Cystic Fibrosis (CF)
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 trial will be a double-blind, placebo-controlled study to evaluate the safety, tolerability and efficacy of levofloxacin administered as MP-376 of three dosage regimens given for 28 days by the aerosol route to CF patients. Study with completed results acquired from Horizon in 2024.
Interventions
DRUGMP-376
3 dose regimens of MP-376 administered twice daily (BID) or once daily (QD) for 28 days
DRUGPlacebo
same frequency as study drug using the same nebulizer
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(selected): * \> 16 years of age * Confirmed Diagnosis of Cystic Fibrosis * Positive sputum culture for P. aeruginosa within the past 18 months * Patients are able to elicit a forced expiratory volume in 1 second (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 30 days * Able to reproducibly produce sputum and perform spirometry
Exclusion criteria
(selected): * Use of any nebulized or systemic antibiotics within 30 days prior to baseline * History of hypersensitivity to fluoroquinolones or intolerance with aerosol medication * Evidence of acute upper within 10 days or lower respiratory infections within 30 days prior to dosing * Creatine clearance \< 50mg/ml, aspartate transaminase (AST), alanine transaminase (ALT) or total bilirubin \>/= 3 x upper limit of normal (ULN) at Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in P. Aeruginosa Density | from baseline to end of treatment (28 days) | Patients were required to cough deeply and then spit sputum into a sterile container. The bacteria contained in the sputum sample was incubated in a laboratory and the number of P. aeruginosa colony forming units per gram of sputum (CFU/g) was determined. The difference in CFUs/g were then compared from baseline to the conclusion of the 28 day treatment period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Administration of Other Anti-pseudomonal Antimicrobials | from baseline until final study visit (up to 56 days) | Time to administration of other anti-pseudomonal antimicrobials in patients with at least one of the following: decreased exercise tolerance, increased cough, increased sputum/chest congestion, or decreased appetite; 25th percentile data reported |
| Percent Change in Forced Expiratory Volume in 1 Second (FEV1) | from baseline to end of the 28-day treatment period (28 days) | Percent change in the amount of air the patient could exhale in 1 second |
| Change in FEV1 Percent Predicted | from baseline to the end of the treatment 28-day treatment period (28 days) | Change in the predicted percent of air the patient could exhale in one second |
| Changes in Respiratory Domain Scores of Cystic Fibrosis Questionnaire - Revised (CFQ-R) | from baseline to the end of the 28-day treatment period (28 days) | Change in the score from 0 to 100 that a patient reports for their respiratory symptoms in the CFQ-R. An increase in score illustrates an improvement in symptoms. An increase of 4 or more is considered clinically significant |
| Changes in Susceptability Patterns of Isolated Organisms | from baseline until the end of the 28-day treatment period (28 days) | All isolates of P. aeruginosa cultures grown from patient sputum samples were evaluated to see whether the minimum concentration of levofloxacin needed to inhibit growth of the bacteria (i.e., minimum inhibitory concentration; MIC) had increased; 2. The MIC50 and MIC90 values were calculated as the 50th percentile value and the 90th percentile value, respectively. Note that percentile values between dilution values were rounded up to the nearest dilution value |
Countries
Germany, Netherlands, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo Group | 37 |
| MP-376 120 mg QD MP-376 120 mg Once Daily (QD) Group | 38 |
| MP-376 240 mg QD MP-376 240 mg Once Daily (QD) Group | 37 |
| MP-376 240 mg BID MP-376 240 mg Twice Daily (BID) Group | 39 |
| Total | 151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 1 | 2 |
| Overall Study | Other reason | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | MP-376 120 mg QD | MP-376 240 mg QD | MP-376 240 mg BID | Total |
|---|---|---|---|---|---|
