored at the time of completion of study or early discontinuation if they did not have a pulmonary exacerbation during the study period.
• Duration of Pulmonary Exacerbation by Exacerbation Category [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The duration of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization.
• Exposure Adjusted Rate of Pulmonary Exacerbations (PE) Over the Entire Study Period [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The exposure adjusted rate of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization. The Exposure adjusted rate = (Number of pulmonary exacerbations reported during the study period) / (sum of study duration in days for all participants/ 365.25). Only descriptive analysis performed.
• Percentage of Participants With at Least One Pulmonary Exacerbation by Exacerbation Category [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: Pulmonary exacerbations are defined as events requiring antibiotic therapy AND for which at least 3 of the following 6 symptoms, signs, or findings were present outside of normal variation: 1. Increased sputum volume, or change in viscosity/consistency or purulence for more than 24 hours; 2. Increased shortness of breath at rest or on exercise for more than 24 hours; 3. Increased cough for more than 24 hours; 4. Fever of ≥38° Celsius within the last 24 hours; 5. Increased malaise/fatigue/lethargy for more than 24 hours; 6. A reduction in forced expiratory volume in the first second of expiration (FEV1) or forced vital capacity (FVC) of least 10% from screening. Participants were categorized as: a) Overall, b) Category 1: treated with oral antibiotics only and c) Category 2: treated with parenteral Antibiotics and/or requiring hospitalization. Only descriptive analysis performed.
• Percentage of Participants Who Permanently Discontinued Study Drug Due to Pulmonary Exacerbation [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The percentage of participants who permanently discontinued study drug due to pulmonary exacerbation compared to placebo was analyzed.
• Time to Permanent Study Drug Discontinuation Due to Pulmonary Exacerbation [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The time to permanent study drug discontinuation due to Pulmonary exacerbation. Participants were censored at the time of last contact if they did not permanently discontinue study drug due to pulmonary exacerbation requiring during the study period. Only descriptive analysis performed.
• Time to First Use (Overall, Oral, and Parenteral) of Anti-pseudomonal Antibiotics Usage [From Baseline (Visit 101/Day 1) up to approximately Day 173]: The time to first use of anti-pseudomonal antibiotics administered compared to placebo was analyzed. Participants were censored at the time of last contact if they did not have anti-pseudomonal antibiotics over the entire study period.
• Percentage of Participants Requiring Anti-pseudomonal Antibiotics [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The percentage of participants requiring anti-pseudomonal antibiotics compared to placebo was analyzed. Only descriptive analysis performed.
• Duration of Anti-pseudomonal Antibiotics Usage [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The total number of days of new anti-pseudomonal antibiotic use compared to placebo was analyzed. Only descriptive analysis
• Percentage of Participants Requiring Hospitalization Due to Serious Respiratory-related Adverse Events [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The percentage of participants requiring hospitalization due to serious respiratory-related adverse events (other than those regularly scheduled hospitalization that were planned prior to study start) was analyzed to define severity of pulmonary exacerbations compared to placebo. Only descriptive analysis performed.
• Duration of Hospitalization Due to Serious Respiratory-related Adverse Events [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The duration of hospitalization due to serious respiratory-related adverse events (other than those regularly scheduled hospitalization that were planned prior to study start) was analyzed to define severity of pulmonary exacerbations compared to placebo. Only descriptive analysis performed.
• Number of Hospitalization Due to Serious Respiratory-related Adverse Events [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: The number of hospitalization due to serious respiratory-related AEs was analyzed to define severity of pulmonary exacerbations compared to placebo. Respiratory related adverse events were identified using the AEs captured under system organ class 'Respiratory, thoracic and mediastinal disorders' and 'Infections and infestations'.
• Time to First Hospitalization Due to Serious Respiratory-related Adverse Events [Baseline (Visit 101/Day 1) to Visit 202 (Day 169)]: Time to first hospitalization due to serious respiratory-related AEs was analyzed to define severity of pulmonary exacerbations compared to placebo. Participants were censored at the time of last contact if they did not have a hospitalization due to serious respiratory-related adverse events over the entire study period.
• Serum Tobramycin Concentration [Baseline (Visit 101/Day 1), Visit 102 (Day 8) and Visits 103 (Day 29): 0-1 hours and 1-2 hours post-dose.]: The serum pharmacokinetic (PK) properties of tobramycin were assessed by evaluating tobramycin concentrations in serum collected from the non-cystic fibrosis bronchiectasis population post administration of o.d. or b.i.d. doses of TIP. Serum specimens for PK tobramycin concentration were assessed at Visit 101 (Day 1/start of treatment) 0 to 1 and 1 to 2 hours post-dose and Visit 102 (Day 8) 0 to 1 and 1 to 2 hours post-dose. Prior to protocol amendment #2, PK samples were assessed on Visits 103 (Day 29) rather than Visit 102. Only descriptive analysis performed.
• Sputum Tobramycin Concentration [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.]: The sputum pharmacokinetic (PK) properties of tobramycin were assessed by evaluating tobramycin concentrations in sputum collected from the non-cystic fibrosis bronchiectasis population post administration of o.d. or b.i.d. doses of TIP. Only descriptive analysis performed.
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]: The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]: The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]: The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Emotional Functioning [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]: The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Social Functioning [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]: The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Treatment Burden [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]: The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Health Perceptions [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]: The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Respiratory Symptoms [Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)]: The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

