Chronic Lung Infection With Pseudomonas Aeruginosa in Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, Pseudomonas aeruginosa, Lung Clearance Index, Multiple Breath Washout, Inhaled Tobramycin, Inhaled Antibiotics.
Brief summary
The purpose of the study was to evaluate lung clearance index (LCI) by a standardized procedure in a well characterized study setting and to assess feasibility of LCI as a more sensitive method than forced expiratory volume at 1 second (FEV1) to measure effectiveness of antibiotic therapy in patients with CF aged 6 years and older with mild to moderate lung disease.
Detailed description
This study was terminated prematurely. The reason for trial termination was challenge with enrollment and patient recruitment. A significant decrease in the eligible patient population had been identified as main driver.
Interventions
DRUGTIS or TIP
300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of CF * Patients with elevated LCI of ≥ 7.5 at screening * Patients with FEV1 of ≥ 50% predicted at screening * Use of inhaled Tobramycin in a 28 days on / off regimen in the past 3 months before screening * chronic lung Infection with Pseudomonas aeruginosa
Exclusion criteria
* Patients who are regularly receiving more than one class of inhaled anti-pseudomonal antibiotic * Patients who have used oral or intravenous anti-pseudomonal antibiotics within 28 days prior to on-phase of study drug * Pregnant or nursing (lactating) women * Change in dose, formulation or strength of the study drug in the past treatment cycle before screening * History of hearing loss or chronic tinnitus * Infection with Burkholderia cenocepacia complex Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Lung Clearance Index (LCI) After 4 Weeks Following Onset of Study | Baseline, week 4 | The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of Colony-forming Units (CFU) After 4 Weeks Following Onset of Study | Baseline, week 4 | Microbacterial density of Pseudomonas aeruginosa in Sputum-Samples in CFU (Colony Forming Units) per gram sputum. |
| Change From Baseline in Lung Clearance Index (LCI) After 1 Week | Baseline, week 1 | The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal. |
| Change From Baseline of Forced Expiratory Volume at 1 Second (FEV1) After 4 Weeks Following Onset of Study | Baseline, week 4 | Change of FEV1 (Forced expiry volume in the first second) measured by Spirometry |
| Change of Forced Expiratory Volume at 1 Second(FEV1) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) | week 4, week 8 | Change of FEV1 (Forced expiry volume in the first second) measured by Spirometry |
| Change of Colony-forming Units (CFU) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) | week 4, week 8 | Microbacterial density of Pseudomonas aeruginosa in Sputum-Samples in CFU (Colony Forming Units) per gram sputum. |
| Change of Lung Clearance Index (LCI) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) | week 4, week 8 | The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal. |
Countries
Germany
Participant flow
Recruitment details
At least 35 patients were planned to be recruited in the study. However, in total, 17 patients entered into the study and completed. Reason for termination was challenge with enrollment and recruitment. A significant decrease in the eligible patient population was main driver.
Participants by arm
| Arm | Count |
|---|---|
| Tobramycin Inhalation Solution(TIS) 300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) twice a day (BID) 28days on / 28 days off | 5 |
| Tobramycin Inhalation Powder (TIP) TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off | 12 |
| Total | 17 |
Baseline characteristics
| Characteristic | Tobramycin Inhalation Solution(TIS) | Tobramycin Inhalation Powder (TIP) | Total |
|---|---|---|---|
| Age, Continuous | 20.2 years STANDARD_DEVIATION 8.26 | 28.9 years STANDARD_DEVIATION 9.79 | 26.4 years STANDARD_DEVIATION 9.99 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 12 Participants | 17 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 9 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 12 |
| other Total, other adverse events | 2 / 5 | 3 / 12 |
| serious Total, serious adverse events | 0 / 5 | 0 / 12 |
Outcome results
Primary
Change From Baseline in Lung Clearance Index (LCI) After 4 Weeks Following Onset of Study
The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal.
