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. Decreased efficacy, intolerance and high treatment burden with currently available therapies indicate a need for additional therapies. MP-376 (Aeroquin™) is a novel formulation of the fluoroquinolone levofloxacin that has been optimized for aerosol delivery. Preclinical and clinical studies conducted to date show that aerosol doses of MP-376 are safe and well tolerated, exert an antimicrobial effect, improve lung function and reduce the need for other anti-pseudomonal antibiotics. High concentrations of levofloxacin in the lung delivered as MP-376 are active against CF pathogens including those with high minimum inhibitory concentration (MIC) levels to aminoglycosides such as tobramycin (TOBI®) and other inhaled antimicrobial agents. Inhaled MP-376 can be delivered rapidly and efficiently using a customized PARI investigational configuration of the eFlow® nebulizer system.
Detailed description
This trial will be a double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin administered as MP-376 given for 28 days by the aerosol route to CF patients. Study with completed results acquired from Horizon in 2024.
Interventions
DRUGAeroquin
Inhalation Solution
DRUGPlacebo
Inhalation Solution
Sponsors
Forest Laboratories
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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 at screening and 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 antimicrobials 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 intolerance with aerosol medication * Evidence of respiratory infections within 14 days prior to dosing * CrCl \< 20ml/min or \< 20ml/min/1.73 m2 at Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to an Exacerbation | Baseline to end of study (up to 59 days) | The start of the exacerbation was determined by the earliest date at which a participant concurrently met at least 4 of the 12 modified Fuchs symptoms/signs; discontinued from the study early; died; or received an antipseudomonal agent for an event that did not meet modified Fuchs criteria but was determined to be an exacerbation by the Blinded Exacerbation. Fuchs symptoms/signs; * Change in sputum * New or increased hemoptysis * Increased cough * Increased dyspnea * Malaise, fatigue or lethargy * Temperature above 38oC * Anorexia or weight loss * Sinus pain or tenderness * Change in sinus discharge * Change in physical examination of the chest * Decrease in pulmonary function by 10 percent or more from a previously recorded value * Radiographic changes indicative of pulmonary infection Median and 95%Ci were estimated using Kaplan Meier estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. LSMean and standard are determined from a repeated measures model with terms for treatment, visit, treatment\*visit, region (US, non-US), age (12-18 years, \>18 years), baseline FEV1 (\<55%, \>=55%), and baseline organism log density. |
| 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. LSMean and standard error were determined from a repeated measures model with terms for treatment, visit, treatment\*visit, region (US, non-US), age (12 to 18 years, \> 18 years), Baseline FEV1 (\<55%, ≥ 55%), and Baseline value. |
| Relative Change From Baseline in Percent Predicted 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 are determined from a repeated measures model with terms for treatment, visit, treatment\*visit, region (US, non-US), age (12-18 years, \>18 years), and baseline FEV1 (\<55%, \>=55%). |
| Absolute Change 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 are determined from a repeated measures model with terms for treatment, visit, treatment\*visit, region (US, non-US), age (12-18 years, \>18 years), and baseline FEV1 (\<55%, \>=55%). |
| Time to First Hospitalization | Baseline to end of study (up to 59 days) | Median and 95%CI was estimated using Kaplan Meier estimates. |
| Number of Participants With Treatment Emergent Adverse Events | From start of study until end of study (Up to 59 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 |
| Time to Administration of Other Systemic and/or Inhaled Antipseudomonal Antimicrobials | Baseline to end of study (up to 59 days) | Participants who had at least one of four worsening respiratory symptoms (increased cough, increased sputum/chest congestion, decreased exercise tolerance, decreased appetite) at the time of administration of the anti-pseudomonal antimicrobial agent were included in the analysis. Median and 95% CI are estimated using Kaplan Meier estimates. |
Countries
Australia, Canada, Israel, New Zealand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aeroquin 240 mg Participants received 240 mg of Aeroquin by inhalation route, BID for a period of 28 days. | 219 |
| Placebo Participants placebo matching Aeroquin by inhalation route, BID for a period of 28 days. | 110 |
| Total | 329 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Miscellaneous | 2 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Aeroquin 240 mg |
|---|---|---|---|
| Age, Continuous | 28.8 years STANDARD_DEVIATION 10.94 | 29.2 years STANDARD_DEVIATION 10.53 | 29.4 years STANDARD_DEVIATION 10.34 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 19 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 101 Participants | 310 Participants | 209 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 100 Participants | 312 Participants | 212 Participants |
| Sex: Female, Male Female | 47 Participants | 152 Participants | 105 Participants |
| Sex: Female, Male Male | 63 Participants | 177 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 219 | 0 / 110 |
| other Total, other adverse events | 207 / 219 | 106 / 110 |
| serious Total, serious adverse events | 21 / 219 | 11 / 110 |
Outcome results
Primary
Time to an Exacerbation
The start of the exacerbation was determined by the earliest date at which a participant concurrently met at least 4 of the 12 modified Fuchs symptoms/signs; discontinued from the study early; died; or received an antipseudomonal agent for an event that did not meet modified Fuchs criteria but was determined to be an exacerbation by the Blinded Exacerbation. Fuchs symptoms/signs; * Change in sputum * New or increased hemoptysis * Increased cough * Increased dyspnea * Malaise, fatigue or lethargy * Temperature above 38oC * Anorexia or weight loss * Sinus pain or tenderness * Change in sinus discharge * Change in physical examination of the chest * Decrease in pulmonary function by 10 percent or more from a previously recorded value * Radiographic changes indicative of pulmonary infection Median and 95%Ci were estimated using Kaplan Meier estimates.