Sex: All, ages: 18 Years to any

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).

Participant flow

Outcome results

• Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs) (Primary), Mean, log10 CFUs: Cohort A (3 Capsules o.d.): TIP 6.80 +/- 1.202; Cohort A (3 Capsules o.d.): TIP/PBO 7.67 +/- 1.507; Cohort B (5 Capsules o.d.): TIP 6.10 +/- 2.419; Cohort B (5 Capsules o.d.): TIP/PBO 6.98 +/- 1.804; Cohort C (4 Capsules b.i.d.): TIP 6.79 +/- 0.908; Cohort C (4 Capsules b.i.d.): TIP/PBO 5.73 +/- 1.885; Pooled TIP 6.57 +/- 1.625; Pooled TIP/PBO 6.74 +/- 1.892; Pooled PBO 7.09 +/- 2.012
• Change From Baseline to Each Post-baseline Visit in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs) (Secondary), Mean, log10 CFUs: Cohort A (3 Capsules o.d.): TIP 6.80 +/- 1.202; Cohort A (3 Capsules o.d.): TIP/PBO 7.67 +/- 1.507; Cohort B (5 Capsules o.d.): TIP 6.10 +/- 2.419; Cohort B (5 Capsules o.d.): TIP/PBO 6.98 +/- 1.804; Cohort C (4 Capsules b.i.d.): TIP 6.79 +/- 0.908; Cohort C (4 Capsules b.i.d.): TIP/PBO 5.73 +/- 1.885; Pooled TIP 6.57 +/- 1.625; Pooled TIP/PBO 6.74 +/- 1.892; Pooled PBO 7.09 +/- 2.012
• Time to First Onset of Pulmonary Exacerbation by Exacerbation Category (Secondary), Median, Days: Cohort A (3 Capsules o.d.): TIP NA (39.00 to NA); Cohort A (3 Capsules o.d.): TIP/PBO NA (48.00 to NA); Cohort B (5 Capsules o.d.): TIP NA (15.00 to NA); Cohort B (5 Capsules o.d.): TIP/PBO NA (85.00 to NA); Cohort C (4 Capsules b.i.d.): TIP NA (127.00 to NA); Cohort C (4 Capsules b.i.d.): TIP/PBO NA (24.00 to NA); Pooled TIP NA (127.00 to NA); Pooled TIP/PBO NA (85.00 to NA); Pooled PBO 173.00 (77.00 to NA)
• Duration of Pulmonary Exacerbation by Exacerbation Category (Secondary), Mean, Days: Cohort A (3 Capsules o.d.): TIP 15.7 +/- 6.22; Cohort A (3 Capsules o.d.): TIP/PBO 18.0 +/- 8.26; Cohort B (5 Capsules o.d.): TIP 20.2 +/- 6.37; Cohort B (5 Capsules o.d.): TIP/PBO 10.3 +/- 5.12; Cohort C (4 Capsules b.i.d.): TIP 25.5 +/- 27.09; Cohort C (4 Capsules b.i.d.): TIP/PBO 14.8 +/- 6.73; Pooled TIP 19.0 +/- 12.64; Pooled TIP/PBO 15.2 +/- 7.39; Pooled PBO 14.5 +/- 5.61
• Exposure Adjusted Rate of Pulmonary Exacerbations (PE) Over the Entire Study Period (Secondary), Number, pulmonary exacerbation per study years: Cohort A (3 Capsules o.d.): TIP 1.71 (0.92 to 3.17); Cohort A (3 Capsules o.d.): TIP/PBO 1.39 (0.70 to 2.78); Cohort B (5 Capsules o.d.): TIP 1.29 (0.58 to 2.87); Cohort B (5 Capsules o.d.): TIP/PBO 1.20 (0.57 to 2.51); Cohort C (4 Capsules b.i.d.): TIP 0.66 (0.25 to 1.76); Cohort C (4 Capsules b.i.d.): TIP/PBO 1.46 (0.73 to 2.93); Pooled TIP 1.21 (0.78 to 1.87); Pooled TIP/PBO 1.35 (0.90 to 2.03); Pooled PBO 1.41 (0.82 to 2.42)
