Cystic Fibrosis
Conditions
Brief summary
Patients with cystic fibrosis (CF) suffer from chronic infections of the lower respiratory tract that can be caused by one or multiple bacteria, including Pseudomonas aeruginosa, which has been particularly problematic to eradicate and been implicated as the major cause of morbidity and mortality in CF patients. Aerosol delivery of antibiotics directly to the lung increases the local concentrations of antibiotic at the site of infection resulting in improved antimicrobial effects compared to systemic administration. Bacterial resistance to current aerosol antibiotic treatments indicate a need for improved therapies to treat CF patients with pulmonary infections caused by multi-drug resistant Pseudomonas aeruginosa and other bacteria. High concentrations of MP-376 delivered directly to the lung are projected to have antimicrobial effects on even the most resistant organisms.
Detailed description
This study will assess the comparative safety of MP-376 (Aeroquin) and Tobramycin Inhalation solution (TIS) \[TOBI® Novartis Pharmaceuticals\] over three consecutive cycles of 28-days treatment followed by 28-days off in stable CF patients with chronic P. aeruginosa lung infection. Efficacy data for MP-376 and TIS at the end of the first 28-day treatment period will also be compared, as well as explored over multiple treatment cycles. Study patients participating in Mpex 209 will be given the option to participate in a six-month open label extension phase of the Mpex 209 protocol. The open label extension will allow enrolled patients to receive three additional courses of MP-376 (levofloxacin inhalation solution, Aeroquin™). Study with completed results acquired from Horizon in 2024.
Interventions
MP-376 (Aeroquin, Levofloxacin solution for Inhalation) 240 mg administered BID for 28-days treatment followed by 28 days off treatment
DRUGTIS (Tobramycin Inhalation Solution)
Tobramycin Inhalation Solution administered BID over 3 consecutive cycles of 28-days treatment followed by 28 days off treatment
Sponsors
Forest Laboratories
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(selected): * \> 12 years of age * Confirmed Diagnosis of Cystic Fibrosis * Positive sputum culture for P. aeruginosa within the past 12 months * Patients are able to elicit an FEV1 \>/= 25% but \</= 85% of predicted value at screening * Have received at least 3 courses of inhaled tobramycin over the preceding 12 months * Clinically stable with no changes in health status within the last 28 days * Able to reproducibly produce sputum and perform spirometry
Exclusion criteria
(selected): * Use of any nebulized or systemic antibiotics within 28 days prior to baseline * History of hypersensitivity to fluoroquinolones or inhaled or systemic aminoglycosides including tobramycin or any excipients * Evidence of acute upper within 10 days or lower respiratory infections within 28 days prior to dosing * CrCl \< 20 at Screening * History of lung transplantation Extension Portion of the Study: Patients enrolled in Mpex 209 are permitted to participate in the open label extension as long as they complete Visit 7 (Day 168), provide informed consent for participation in the open label extension of in the study and are clinically stable, as assessed by the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From start of study until end of the study (up to 168 days) | An AE was defined as any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a Study Drug, whether or not considered related to the Study Drug. An AE could potentially be a new disease, any untoward event, or an exacerbation of a pre-existing condition. AEs included, but were not limited to: Any symptom not previously reported by the patient (medical history) An exacerbation of a pre-existing illness An increase in frequency or intensity of a pre-existing episodic event or condition A condition first detected or diagnosed after Study Drug administration even though the condition may have been present before the start of the study Overdose of Study Drug |
| Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in One Second (FEV1) | Baseline, day 28 | FEV1 was the volume of air exhaled in first second of a forced expiration as measured by spirometer. Least squares (LS) mean and standard error (SE) were determined from an analysis of covariance model with terms for treatment, region (US, non-US), and age (12 to 18 years, \> 18 years), and Baseline FEV1 (\< 55%, . 55%). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Day 28 | FEV1 was the volume of air exhaled in first second of a forced expiration as measured by spirometer. |
| Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Day 28 | FEV1 was the volume of air exhaled in first second of a forced expiration as measured by spirometer. |
| Change From Baseline in Pseudomonas Aeruginosa Sputum Density | Baseline, day 28 | Pseudomonas aeruginosa density was measured as log10 colony-forming units \[CFU\] per gram sputum. |
| Percent Change From Baseline in Average Expired Flow Over the Middle Half of The FVC Maneuver (FEF25-75) | Baseline, day 28 | LSMean and SE were determined from an ANCOVA model with terms for treatment, region (US, non-US), age (12-18 years, \>18 years), baseline FEV1 (\<55%, \>=55%), and baseline as a covariate. |
| Change From Baseline in the Respiratory Domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R) | Baseline, day 28 | The Cystic Fibrosis Questionnaire (CFQ-R) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents and adults with cystic fibrosis (CF). Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. |
| Number of Participants in Each Category of Change From Baseline in the Respiratory Domain of CFQ-R | Baseline, day 28 | The Cystic Fibrosis Questionnaire (CFQ-R) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents and adults with cystic fibrosis (CF). Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. |
| Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | Baseline, day 28 | Pseudomonas aeruginosa density was measured as log10 colony-forming units \[CFU\] per gram sputum. |
| Percent Change From Baseline in Forced Vital Capacity (FVC) | Baseline, day 28 | LSMean and SE were determined from an ANCOVA model with terms for treatment, region (US, non-US), age (12-18 years, \>18 years), baseline FEV1 (\<55%, \>=55%), and baseline as a covariate |
Countries
France, Germany, Ireland, Israel, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tobramycin Inhalation Solution 300 mg Participants received 300 mg of Tobramycin by inhalation route, BID over 3 consecutive 56-day cycles (28 days on treatment and 28 days off treatment). | 90 |
| Levofloxacin Inhalation Solution 240 mg Participants received 240 mg of Levofloxacin by inhalation route, BID over 3 consecutive 56-day cycles (28 days on treatment and 28 days off treatment). | 182 |
| Total | 272 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Phase | Adverse Event | 1 | 6 |
| Core Phase | Lost to Follow-up | 0 | 1 |
| Core Phase | Miscellaneous | 8 | 14 |
| Core Phase | Withdrawal by Subject | 1 | 2 |
| Extension Phase | Adverse Event | 1 | 3 |
| Extension Phase | Miscellaneous | 2 | 2 |
| Extension Phase | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Total | Levofloxacin Inhalation Solution 240 mg | Tobramycin Inhalation Solution 300 mg |
|---|---|---|---|
| Age, Continuous | 28.5 years STANDARD_DEVIATION 9.71 | 28.3 years STANDARD_DEVIATION 9 | 28.9 years STANDARD_DEVIATION 11.05 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 14 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 255 Participants | 168 Participants | 87 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 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 | 5 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 261 Participants | 174 Participants | 87 Participants |
| Sex: Female, Male Female | 118 Participants | 81 Participants | 37 Participants |
| Sex: Female, Male Male | 154 Participants | 101 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 90 | 0 / 182 | 0 / 88 |
| other Total, other adverse events | 88 / 90 | 180 / 182 | 82 / 88 |
| serious Total, serious adverse events | 29 / 90 | 40 / 182 | 22 / 88 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An AE was defined as any unfavorable or unintended sign, symptom, or disease temporally associated with the use of a Study Drug, whether or not considered related to the Study Drug. An AE could potentially be a new disease, any untoward event, or an exacerbation of a pre-existing condition. AEs included, but were not limited to: Any symptom not previously reported by the patient (medical history) An exacerbation of a pre-existing illness An increase in frequency or intensity of a pre-existing episodic event or condition A condition first detected or diagnosed after Study Drug administration even though the condition may have been present before the start of the study Overdose of Study Drug
Time frame: From start of study until end of the study (up to 168 days)
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 90 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 180 participants |
Primary
Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in One Second (FEV1)
FEV1 was the volume of air exhaled in first second of a forced expiration as measured by spirometer. Least squares (LS) mean and standard error (SE) were determined from an analysis of covariance model with terms for treatment, region (US, non-US), and age (12 to 18 years, \> 18 years), and Baseline FEV1 (\< 55%, . 55%).
Time frame: Baseline, day 28
Population: Intent-to-treat population included all participants randomized in the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in One Second (FEV1) | 0.38 percent predicted FEV1 | Standard Error 1.262 |
| Levofloxacin Inhalation Solution 240 mg | Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in One Second (FEV1) | 2.24 percent predicted FEV1 | Standard Error 1.019 |
p-value: 0.148195% CI: [-0.66, 4.39]ANCOVA
Secondary
Change From Baseline in Pseudomonas Aeruginosa Sputum Density
Pseudomonas aeruginosa density was measured as log10 colony-forming units \[CFU\] per gram sputum.
Time frame: Baseline, day 28
Population: ITT population with available data at specified time point
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Change From Baseline in Pseudomonas Aeruginosa Sputum Density | -1.19 log10 CFU per gram | Standard Error 0.243 |
| Levofloxacin Inhalation Solution 240 mg | Change From Baseline in Pseudomonas Aeruginosa Sputum Density | -0.75 log10 CFU per gram | Standard Error 0.196 |
p-value: 0.05395% CI: [-0.01, 0.88]ANCOVA
Secondary
Change From Baseline in the Respiratory Domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R)
The Cystic Fibrosis Questionnaire (CFQ-R) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents and adults with cystic fibrosis (CF). Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time frame: Baseline, day 28
Population: ITT population with available data at specified time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Change From Baseline in the Respiratory Domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R) | -1.31 Score on a scale | Standard Error 1.576 |
| Levofloxacin Inhalation Solution 240 mg | Change From Baseline in the Respiratory Domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R) | 1.88 Score on a scale | Standard Error 1.278 |
p-value: 0.046395% CI: [0.05, 6.32]ANCOVA
Secondary
Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density
Pseudomonas aeruginosa density was measured as log10 colony-forming units \[CFU\] per gram sputum.
