Aerosolized Amikacin and Fosfomycin in Mechanically Ventilated Patients With Gram-negative Pneumonia

Study Overview
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Brief Summary
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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
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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

Official Title
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A Randomized Blinded, Placebo-Controlled, Phase 2 Study of Aerosolized Amikacin and Fosfomycin Delivered Via the Investigational eFlow® Inline System in Mechanically Ventilated Patients With Gram-negative Bacterial Pneumonia (IASIS)

Conditions
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Pneumonia, Bacterial

Intervention / Treatment
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* Drug: Amikacin fosfomycin inhalation solution
* Drug: Aerosolized placebo


Participation Criteria
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Eligibility Criteria
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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): Fever (> 38ºC or > 100.4ºF); or 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: chest trauma with ongoing loss of stability of the thoracic cage following a fracture of the sternum, ribs, or both; increased amounts of fluid in the lung cavities requiring chest tube drainage; lung cancer within the last 2 years; lung abscess(s); anatomical bronchial obstruction; suspected atypical pneumonia; chemical pneumonitis (e.g., inhalation injury); 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amikacin fosfomycin inhalation solution<br>300 mg of amikacin and 120 mg of fosfomycin twice daily for 10 days to be administered by aerosol via the eFlow Inline System. | Drug: Amikacin fosfomycin inhalation solution<br>* 300 mg of amikacin and 120 mg of fosfomycin twice daily for 10 days to be administered by aerosol via the eFlow Inline System<br>* Other names: eFlow Inline System;|
| Placebo Comparator: Aerosolized placebo<br>Aerosolized placebo twice daily for 10 days administered using the eFlow Inline System | Drug: Aerosolized placebo<br>* Placebo twice daily for 10 days to be administered by aerosol the eFlow Inline System<br>* Other names: eFlow Inline System;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 10 day treatment period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 - Day 28 | 
| 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. | Day 1- Day 28 | 
| 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. | Day 1 - Day 28 | 
| Number of ICU Days From Day 1 Through Day 28 |  | Day 1 - Day 28 | 
| 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 | Day 14 | 
| Mortality From Day 1 Through Day 28 | Mortality from Day 1 through Day 28, all causes, does not reflect just infection only | Day 1 - Day 28 | 
| Clinical Relapse Rate | Clinical relapse rates (defined as a new episode of pneumonia requiring reinstitution of IV antibiotics) from Day 11 through Day 28 | Day 11 - Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Respiratory Tract Diseases, Gram-negative pneumonia, Aerosol antibiotics, Mechanical ventilation, Amikacin, Fosfomycin, Pneumonia, Bacterial, Pneumonia, Bacterial Infections, Lung Diseases, Respiratory Tract Infections, Anti-Bacterial Agents, Anti-Infective Agents, Therapeutic Uses, Pharmacologic Actions