• Percentage of Participants With at Least One Pulmonary Exacerbation by Exacerbation Category (Secondary), Count of participants, Participants: Cohort A (3 Capsules o.d.): TIP 8; Cohort A (3 Capsules o.d.): TIP/PBO 9; Cohort B (5 Capsules o.d.): TIP 10; Cohort B (5 Capsules o.d.): TIP/PBO 9; Cohort C (4 Capsules b.i.d.): TIP 11; Cohort C (4 Capsules b.i.d.): TIP/PBO 9; Pooled TIP 29; Pooled TIP/PBO 27; Pooled PBO 11
• Percentage of Participants Who Permanently Discontinued Study Drug Due to Pulmonary Exacerbation (Secondary), Count of participants, Participants: Cohort A (3 Capsules o.d.): TIP 2; Cohort A (3 Capsules o.d.): TIP/PBO 0; Cohort B (5 Capsules o.d.): TIP 1; Cohort B (5 Capsules o.d.): TIP/PBO 0; Cohort C (4 Capsules b.i.d.): TIP 0; Cohort C (4 Capsules b.i.d.): TIP/PBO 2; Pooled TIP 41; Pooled TIP/PBO 40; Pooled PBO 0
• Time to Permanent Study Drug Discontinuation Due to Pulmonary Exacerbation (Secondary), Median, Days: Cohort A (3 Capsules o.d.): TIP NA (94.00 to NA); Cohort A (3 Capsules o.d.): TIP/PBO NA (NA to NA); Cohort B (5 Capsules o.d.): TIP NA (NA to NA); Cohort B (5 Capsules o.d.): TIP/PBO NA (NA to NA); Cohort C (4 Capsules b.i.d.): TIP NA (NA to NA); Cohort C (4 Capsules b.i.d.): TIP/PBO NA (84.00 to NA); Pooled TIP NA (NA to NA); Pooled TIP/PBO NA (NA to NA); Pooled PBO NA (NA to NA)
• Time to First Use (Overall, Oral, and Parenteral) of Anti-pseudomonal Antibiotics Usage (Secondary), Median, Days: Cohort A (3 Capsules o.d.): TIP 122.00 (29.00 to NA); Cohort A (3 Capsules o.d.): TIP/PBO NA (50.00 to NA); Cohort B (5 Capsules o.d.): TIP 116.00 (17.00 to NA); Cohort B (5 Capsules o.d.): TIP/PBO 161.00 (58.00 to NA); Cohort C (4 Capsules b.i.d.): TIP NA (127.00 to NA); Cohort C (4 Capsules b.i.d.): TIP/PBO NA (11.00 to NA); Pooled TIP NA (110.00 to NA); Pooled TIP/PBO NA (84.00 to NA); Pooled PBO 141.00 (57.00 to NA)
• Percentage of Participants Requiring Anti-pseudomonal Antibiotics (Secondary), Count of participants, Participants: Cohort A (3 Capsules o.d.): TIP 8; Cohort A (3 Capsules o.d.): TIP/PBO 4; Cohort B (5 Capsules o.d.): TIP 6; Cohort B (5 Capsules o.d.): TIP/PBO 7; Cohort C (4 Capsules b.i.d.): TIP 3; Cohort C (4 Capsules b.i.d.): TIP/PBO 7; Pooled TIP 17; Pooled TIP/PBO 18; Pooled PBO 12
