Pharmacokinetic Evaluation and Tolerability of Dry Powder Tobramycin by a Novel Device in Patients With Non Cystic Fibrosis Bronchiectasis

• ClinicalTrials.gov Identifier: NCT02035488
• Recruitment Status: Completed
• First Posted: January 14, 2014
• Last Update Posted: December 16, 2014
• Sponsor: University Medical Center Groningen
• Information provided by (Responsible Party): Onno Akkerman, University Medical Center Groningen

Study Description

Brief Summary:

Bronchiectasis is a persistent and frequently progressive condition characterized by dilated and thick-walled bronchi retaining sputum. The main symptoms of bronchiectasis are cough and chronic sputum production. Until now, most patients with non-CF bronchiectasis receive inhaled tobramycin every other month, by use of a nebulizer. However, this delivery system has several disadvantages, like a low lung deposition and pollution with tobramycin in the surrounding environment. With an efficient dry powder inhaler (DPI), a three to six fold higher lung deposition compared to a nebulizer can be obtained. Therapy with a DPI is also less time consuming compared to nebulisation. We will investigate dry powder tobramycin (DP tobramycin) in a novel device in patients with non-CF bronchiectasis. The main objectives of this study are to investigate the pharmacokinetic properties of DP tobramycin at different dosages together with the local tolerability of DP tobramycin via the Cyclops® at different dosages.

Condition or disease	Intervention/treatment	Phase
Bronchiectasis	Drug: Tobramycin	Phase 1; Phase 2

Detailed Description:

Rationale: Bronchiectasis is a persistent and frequently progressive condition characterized by dilated and thick-walled bronchi retaining sputum. The main symptoms of bronchiectasis are cough and chronic sputum production. There is a state of constant colonization with bacteria, which frequently causes exacerbations. The presence of Pseudomonas aeruginosa is an unfavorable prognostic indicator and is associated with increased sputum production, more extensive bronchiectasis on HR-CT of the thorax, more hospitalizations and reduced quality of life. Until now, most patients with non-CF bronchiectasis who are colonized with P. aeruginosa receive inhaled tobramycin every other month, by use of a nebulizer. However, this delivery system has several disadvantages, like a low lung deposition and pollution with tobramycin in the surrounding environment. With an efficient dry powder inhaler (DPI), a three to six fold higher lung deposition compared to a nebulizer can be obtained. Therapy with a DPI is also less time consuming compared to nebulisation. Nebulised tobramycin is used most in routine care; there is also one, rather poorly characterized DPI for tobramycin available, though this DPI is not registrered for non-CF bronchiectasis. We will investigate dry powder tobramycin (DP tobramycin) in a novel device in patients with non-CF bronchiectasis colonized with P. aeruginosa.

Objective: The main objectives are to investigate the pharmacokinetic properties of DP tobramycin at different dosages together with the local tolerability of DP tobramycin via the Cyclops® at different dosages.

Study design: single center, single ascending, single dose, response study. Study population: 8 patients with non-CF bronchiectasis

Main study parameters:

The following pharmacokinetic parameters will be calculated: actual dose (dose minus remainder in inhaler after inhalation), AUC0-12 (area under the curve from 0 -12 h), Cmax (maximum plasma concentration), Tmax (time to maximum plasma concentration), Ka (absorption rate constant), T1/2 el (terminal elimination half-life), CL/F (clearance following pulmonary administration (F= bioavailability)).

Local tolerability of DP tobramycin is determined by scoring adverse events, specifically coughing, and lung function measurement.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: All participants included in this study are patients recruited from the outpatient department of pulmonology. To investigate safety, lung function tests will be performed and the occurrence of adverse events will be scored.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetic Evaluation and Tolerability of Dry Powder Tobramycin by a Novel Device in Patients With Non Cystic Fibrosis Bronchiectasis
• Study Start Date: October 2013
• Actual Primary Completion Date: December 2014
• Actual Study Completion Date: December 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tobramycin; Patients with bronchiectasis	Drug: Tobramycin; Tobramycin dry powder 30 mg inhalation per dose; Dose escalation: 30-60-120 and 240 mg, each one time. One dose per week.; Other Name: Dry powder tobramycin free base

Outcome Measures

Primary Outcome Measures :

1. Actual dose (dose minus remainder in inhaler after inhalation) of tobramycin [ Time Frame: one day ]
2. Area Under the plasma concentration versus time curve from 0 -12 hours (AUC0-12) of tobramycin •Area Under the plasma concentration versus time curve from 0 -12 hours (AUC0-12) of tobramycin [ Time Frame: One day ]
3. Maximum plasma concentration (Cmax ) of tobramycin [ Time Frame: One day ]
4. Time to maximum plasma concentration (Tmax) of tobramycin [ Time Frame: One day ]
5. Absorption rate constant (Ka) of tobramycin [ Time Frame: One day ]
6. Terminal elimination half-life (T1/2 el ) of tobramycin [ Time Frame: One day ]
7. Clearance following pulmonary administration (CL/F) (F= bioavailability) of tobramycin [ Time Frame: One day ]
8. Decrease of FEV1 in percentage measured by spirometry [ Time Frame: One day ]
9. Number of Participants with Adverse Events [ Time Frame: One day ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

• Age 18 years or older
• Obtained informed consent
• Patients having bronchiectasis (confirmed with HR-CT of the chest)

Exclusion criteria:

• Pregnant or breast feeding
• Subjects with known or suspected renal, auditory, vestibular or neuromuscular dysfunction, or with severe, active haemoptysis,
• History of adverse events on previous tobramycin or other aminoglycoside use
• No concurrent use of cyclosporin, cisplatin, amfotericin B, cephalosporins, polymyxins, vancomycin and NSAIDs.

Contacts and Locations

Locations

Netherlands

University Medical Center Groningen

Groningen, Netherlands

Sponsors and Collaborators

University Medical Center Groningen

Investigators

• Principal Investigator: Huib Kerstjens, MD, PhD; University Medical Center Groningen

More Information

• Responsible Party: Onno Akkerman, Drs, University Medical Center Groningen
• ClinicalTrials.gov Identifier: NCT02035488
• Other Study ID Numbers: Tobra-02
• First Posted: January 14, 2014
• Last Update Posted: December 16, 2014
• Last Verified: December 2014

Keywords provided by Onno Akkerman, University Medical Center Groningen:

Dry powder inhalation; Bronchiectasis; Tobramycin

Additional relevant MeSH terms:

Bronchiectasis; Bronchial Diseases; Respiratory Tract Diseases; Tobramycin; Anti-Bacterial Agents; Anti-Infective Agents