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

NCT02712983 | Completed Phase 2 Results DMC

• 2 other identifiers: CTBM100G22022015-003040-39
• Study Type: interventional
• Target: 107
• Locations: 6 countries
• Sites: 34

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.

Conditions

Non-cystic Fibrosis Bronchiectasis

Keywords

Inhaled tobramycin; tobramycin inhalation powder; bronchiectasis; pulmonary Pseudomonas aeruginosa infection; dose-finding study

Outcome Measures

Primary Outcomes (1)

• Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. Aeruginosa) Density in Sputum (log10 CFUs)

  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.

  Baseline (Visit 101/Day 1), Visit 102 (Day 8), Visit 103 (Day 29)

Secondary Outcomes (24)

• 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)

• Time to First Onset of Pulmonary Exacerbation by Exacerbation Category

  Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

• Duration of Pulmonary Exacerbation by Exacerbation Category

  Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

• Exposure Adjusted Rate of Pulmonary Exacerbations (PE) Over the Entire Study Period

  Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

• Percentage of Participants With at Least One Pulmonary Exacerbation by Exacerbation Category

  Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Study Arms (9)

Cohort A (3 capsules o.d.): TIP

EXPERIMENTAL

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)

Drug: TIP

Cohort A (3 capsules o.d.): TIP/PBO

EXPERIMENTAL

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Drug: TIP and placebo

Cohort A (3 capsules o.d.): PBO

PLACEBO COMPARATOR

Cohort A (3 capsules o.d.): Inhaled placebo (PBO)

Drug: Placebo

Cohort B (5 capsules o.d.): TIP

EXPERIMENTAL

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)

Drug: TIP

Cohort B (5 capsules o.d.): TIP/PBO

EXPERIMENTAL

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Drug: TIP and placebo

Cohort B (5 capsules o.d.): PBO

PLACEBO COMPARATOR

Cohort B (5 capsules o.d.): inhaled placebo (PBO)

Drug: Placebo

Cohort C (4 capsules b.i.d.): TIP

EXPERIMENTAL

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)

Drug: TIP

Cohort C (4 capsules b.i.d.): TIP/PBO

EXPERIMENTAL

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Drug: TIP and placebo

Cohort C (4 capsules b.i.d.): PBO

PLACEBO COMPARATOR

Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)

Drug: Placebo

Interventions

TIP DRUG

TIP dose regimen

Cohort A (3 capsules o.d.): TIP; Cohort B (5 capsules o.d.): TIP; Cohort C (4 capsules b.i.d.): TIP

TIP and placebo DRUG

TIP and inhaled placebo dose regimen

Cohort A (3 capsules o.d.): TIP/PBO; Cohort B (5 capsules o.d.): TIP/PBO; Cohort C (4 capsules b.i.d.): TIP/PBO

Placebo DRUG

Inhaled placebo dose regimen

Cohort A (3 capsules o.d.): PBO; Cohort B (5 capsules o.d.): PBO; Cohort C (4 capsules b.i.d.): PBO

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• Queen's University, Belfast: collaborator
• University Hospital, Antwerp: collaborator
• University of Milan: collaborator
• Fundacion Clinic per a la Recerca Biomédica: collaborator
• Erasmus Medical Center: collaborator
• Papworth Hospital NHS Foundation Trust: collaborator
• Royal Brompton & Harefield NHS Foundation Trust: collaborator
• University of Dundee: collaborator
• University of Edinburgh: collaborator

Study Sites (34)

Novartis Investigative Site

Brussels, 1070, Belgium

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Nice, Cedex1, 06001, France

Location

Novartis Investigative Site

Montpellier, Herault, 34059, France

Location

Novartis Investigative Site

Grenoble, 38043, France

Location

Novartis Investigative Site

Toulouse, 31059, France

Location

Novartis Investigative Site

Essen, North Rhine-Westphalia, 45239, Germany

Location

Novartis Investigative Site

Berlin, 14059, Germany

Location

Novartis Investigative Site

Frankfurt, 60596, Germany

Location

Novartis Investigative Site

Hanover, 30625, Germany

Location

Novartis Investigative Site

Leipzig, 04357, Germany

Location

Novartis Investigative Site

Monza, MB, 20900, Italy

Location

Novartis Investigative Site

Pisa, PI, 56124, Italy

Location

Novartis Investigative Site

Pordenone, PN, 33170, Italy

Location

Novartis Investigative Site

Milan, 20112, Italy

Location

Novartis Investigative Site

Pavia, 27100, Italy

Location

Novartis Investigative Site

Scafati, 84018, Italy

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

Location

Novartis Investigative Site

Barcelona, Catalonia, 08041, Spain

Location

Novartis Investigative Site

Valencia, Comunitat Valencia, 46014, Spain

Location

Novartis Investigative Site

Baracaldo - Vizcaya, 48903, Spain

Location

Novartis Investigative Site

Barcelona, 08003, Spain

Location

Novartis Investigative Site

Valencia, 46009, Spain

Location

Novartis Investigative Site

Valladolid, 47003, Spain

Location

Novartis Investigative Site

Cambridge, Cambridgeshire, CB23 3RE, United Kingdom

Location

Novartis Investigative Site

Dundee, Perthshire, DD1 9SY, United Kingdom

Location

Novartis Investigative Site

Birmingham, B15 2TH, United Kingdom

Location

Novartis Investigative Site

Edinburgh, ED16 4SA, United Kingdom

Location

Novartis Investigative Site

Lancaster, LA1 4RP, United Kingdom

Location

Novartis Investigative Site

Leeds, LS9 7TF, United Kingdom

Location

Novartis Investigative Site

London, SW 6NP, United Kingdom

Location

Novartis Investigative Site

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Novartis Investigative Site

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (2)

• 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 DERIVED

• 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 DERIVED

MeSH Terms

Conditions

Bronchiectasis

Interventions

Lysine Acetyltransferase 5

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Histone Acetyltransferases; Lysine Acetyltransferases; Acetyltransferases; Acyltransferases; Transferases; Enzymes; Enzymes and Coenzymes

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 Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharma

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2016
• First Posted: March 18, 2016
• Study Start: February 8, 2017
• Primary Completion: March 20, 2019
• Study Completion: March 20, 2019
• Last Updated: August 25, 2020
• Results First Posted: August 14, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will share

Locations

FR (4); IT (6); BE (2); ES (8); DE (5); GB (9)