• Duration of Anti-pseudomonal Antibiotics Usage (Secondary), Mean, Days: Cohort A (3 Capsules o.d.): TIP 18.4 +/- 10.39; Cohort A (3 Capsules o.d.): TIP/PBO 20.0 +/- 12.03; Cohort B (5 Capsules o.d.): TIP 19.2 +/- 14.84; Cohort B (5 Capsules o.d.): TIP/PBO 25.7 +/- 13.21; Cohort C (4 Capsules b.i.d.): TIP 15.3 +/- 10.07; Cohort C (4 Capsules b.i.d.): TIP/PBO 15.7 +/- 10.90; Pooled TIP 18.1 +/- 11.43; Pooled TIP/PBO 20.6 +/- 12.24; Pooled PBO 14.6 +/- 8.27
• Percentage of Participants Requiring Hospitalization Due to Serious Respiratory-related Adverse Events (Secondary), Count of participants, Participants: Cohort A (3 Capsules o.d.): TIP 10; Cohort A (3 Capsules o.d.): TIP/PBO 13; Cohort B (5 Capsules o.d.): TIP 13; Cohort B (5 Capsules o.d.): TIP/PBO 12; Cohort C (4 Capsules b.i.d.): TIP 14; Cohort C (4 Capsules b.i.d.): TIP/PBO 11; Pooled TIP 37; Pooled TIP/PBO 36; Pooled PBO 19
• Duration of Hospitalization Due to Serious Respiratory-related Adverse Events (Secondary), Mean, Days: Cohort A (3 Capsules o.d.): TIP 15.2 +/- 5.19; Cohort A (3 Capsules o.d.): TIP/PBO ; Cohort B (5 Capsules o.d.): TIP 22.0 +/- 12.73; Cohort B (5 Capsules o.d.): TIP/PBO 12.2 +/- 6.06; Cohort C (4 Capsules b.i.d.): TIP 11.0 +/- NA; Cohort C (4 Capsules b.i.d.): TIP/PBO 19.0 +/- 5.23; Pooled TIP 16.2 +/- 7.05; Pooled TIP/PBO 15.2 +/- 6.44; Pooled PBO 10.5 +/- 0.71
• Number of Hospitalization Due to Serious Respiratory-related Adverse Events (Secondary), Number, Hospitalization: Cohort A (3 Capsules o.d.): TIP 6; Cohort A (3 Capsules o.d.): TIP/PBO 0; Cohort B (5 Capsules o.d.): TIP 2; Cohort B (5 Capsules o.d.): TIP/PBO 5; Cohort C (4 Capsules b.i.d.): TIP 2; Cohort C (4 Capsules b.i.d.): TIP/PBO 4; Pooled TIP 10; Pooled TIP/PBO 9; Pooled PBO 2
• Time to First Hospitalization Due to Serious Respiratory-related Adverse Events (Secondary), Median, Day: Cohort A (3 Capsules o.d.): TIP NA (93.00 to NA); Cohort A (3 Capsules o.d.): TIP/PBO NA (NA to NA); Cohort B (5 Capsules o.d.): TIP NA (60.00 to NA); Cohort B (5 Capsules o.d.): TIP/PBO NA (NA to NA); Cohort C (4 Capsules b.i.d.): TIP NA (NA to NA); Cohort C (4 Capsules b.i.d.): TIP/PBO NA (65.00 to NA); Pooled TIP NA (NA to NA); Pooled TIP/PBO NA (NA to NA); Pooled PBO NA (NA to NA)
• Serum Tobramycin Concentration (Secondary), Mean, microgram/milliliter: Cohort A (3 Capsules o.d.): TIP 0.256 +/- 0.144; Cohort A (3 Capsules o.d.): TIP/PBO 0.479 +/- 0.47; Cohort B (5 Capsules o.d.): TIP 0.4 +/- 0.259; Cohort B (5 Capsules o.d.): TIP/PBO 0.441 +/- 0.273; Cohort C (4 Capsules b.i.d.): TIP 0.59 +/- 0.37; Cohort C (4 Capsules b.i.d.): TIP/PBO 0.321 +/- 0.21