Time frame: Baseline to end of study (up to 59 days)
Population: Intent-to-treat (IIT) population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aeroquin 240 mg | Time to an Exacerbation | 58 Days |
| Placebo | Time to an Exacerbation | 51.5 Days |
p-value: 0.071595% CI: [0.96, 1.84]Log Rank
Secondary
Absolute Change 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 are determined from a repeated measures model with terms for treatment, visit, treatment\*visit, region (US, non-US), age (12-18 years, \>18 years), and baseline FEV1 (\<55%, \>=55%).
Time frame: Baseline, day 28
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aeroquin 240 mg | Absolute Change in Percent Predicted Forced Expiratory Volume in One Second (FEV1) | 0.08 Percent Predicted FEV1 | Standard Error 0.638 |
| Placebo | Absolute Change in Percent Predicted Forced Expiratory Volume in One Second (FEV1) | 1.49 Percent Predicted FEV1 | Standard Error 0.531 |
p-value: 0.021395% CI: [0.21, 2.6]Repeared Measures Model
Secondary
Change From Baseline in Pseudomonas Aeruginosa Sputum Density
Pseudomonas aeruginosa density was measured as log10 colony-forming units \[CFU\] per gram sputum. LSMean and standard are determined from a repeated measures model with terms for treatment, visit, treatment\*visit, region (US, non-US), age (12-18 years, \>18 years), baseline FEV1 (\<55%, \>=55%), and baseline organism log density.
Time frame: Baseline, Day 28
Population: ITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aeroquin 240 mg | Change From Baseline in Pseudomonas Aeruginosa Sputum Density | 0.04 log10 CFU/g | Standard Error 0.17 |
| Placebo | Change From Baseline in Pseudomonas Aeruginosa Sputum Density | -0.59 log10 CFU/g | Standard Error 0.139 |
p-value: 0.000295% CI: [-0.95, -0.3]Repeated Measures Model
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. LSMean and standard error were determined from a repeated measures model with terms for treatment, visit, treatment\*visit, region (US, non-US), age (12 to 18 years, \> 18 years), Baseline FEV1 (\<55%, ≥ 55%), and Baseline value.
Time frame: Baseline, Day 28
Population: ITT population with available data at specified time point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aeroquin 240 mg | Change From Baseline in the Respiratory Domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R) | 4.66 Score on a scale | Standard Error 1.374 |
| Placebo | Change From Baseline in the Respiratory Domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R) | 4.94 Score on a scale | Standard Error 1.118 |
p-value: 0.833595% CI: [-2.3, 2.85]Repeated Measures Model
Secondary
Number of Participants With Treatment Emergent Adverse Events
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 study (Up to 59 days)
Population: Safety population included all randomized participants in the study who received at least 1 dose of study drug or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aeroquin 240 mg | Number of Participants With Treatment Emergent Adverse Events | 214 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events | 108 participants |
Secondary
Relative Change From Baseline in Percent Predicted 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 are determined from a repeated measures model with terms for treatment, visit, treatment\*visit, region (US, non-US), age (12-18 years, \>18 years), and baseline FEV1 (\<55%, \>=55%).
Time frame: Baseline, Day 28
Population: ITT population with available data at specific timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aeroquin 240 mg | Relative Change From Baseline in Percent Predicted FEV1 | 1.24 Percent Predicted FEV1 | Standard Error 1.041 |
| Placebo | Relative Change From Baseline in Percent Predicted FEV1 | 3.66 Percent Predicted FEV1 | Standard Error 0.866 |
p-value: 0.012295% CI: [0.53, 4.31]Repeated Measures Model
Secondary
Time to Administration of Other Systemic and/or Inhaled Antipseudomonal Antimicrobials
Participants who had at least one of four worsening respiratory symptoms (increased cough, increased sputum/chest congestion, decreased exercise tolerance, decreased appetite) at the time of administration of the anti-pseudomonal antimicrobial agent were included in the analysis. Median and 95% CI are estimated using Kaplan Meier estimates.
Time frame: Baseline to end of study (up to 59 days)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aeroquin 240 mg | Time to Administration of Other Systemic and/or Inhaled Antipseudomonal Antimicrobials | 59 Days |
| Placebo | Time to Administration of Other Systemic and/or Inhaled Antipseudomonal Antimicrobials | 55 Days |
p-value: 0.395% CI: [0.6, 1.12]Log Rank
Secondary
Time to First Hospitalization
Median and 95%CI was estimated using Kaplan Meier estimates.
Time frame: Baseline to end of study (up to 59 days)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aeroquin 240 mg | Time to First Hospitalization | NA Days |
| Placebo | Time to First Hospitalization | NA Days |
p-value: 0.86795% CI: [0.47, 2.04]Log Rank