Pneumonia, Bacterial
Conditions
Keywords
Gram-negative pneumonia, Aerosol antibiotics, Mechanical ventilation, Amikacin, Fosfomycin, Pneumonia, Bacterial, Pneumonia, Bacterial Infections, Lung Diseases, Respiratory Tract Diseases, Respiratory Tract Infections, Anti-Bacterial Agents, Anti-Infective Agents, Therapeutic Uses, Pharmacologic Actions
Brief summary
To demonstrate the safety and efficacy of adjunctive therapy with the Amikacin fosfomycin inhalation system (AFIS) versus aerosolized placebo to treat Gram-negative pneumonia in mechanically ventilated patients receiving IV antibiotics.
Detailed description
The primary purpose of this study is to demonstrate the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS). AFIS consists of amikacin solution and fosfomycin solution, delivered by aerosol to the lungs via the PARI Investigational eFlow Inline System (eFlow Inline System). All patients will receive a standardized course of intravenous (IV) antibiotics for a minimum of 7 days. Patients will be randomized to receive 10 days of treatment with either AFIS or placebo, in addition to the IV therapy. The primary efficacy endpoint is defined as the change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of study drug. The study was designed to enroll up to 150 patients with the desire to enroll at least 140 patients with gram negative pneumonia. The study was terminated at 143 when that goal was achieved
Interventions
300 mg of amikacin and 120 mg of fosfomycin twice daily for 10 days to be administered by aerosol via the eFlow Inline System
Placebo twice daily for 10 days to be administered by aerosol the eFlow Inline System
Sponsors
Cardeas Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Males and non-pregnant, non-lactating females, ≥ 18 years and ≤ 80 years of age * Intubated and mechanically ventilated * Diagnosis of pneumonia, defined as presence of a new or progressive infiltrate(s) on the most recent chest radiograph prior to screening, as determined by the treating physician * Signs of infection (within 24 hours prior to screening): 1. Fever (\> 38ºC or \> 100.4ºF); or 2. Leukopenia (\< 4,000 WBC/mm3) or leukocytosis (≥ 12,000 WBC/mm3) * Impaired oxygenation (within 24 hours prior to screening): a. PaO2/FiO2 ≤ 350 mmHg * Acute Physiology and Chronic Health Evaluation (APACHE) II score \> 10 (within 24 hours prior to screening) * Presence, or high suspicion, of Gram-negative organism(s) by either Gram stain or culture of respiratory secretions from a sample obtained within the previous 7 days (enrollment can occur before culture results are available)
Exclusion criteria
* History of hypersensitivity to amikacin, other aminoglycosides, fosfomycin, imipenem, meropenem, or colistin * Received systemic antibiotic therapy for this episode of Gram-negative pneumonia for greater than 72 hours at the time of randomization * PaO2/FiO2 ≤ 100 mmHg and diffuse infiltrates on Chest X-ray * Refractory septic shock (severe sepsis plus unstable hypotension, in spite of adequate fluid resuscitation and vasopressors) * Any of the following conditions that interfere with the assessment or interpretation of the diagnosis or response to therapy: 1. chest trauma with ongoing loss of stability of the thoracic cage following a fracture of the sternum, ribs, or both; 2. increased amounts of fluid in the lung cavities requiring chest tube drainage; 3. lung cancer within the last 2 years; 4. lung abscess(s); 5. anatomical bronchial obstruction; 6. suspected atypical pneumonia; 7. chemical pneumonitis (e.g., inhalation injury); 8. cystic fibrosis * Immunocompromised patients, including those with neutropenia NOT due to the current infection (absolute neutrophil count \< 500/mm3), leukemia, lymphoma, human immunodeficiency virus (HIV) infection with CD4 count \< 200 cells/mm3, or splenectomy; those who are early post-transplantation (\< 3 months post-transplant, or \> 3 months post-transplant with evidence of organ rejection by clinical criteria, pathologic confirmation, or modification of immunosuppression within the past 4 weeks), are on cytotoxic chemotherapy, or are on high-dose steroids (e.g., \> 40 mg of prednisone or its equivalent \[\> 160 mg hydrocortisone, \> 32 mg methylprednisolone, \> 6 mg dexamethasone, \> 200 mg cortisone\] daily for \> 2 weeks) * Evidence of significant renal impairment (serum creatinine \> 4.0 mg/dL within 24 hours prior to screening). If serum creatinine is \>2.0 mg/dL, site must be capable of performing continuous renal replacement therapy, if clinically indicated. Patients with serum creatinine \> 4.0 mg/dL and being treated with continuous renal replacement therapy (continuous venous-venous hemofiltration or continuous venous-venous hemodialysis) or chronic hemodialysis are eligible * Evidence of ototoxicity (history of hearing aid use prior to current hospitalization) * Evidence of hepatotoxicity (alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \>3X the upper limit of normal value within 24 hours prior to screening) * Positive urine and/or serum beta-hCG pregnancy test (only in women of reproductive age) * On mechanical ventilation for \> 28 days * Glasgow Coma Scale score =3 at Screening * Participating in or has participated in other investigational interventional studies (drug or device) within the last 30 days (or 5 times the half-life