| Age, Continuous | 30.1 years STANDARD_DEVIATION 9.94 | 28.0 years STANDARD_DEVIATION 6.86 | 27.5 years STANDARD_DEVIATION 9.05 | 29.2 years STANDARD_DEVIATION 9.98 | 28.7 years STANDARD_DEVIATION 9.02 |
| Region of Enrollment Europe | 7 Participants | 6 Participants | 7 Participants | 7 Participants | 27 Participants |
| Region of Enrollment United States | 30 Participants | 32 Participants | 30 Participants | 32 Participants | 124 Participants |
| Sex: Female, Male Female | 18 Participants | 18 Participants | 16 Participants | 14 Participants | 66 Participants |
| Sex: Female, Male Male | 19 Participants | 20 Participants | 21 Participants | 25 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 37 | 33 / 38 | 32 / 37 | 33 / 39 |
| serious Total, serious adverse events | 4 / 37 | 1 / 38 | 4 / 37 | 4 / 39 |
Outcome results
Primary
Change in P. Aeruginosa Density
Patients were required to cough deeply and then spit sputum into a sterile container. The bacteria contained in the sputum sample was incubated in a laboratory and the number of P. aeruginosa colony forming units per gram of sputum (CFU/g) was determined. The difference in CFUs/g were then compared from baseline to the conclusion of the 28 day treatment period
Time frame: from baseline to end of treatment (28 days)
Population: Modified Intent-to-Treat (MITT; patients who received at least one dose of study drug)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in P. Aeruginosa Density | 0.23 log10 CFU/g sputum | Standard Error 0.22 |
| MP-376 120 mg QD | Change in P. Aeruginosa Density | -0.31 log10 CFU/g sputum | Standard Error 0.227 |
| MP-376 240 mg QD | Change in P. Aeruginosa Density | -0.31 log10 CFU/g sputum | Standard Error 0.22 |
| MP-376 240 mg BID | Change in P. Aeruginosa Density | -0.73 log10 CFU/g sputum | Standard Error 0.222 |
Comparison: LS Mean Differencep-value: 0.001495% CI: [-1.54, -0.38]Mixed Models Analysis
Secondary
Change in FEV1 Percent Predicted
Change in the predicted percent of air the patient could exhale in one second
Time frame: from baseline to the end of the treatment 28-day treatment period (28 days)
Population: MITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in FEV1 Percent Predicted | -2.39 Percent | Standard Error 2.37 |
| MP-376 120 mg QD | Change in FEV1 Percent Predicted | 1.96 Percent | Standard Error 2.402 |
| MP-376 240 mg QD | Change in FEV1 Percent Predicted | 3.10 Percent | Standard Error 2.361 |
| MP-376 240 mg BID | Change in FEV1 Percent Predicted | 8.55 Percent | Standard Error 2.358 |
Comparison: LS Mean Difference Between Placebo and MP-376 240 mg BID groupsp-value: 0.000895% CI: [4.63, 17.25]Mixed Models Analysis
Secondary
Changes in Respiratory Domain Scores of Cystic Fibrosis Questionnaire - Revised (CFQ-R)
Change in the score from 0 to 100 that a patient reports for their respiratory symptoms in the CFQ-R. An increase in score illustrates an improvement in symptoms. An increase of 4 or more is considered clinically significant
Time frame: from baseline to the end of the 28-day treatment period (28 days)
Population: MITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Respiratory Domain Scores of Cystic Fibrosis Questionnaire - Revised (CFQ-R) | -0.44 units on a scale | Standard Error 2.715 |
| MP-376 120 mg QD | Changes in Respiratory Domain Scores of Cystic Fibrosis Questionnaire - Revised (CFQ-R) | 2.00 units on a scale | Standard Error 2.728 |
| MP-376 240 mg QD | Changes in Respiratory Domain Scores of Cystic Fibrosis Questionnaire - Revised (CFQ-R) | 0.31 units on a scale | Standard Error 2.689 |
| MP-376 240 mg BID | Changes in Respiratory Domain Scores of Cystic Fibrosis Questionnaire - Revised (CFQ-R) | 4.06 units on a scale | Standard Error 2.69 |
Comparison: LS Mean Difference from MP-376 240 mg BID to placebo groupsp-value: 0.217495% CI: [-2.68, 11.67]Mixed Models Analysis
Secondary
Changes in Susceptability Patterns of Isolated Organisms
All isolates of P. aeruginosa cultures grown from patient sputum samples were evaluated to see whether the minimum concentration of levofloxacin needed to inhibit growth of the bacteria (i.e., minimum inhibitory concentration; MIC) had increased; 2. The MIC50 and MIC90 values were calculated as the 50th percentile value and the 90th percentile value, respectively. Note that percentile values between dilution values were rounded up to the nearest dilution value