• Sputum Tobramycin Concentration (Secondary), Mean, microgram/milliliter: Cohort A (3 Capsules o.d.): TIP 1750 +/- 2160; Cohort A (3 Capsules o.d.): TIP/PBO 637 +/- 608; Cohort B (5 Capsules o.d.): TIP 2640 +/- 2680; Cohort B (5 Capsules o.d.): TIP/PBO 2020 +/- 2360; Cohort C (4 Capsules b.i.d.): TIP 2820 +/- 2250; Cohort C (4 Capsules b.i.d.): TIP/PBO 2060 +/- 1840
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning (Secondary), Mean, Score on Scale: Cohort A (3 Capsules o.d.): TIP 51.33 +/- 38.33; Cohort A (3 Capsules o.d.): TIP/PBO 60.5 +/- 28.60; Cohort B (5 Capsules o.d.): TIP 45.8 +/- 19.98; Cohort B (5 Capsules o.d.): TIP/PBO 50.5 +/- 33.04; Cohort C (4 Capsules b.i.d.): TIP 46.2 +/- 30.29; Cohort C (4 Capsules b.i.d.): TIP/PBO 53.8 +/- 26.72; Pooled TIP 47.6 +/- 29.41; Pooled TIP/PBO 54.8 +/- 29.10; Pooled PBO 49.8 +/- 27.97
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning (Secondary), Mean, Score on Scale: Cohort A (3 Capsules o.d.): TIP 63.1 +/- 24.28; Cohort A (3 Capsules o.d.): TIP/PBO 67.2 +/- 14.26; Cohort B (5 Capsules o.d.): TIP 53.3 +/- 21.68; Cohort B (5 Capsules o.d.): TIP/PBO 64.3 +/- 29.77; Cohort C (4 Capsules b.i.d.): TIP 57.8 +/- 26.86; Cohort C (4 Capsules b.i.d.): TIP/PBO 67.6 +/- 24.67; Pooled TIP 57.8 +/- 24.11; Pooled TIP/PBO 66.3 +/- 23.46; Pooled PBO 63.9 +/- 19.79
• Change From Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality (Secondary), Mean, Score on Scale: Cohort A (3 Capsules o.d.): TIP 56.4 +/- 22.89; Cohort A (3 Capsules o.d.): TIP/PBO 47.9 +/- 17.21; Cohort B (5 Capsules o.d.): TIP 52.4 +/- 21.54; Cohort B (5 Capsules o.d.): TIP/PBO 44.4 +/- 26.51; Cohort C (4 Capsules b.i.d.): TIP 47.4 +/- 25.36; Cohort C (4 Capsules b.i.d.): TIP/PBO 51.9 +/- 18.63; Pooled TIP 51.9 +/- 23.11; Pooled TIP/PBO 48.1 +/- 20.92; Pooled PBO 46.2 +/- 25.46
• 5 more outcome measures not shown.

Adverse events

Time frame: Adverse events were collected from first dose of study drug treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 134 days.

Serious adverse events by term

Other adverse events by term

106 more terms not shown.

Limitations and caveats: Novartis decided to close the recruitment of new subjects into this study earlier than scheduled. The early recruitment halt of the study was not due to safety or lack of efficacy.

• Results publication: 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. PMID 32855225
• Results publication: 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. PMID 31433997

• Study Protocol (PDF, 2018-06-21)
• Statistical Analysis Plan (PDF, 2019-05-21)

• Novartis Pharma, Study director, Novartis Pharmaceuticals

NIH grants: 2015