Time frame: Baseline, day 28
Population: ITT population with available data at specified time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | > 1.5 log decrease | 20 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | >= 0.5 to <= 1.5 log increase | 4 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | < 0.5 decrease and < 0.5 log increase | 34 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | > 1.5 log increase | 4 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | >= 0.5 to <= 1.5 log decrease | 17 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | > 1.5 log increase | 14 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | > 1.5 log decrease | 32 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | < 0.5 decrease and < 0.5 log increase | 61 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | >= 0.5 to <= 1.5 log increase | 18 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density | >= 0.5 to <= 1.5 log decrease | 36 participants |
Secondary
Number of Participants in Each Category of Change From Baseline in the Respiratory Domain of CFQ-R
The Cystic Fibrosis Questionnaire (CFQ-R) is a disease-specific instrument that measures health-related quality of life (HRQOL) for adolescents and adults with cystic fibrosis (CF). Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time frame: Baseline, day 28
Population: ITT population with available data at specified time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Change From Baseline in the Respiratory Domain of CFQ-R | >= 4 increase | 25 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Change From Baseline in the Respiratory Domain of CFQ-R | < 4 increase and < 4 decrease | 32 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Change From Baseline in the Respiratory Domain of CFQ-R | >= 4 decrease | 34 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Change From Baseline in the Respiratory Domain of CFQ-R | >= 4 increase | 81 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Change From Baseline in the Respiratory Domain of CFQ-R | < 4 increase and < 4 decrease | 49 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Change From Baseline in the Respiratory Domain of CFQ-R | >= 4 decrease | 56 participants |
Secondary
Number of Participants in Each Category of Percent Change From Baseline in FEV1
FEV1 was the volume of air exhaled in first second of a forced expiration as measured by spirometer.
Time frame: Day 28
Population: ITT population with available data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Mild decline (0% < decline < 10%) | 31 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Moderate improvement (10% <= improvement < 20%) | 8 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Mild improvement (0% <= improvement < 10%) | 37 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Significant improvement (improvement >= 20%) | 4 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Moderate decline (decline >=10%, death, or lung transplant) | 13 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Significant improvement (improvement >= 20%) | 3 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Moderate decline (decline >=10%, death, or lung transplant) | 9 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Mild decline (0% < decline < 10%) | 48 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Mild improvement (0% <= improvement < 10%) | 103 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Percent Change From Baseline in FEV1 | Moderate improvement (10% <= improvement < 20%) | 26 participants |
Secondary
Number of Participants in Each Category of Relative Change in Percent Predicted FEV1
FEV1 was the volume of air exhaled in first second of a forced expiration as measured by spirometer.
Time frame: Day 28
Population: ITT population with available data at specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Mild decline (0% < decline < 10%) | 26 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Moderate improvement (10% <= improvement < 20%) | 6 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Mild improvement (0% <= improvement < 10%) | 37 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Significant improvement (improvement >= 20%) | 3 participants |
| Tobramycin Inhalation Solution 300 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Moderate decline (decline >=10%, death, or lung transplant) | 16 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Significant improvement (improvement >= 20%) | 5 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Moderate decline (decline >=10%, death, or lung transplant) | 30 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Mild decline (0% < decline < 10%) | 59 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Mild improvement (0% <= improvement < 10%) | 72 participants |
| Levofloxacin Inhalation Solution 240 mg | Number of Participants in Each Category of Relative Change in Percent Predicted FEV1 | Moderate improvement (10% <= improvement < 20%) | 6 participants |
Secondary
Percent Change From Baseline in Average Expired Flow Over the Middle Half of The FVC Maneuver (FEF25-75)
LSMean and SE were determined from an ANCOVA model with terms for treatment, region (US, non-US), age (12-18 years, \>18 years), baseline FEV1 (\<55%, \>=55%), and baseline as a covariate.
Time frame: Baseline, day 28
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Percent Change From Baseline in Average Expired Flow Over the Middle Half of The FVC Maneuver (FEF25-75) | 4.705 Percent change | Standard Error 8.8115 |
| Levofloxacin Inhalation Solution 240 mg | Percent Change From Baseline in Average Expired Flow Over the Middle Half of The FVC Maneuver (FEF25-75) | 9.673 Percent change | Standard Error 2.2691 |
p-value: 0.08395% CI: [-0.653, 10.59]ANCOVA
Secondary
Percent Change From Baseline in Forced Vital Capacity (FVC)
LSMean and SE were determined from an ANCOVA model with terms for treatment, region (US, non-US), age (12-18 years, \>18 years), baseline FEV1 (\<55%, \>=55%), and baseline as a covariate
Time frame: Baseline, day 28
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tobramycin Inhalation Solution 300 mg | Percent Change From Baseline in Forced Vital Capacity (FVC) | -1.152 Percent change | Standard Error 0.9191 |
| Levofloxacin Inhalation Solution 240 mg | Percent Change From Baseline in Forced Vital Capacity (FVC) | 0.417 Percent change | Standard Error 0.7441 |
p-value: 0.094595% CI: [-0.272, 3.411]ANCOVA