of the previously administered investigational compound, whichever is longer) prior to study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Pulmonary Infection Score (CPIS) For Each Patient, Value Obtained From a Daily Assessment Over the 10 Day Study Period Was Compared to Baseline, and the LSM Data Represent the Change From Baseline Data Over All Days . | 10 day treatment period. | Change from baseline in Clinical Pulmonary Infection Score (CPIS) For each patient, value obtained from a daily assessment over the 10 day study period was compared to baseline, and the LSM data represent the change from baseline data over all days. Daily CPIS will be determined by one blinded, central reviewer in order to minimize inter-observer variability. The scale ranges from 0 to 13, with 13 being the worst. The value of zero would be a healthy patient with no evidence of pneumonia. For each patient, there was a daily assessment for the 10 day study period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Endpoint of Mortality and Ventilator-free Days | Day 1- Day 28 | The hierarchical composite endpoint of mortality, then ventilator-free days. The table reflects winners of matched pairs, ties are not noted. |
| Number of Days Free of Mechanical Ventilation From Day 1 Through Day 28 | Day 1 - Day 28 | Number of days free of mechanical ventilation from Day 1 through Day 28 mean days. |
| Number of ICU Days From Day 1 Through Day 28 | Day 1 - Day 28 | — |
| Composite Endpoint of Mortality and Clinical Cure | Day 1 - Day 28 | The hierarchical composite endpoint of mortality, then clinical cure (defined as both absence of Gram-negative bacteria and CPIS at Day 14 \< 6). The tables reflect a winner of matched pairs, ties are not noted. |
| Mortality From Day 1 Through Day 28 | Day 1 - Day 28 | Mortality from Day 1 through Day 28, all causes, does not reflect just infection only |
| Clinical Relapse Rate | Day 11 - Day 28 | Clinical relapse rates (defined as a new episode of pneumonia requiring reinstitution of IV antibiotics) from Day 11 through Day 28 |
| Microbiological Response Rates in Patients Positive for Multi-drug Resistant Gram-negative Bacteria | Day 14 | Microbiological response rates at Day 14 in patients whose pre-study treatment bronchoalveolar lavage (BAL) was positive for multi-drug resistant Gram-negative bacteria. Response is defined as not have a positive tracheal aspirate culture on Day 14 |
Countries
France, Greece, Hungary, Puerto Rico, Spain, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
The trial was designed to have 150 patients, hoping to have at least 140 patients with proven gram negative pneumonia. The trial was terminated at 143 when that goal was achieved.
Participants by arm
| Arm | Count |
|---|---|
| Amikacin Fosfomycin Inhalation Solution 300 mg of amikacin and 120 mg of fosfomycin twice daily for 10 days to be administered by aerosol via the eFlow Inline System.
Amikacin fosfomycin inhalation solution: 300 mg of amikacin and 120 mg of fosfomycin twice daily for 10 days to be administered by aerosol via the eFlow Inline System | 71 |
| Aerosolized Placebo Aerosolized placebo twice daily for 10 days administered using the eFlow Inline System
Aerosolized placebo: Placebo twice daily for 10 days to be administered by aerosol the eFlow Inline System | 72 |
| Total | 143 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 16 | 11 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Amikacin Fosfomycin Inhalation Solution | Aerosolized Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 35 Participants | 43 Participants | 78 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants | 29 Participants | 65 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 41 Participants | 82 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 28 Participants | 29 Participants | 57 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 22 Participants | 24 Participants | 46 Participants |
| Race (NIH/OMB) White | 43 Participants | 43 Participants | 86 Participants |
| Region of Enrollment Europe | 58 participants | 53 participants | 111 participants |
| Region of Enrollment United States | 13 participants | 19 participants | 32 participants |
| Sex: Female, Male Female | 19 Participants | 25 Participants | 44 Participants |
| Sex: Female, Male Male | 52 Participants | 47 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 71 | 58 / 72 |
| serious Total, serious adverse events | 28 / 71 | 27 / 72 |
Outcome results
Primary
Change From Baseline in Clinical Pulmonary Infection Score (CPIS) For Each Patient, Value Obtained From a Daily Assessment Over the 10 Day Study Period Was Compared to Baseline, and the LSM Data Represent the Change From Baseline Data Over All Days .
Change from baseline in Clinical Pulmonary Infection Score (CPIS) For each patient, value obtained from a daily assessment over the 10 day study period was compared to baseline, and the LSM data represent the change from baseline data over all days. Daily CPIS will be determined by one blinded, central reviewer in order to minimize inter-observer variability. The scale ranges from 0 to 13, with 13 being the worst. The value of zero would be a healthy patient with no evidence of pneumonia. For each patient, there was a daily assessment for the 10 day study period.
Time frame: 10 day treatment period.