Time frame: Baseline, week 4
Population: Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tobramycin ALL | Change From Baseline in Lung Clearance Index (LCI) After 4 Weeks Following Onset of Study | Baseline | 17.985 units on a scale | Standard Error 1.1494 |
| Tobramycin ALL | Change From Baseline in Lung Clearance Index (LCI) After 4 Weeks Following Onset of Study | Week 4 | 17.101 units on a scale | Standard Error 0.8409 |
p-value: 0.4099ANOVA
Secondary
Change From Baseline in Lung Clearance Index (LCI) After 1 Week
The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal.
Time frame: Baseline, week 1
Population: Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tobramycin ALL | Change From Baseline in Lung Clearance Index (LCI) After 1 Week | Baseline | 17.985 units on a scale | Standard Error 1.1494 |
| Tobramycin ALL | Change From Baseline in Lung Clearance Index (LCI) After 1 Week | Week 1 | 17.506 units on a scale | Standard Error 1.0002 |
p-value: 0.591ANOVA
Secondary
Change From Baseline of Colony-forming Units (CFU) After 4 Weeks Following Onset of Study
Microbacterial density of Pseudomonas aeruginosa in Sputum-Samples in CFU (Colony Forming Units) per gram sputum.
Time frame: Baseline, week 4
Population: Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm. n is the number of patients of safety set with a non-missing value at the specific time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tobramycin ALL | Change From Baseline of Colony-forming Units (CFU) After 4 Weeks Following Onset of Study | Baseline | 56594.3 CFU per gram sputum | Standard Error 28018.89 |
| Tobramycin ALL | Change From Baseline of Colony-forming Units (CFU) After 4 Weeks Following Onset of Study | Week 4 | 26113.0 CFU per gram sputum | Standard Error 27280.98 |
p-value: 0.354ANOVA
Secondary
Change From Baseline of Forced Expiratory Volume at 1 Second (FEV1) After 4 Weeks Following Onset of Study
Change of FEV1 (Forced expiry volume in the first second) measured by Spirometry
Time frame: Baseline, week 4
Population: Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tobramycin ALL | Change From Baseline of Forced Expiratory Volume at 1 Second (FEV1) After 4 Weeks Following Onset of Study | Baseline | 76.964 % predicted | Standard Error 4.5121 |
| Tobramycin ALL | Change From Baseline of Forced Expiratory Volume at 1 Second (FEV1) After 4 Weeks Following Onset of Study | Week 4 | 77.481 % predicted | Standard Error 4.9877 |
p-value: 0.6961ANOVA
Secondary
Change of Colony-forming Units (CFU) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle)
Microbacterial density of Pseudomonas aeruginosa in Sputum-Samples in CFU (Colony Forming Units) per gram sputum.
Time frame: week 4, week 8
Population: Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm. n is the number of patients of safety set with a non-missing value at the specific time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tobramycin ALL | Change of Colony-forming Units (CFU) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) | Week 4 | 26113.0 CFU per gram sputum | Standard Error 27280.98 |
| Tobramycin ALL | Change of Colony-forming Units (CFU) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) | Week 8 | 56285.0 CFU per gram sputum | Standard Error 28022.28 |
p-value: 0.3502ANOVA
Secondary
Change of Forced Expiratory Volume at 1 Second(FEV1) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle)
Change of FEV1 (Forced expiry volume in the first second) measured by Spirometry
Time frame: week 4, week 8
Population: Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tobramycin ALL | Change of Forced Expiratory Volume at 1 Second(FEV1) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) | Week 4 | 77.481 % predicted | Standard Error 4.9877 |
| Tobramycin ALL | Change of Forced Expiratory Volume at 1 Second(FEV1) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) | Week 8 | 78.705 % predicted | Standard Error 5.4782 |
p-value: 0.3963ANOVA
Secondary
Change of Lung Clearance Index (LCI) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle)
The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal.
Time frame: week 4, week 8
Population: Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tobramycin ALL | Change of Lung Clearance Index (LCI) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) | Week 4 | 17.101 Units on a scale | Standard Error 0.8409 |
| Tobramycin ALL | Change of Lung Clearance Index (LCI) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) | Week 8 | 16.489 Units on a scale | Standard Error 1.1473 |
p-value: 0.4249ANOVA