Time frame: from baseline until the end of the 28-day treatment period (28 days)
Population: MITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Changes in Susceptability Patterns of Isolated Organisms | Baseline Minimum Inhibitory Concentration (MIC)50 | 4 ug/mL |
| Placebo | Changes in Susceptability Patterns of Isolated Organisms | Day 28 MIC for 50% (MIC50) | 4 ug/mL |
| Placebo | Changes in Susceptability Patterns of Isolated Organisms | Baseline MIC for 90% (MIC90) | 16 ug/mL |
| Placebo | Changes in Susceptability Patterns of Isolated Organisms | Day 28 MIC90 | 8 ug/mL |
| MP-376 120 mg QD | Changes in Susceptability Patterns of Isolated Organisms | Day 28 MIC for 50% (MIC50) | 4 ug/mL |
| MP-376 120 mg QD | Changes in Susceptability Patterns of Isolated Organisms | Baseline MIC for 90% (MIC90) | 32 ug/mL |
| MP-376 120 mg QD | Changes in Susceptability Patterns of Isolated Organisms | Day 28 MIC90 | 16 ug/mL |
| MP-376 120 mg QD | Changes in Susceptability Patterns of Isolated Organisms | Baseline Minimum Inhibitory Concentration (MIC)50 | 4 ug/mL |
| MP-376 240 mg QD | Changes in Susceptability Patterns of Isolated Organisms | Baseline MIC for 90% (MIC90) | 16 ug/mL |
| MP-376 240 mg QD | Changes in Susceptability Patterns of Isolated Organisms | Day 28 MIC for 50% (MIC50) | 4 ug/mL |
| MP-376 240 mg QD | Changes in Susceptability Patterns of Isolated Organisms | Day 28 MIC90 | 16 ug/mL |
| MP-376 240 mg QD | Changes in Susceptability Patterns of Isolated Organisms | Baseline Minimum Inhibitory Concentration (MIC)50 | 4 ug/mL |
| MP-376 240 mg BID | Changes in Susceptability Patterns of Isolated Organisms | Day 28 MIC90 | 32 ug/mL |
| MP-376 240 mg BID | Changes in Susceptability Patterns of Isolated Organisms | Day 28 MIC for 50% (MIC50) | 4 ug/mL |
| MP-376 240 mg BID | Changes in Susceptability Patterns of Isolated Organisms | Baseline Minimum Inhibitory Concentration (MIC)50 | 4 ug/mL |
| MP-376 240 mg BID | Changes in Susceptability Patterns of Isolated Organisms | Baseline MIC for 90% (MIC90) | 16 ug/mL |
Secondary
Percent Change in Forced Expiratory Volume in 1 Second (FEV1)
Percent change in the amount of air the patient could exhale in 1 second
Time frame: from baseline to end of the 28-day treatment period (28 days)
Population: MITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change in Forced Expiratory Volume in 1 Second (FEV1) | -2.36 Percent change | Standard Error 2.085 |
| MP-376 120 mg QD | Percent Change in Forced Expiratory Volume in 1 Second (FEV1) | 1.93 Percent change | Standard Error 2.114 |
| MP-376 240 mg QD | Percent Change in Forced Expiratory Volume in 1 Second (FEV1) | 2.56 Percent change | Standard Error 2.077 |
| MP-376 240 mg BID | Percent Change in Forced Expiratory Volume in 1 Second (FEV1) | 6.25 Percent change | Standard Error 2.081 |
Comparison: LS Mean Difference Between MP-376 240 mg and Placebo groupsp-value: 0.002695% CI: [3.05, 14.17]Mixed Models Analysis
Secondary
Time to Administration of Other Anti-pseudomonal Antimicrobials
Time to administration of other anti-pseudomonal antimicrobials in patients with at least one of the following: decreased exercise tolerance, increased cough, increased sputum/chest congestion, or decreased appetite; 25th percentile data reported
Time frame: from baseline until final study visit (up to 56 days)
Population: MITT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Time to Administration of Other Anti-pseudomonal Antimicrobials | 31 days |
| MP-376 120 mg QD | Time to Administration of Other Anti-pseudomonal Antimicrobials | NA days |
| MP-376 240 mg QD | Time to Administration of Other Anti-pseudomonal Antimicrobials | 56 days |
| MP-376 240 mg BID | Time to Administration of Other Anti-pseudomonal Antimicrobials | 59 days |
Comparison: Hazard Ratio for need of anti-pseudomonal antimicrobials; Estimates are obtained from a Cox proportional hazards regression model including terms for treatment, region, baseline P.aeruginosa density (log10 ), highest baseline MIC of levofloxacin against P. aeruginosa (log2 ), and baseline percent predicted FEV1 (quartiles)p-value: 0.000795% CI: [0.09, 0.52]Regression, Cox