Population: MITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Amikacin Fosfomycin Inhalation Solution | Change From Baseline in Clinical Pulmonary Infection Score (CPIS) For Each Patient, Value Obtained From a Daily Assessment Over the 10 Day Study Period Was Compared to Baseline, and the LSM Data Represent the Change From Baseline Data Over All Days . | -0.76 units on a scale | Standard Error 0.403 |
| Aerosolized Placebo | Change From Baseline in Clinical Pulmonary Infection Score (CPIS) For Each Patient, Value Obtained From a Daily Assessment Over the 10 Day Study Period Was Compared to Baseline, and the LSM Data Represent the Change From Baseline Data Over All Days . | -0.88 units on a scale | Standard Error 0.391 |
Secondary
Clinical Relapse Rate
Clinical relapse rates (defined as a new episode of pneumonia requiring reinstitution of IV antibiotics) from Day 11 through Day 28
Time frame: Day 11 - Day 28
Population: MITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amikacin Fosfomycin Inhalation Solution | Clinical Relapse Rate | 10 participants |
| Aerosolized Placebo | Clinical Relapse Rate | 14 participants |
Secondary
Composite Endpoint of Mortality and Clinical Cure
The hierarchical composite endpoint of mortality, then clinical cure (defined as both absence of Gram-negative bacteria and CPIS at Day 14 \< 6). The tables reflect a winner of matched pairs, ties are not noted.
Time frame: Day 1 - Day 28
Population: MITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amikacin Fosfomycin Inhalation Solution | Composite Endpoint of Mortality and Clinical Cure | Mortality first | 10 participants |
| Amikacin Fosfomycin Inhalation Solution | Composite Endpoint of Mortality and Clinical Cure | Clinical Cure first | 15 participants |
| Aerosolized Placebo | Composite Endpoint of Mortality and Clinical Cure | Mortality first | 10 participants |
| Aerosolized Placebo | Composite Endpoint of Mortality and Clinical Cure | Clinical Cure first | 18 participants |
Secondary
Composite Endpoint of Mortality and Ventilator-free Days
The hierarchical composite endpoint of mortality, then ventilator-free days. The table reflects winners of matched pairs, ties are not noted.
Time frame: Day 1- Day 28
Population: MITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amikacin Fosfomycin Inhalation Solution | Composite Endpoint of Mortality and Ventilator-free Days | Mortality first | 10 participants |
| Amikacin Fosfomycin Inhalation Solution | Composite Endpoint of Mortality and Ventilator-free Days | Ventilator free days | 13 participants |
| Aerosolized Placebo | Composite Endpoint of Mortality and Ventilator-free Days | Mortality first | 10 participants |
| Aerosolized Placebo | Composite Endpoint of Mortality and Ventilator-free Days | Ventilator free days | 27 participants |
Secondary
Microbiological Response Rates in Patients Positive for Multi-drug Resistant Gram-negative Bacteria
Microbiological response rates at Day 14 in patients whose pre-study treatment bronchoalveolar lavage (BAL) was positive for multi-drug resistant Gram-negative bacteria. Response is defined as not have a positive tracheal aspirate culture on Day 14
Time frame: Day 14
Population: patients with MDR bacteria at baseline BAL
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amikacin Fosfomycin Inhalation Solution | Microbiological Response Rates in Patients Positive for Multi-drug Resistant Gram-negative Bacteria | 10 Participants |
| Aerosolized Placebo | Microbiological Response Rates in Patients Positive for Multi-drug Resistant Gram-negative Bacteria | 7 Participants |
Secondary
Mortality From Day 1 Through Day 28
Mortality from Day 1 through Day 28, all causes, does not reflect just infection only
Time frame: Day 1 - Day 28
Population: MITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amikacin Fosfomycin Inhalation Solution | Mortality From Day 1 Through Day 28 | 17 participants |
| Aerosolized Placebo | Mortality From Day 1 Through Day 28 | 12 participants |
Secondary
Number of Days Free of Mechanical Ventilation From Day 1 Through Day 28
Number of days free of mechanical ventilation from Day 1 through Day 28 mean days.
Time frame: Day 1 - Day 28
Population: MITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amikacin Fosfomycin Inhalation Solution | Number of Days Free of Mechanical Ventilation From Day 1 Through Day 28 | 9.8 Days ± SD | Standard Deviation 9.71 |
| Aerosolized Placebo | Number of Days Free of Mechanical Ventilation From Day 1 Through Day 28 | 12.5 Days ± SD | Standard Deviation 9.72 |
Secondary
Number of ICU Days From Day 1 Through Day 28
Time frame: Day 1 - Day 28
Population: MITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amikacin Fosfomycin Inhalation Solution | Number of ICU Days From Day 1 Through Day 28 | 28.9 Days | Standard Deviation 12.44 |
| Aerosolized Placebo | Number of ICU Days From Day 1 Through Day 28 | 26.2 Days | Standard Deviation 12.44 |