Aerosolized Amikacin and Fosfomycin in Mechanically Ventilated Patients With Gram-negative and / or Gram-positive Bacterial Colonization

A Randomized Double-Blind, Placebo-Controlled, Crossover to Open Label, Phase 2 Study of Aerosolized Amikacin and Fosfomycin Delivered Via the Investigational eFlow® AFIS Inline System in Mechanically Ventilated Patients With Gram-negative and/or Gram-positive Bacterial Colonization

To demonstrate the safety and efficacy of adjunctive therapy with the Amikacin Fosfomycin Inhalation System (AFIS) versus aerosolized placebo in mechanically ventilated patients with Gram-negative and / or Gram-positive bacterial colonization.

Study Overview

• Status: Withdrawn
• Conditions: Pneumonia, Bacterial
• Intervention / Treatment: Drug: Amikacin Fosfomycin Inhalation Solution; Drug: Amikacin Fosfomycin Inhalation Solution; Drug: Aerosolized placebo

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 (AMS) and fosfomycin solution (FFS), delivered by aerosol to the lungs via the Investigational eFlow AFIS Inline System (AFIS Inline System) with tamper evident reservoir. Patients will be randomized to receive 5 days of treatment with either AFIS or placebo, followed by all patients receiving open label AFIS for five days. The primary efficacy endpoint is the change from baseline in tracheal aspirate Gram-negative and/or Gram-positive bacterial density at the end of the 5-day randomized course of study drug.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and non-pregnant, non-lactating females, ≥ 18 years and ≤ 80 years of age
• Intubated and mechanically-ventilated
• Presence of Gram-negative and/or Gram-positive organism(s) by culture of respiratory secretions from a sample obtained within the previous 7 days

Exclusion Criteria:

• History of hypersensitivity to amikacin or fosfomycin.
• Diagnosis of pneumonia, defined as presence of a new or progressive infiltrate(s) on chest radiograph (within 7 days prior to screening), as determined by the treating physician
• Use of systemic antibiotics with efficacy against likely respiratory tract pathogens at the time of randomization
• Severe acute respiratory distress syndrome (defined as 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)
• 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)
• Any of the following conditions that interfere with the assessment or interpretation of the diagnosis or response to therapy: chest trauma with 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; congestive heart failure (leading to a PaO2/FiO2 ratio ≤ 100 mmHg and diffuse infiltrates on Chest X-ray)
• 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, 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)
• Positive urine and/or serum beta-hCG pregnancy test (only in women of reproductive age)
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amikacin Fosfomycin Inhalation Solution; 300 mg of amikacin and 120 mg of fosfomycin to be administered by aerosol via the AFIS Inline System.	Drug: 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 AFIS Inline System; Other Names: Amikacin Fosfomycin Inhalation System (AFIS); eFlow Inline System; Drug: Amikacin Fosfomycin Inhalation Solution; Open-label crossover for all patients Days 6-10; Other Names: Amikacin Fosfomycin Inhalation System (AFIS); eFlow Inline System
Placebo Comparator: Aerosolized Placebo; Aerosolized placebo to be administered by aerosol using the AFIS Inline System.	Drug: 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 AFIS Inline System; Other Names: Amikacin Fosfomycin Inhalation System (AFIS); eFlow Inline System; Drug: Amikacin Fosfomycin Inhalation Solution; Open-label crossover for all patients Days 6-10; Other Names: Amikacin Fosfomycin Inhalation System (AFIS); eFlow Inline System; Drug: Aerosolized placebo; Placebo twice daily for Days 1 -5 to be administered by aerosol using the eFlow Inline System.; Other Names: eFlow Inline System

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in tracheal aspirate Gram-negative and Gram-positive bacterial density	Change from baseline in tracheal aspirate Gram-negative and Gram-positive bacterial density at the end of the 5-day randomized course of study drug	5 day randomized course of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiological response rate in patients with multidrug resistant Gram-negative bacteria	Microbiological response rates at Day 5 in patients whose pre-study treatment tracheal aspirate culture was positive for multidrug resistant (MDR) Gram-negative bacteria	Day 5
Eradication of bacteria	Eradication of bacteria at Days 10, 21, and 28	Days 10, 21, and 28
Clinical worsening	Clinical worsening (defined as requiring institution of IV antibiotics) from Day 1 through Day 28	Day 1 - Day 28
Microbiological response rates	Microbiological response rates at Day 10 in all patients	Day 10
Microbiological response rates in patients with MRSA	Microbiological response rates at Day 5 in patients whose pre-study treatment tracheal aspirate culture was positive for methicillin resistant Staphylococcus aureus (MRSA)	Day 5

Collaborators and Investigators

• Sponsor: Cardeas Pharma
• Investigators: Study Director: Bruce Montgomery, M.D., Cardeas Pharma

Publications and helpful links

Helpful Links

• U.S. FDA Resources
• MedlinePlus related topics: Antibiotics
• MedlinePlus related topics: Pneumonia
• Drug Information available for amikacin
• Drug information available for fosfomycin

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Anticipated): December 1, 2015
• Study Completion (Anticipated): January 1, 2016

Study Registration Dates

• First Submitted: August 14, 2014
• First Submitted That Met QC Criteria: August 14, 2014
• First Posted (Estimate): August 18, 2014

Study Record Updates

• Last Update Posted (Estimate): November 18, 2015
• Last Update Submitted That Met QC Criteria: November 16, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Respiratory Tract Diseases; Anti-Infective Agents; MRSA; Pneumonia; Bacterial Infections; Lung Diseases; Respiratory Tract Infections; Pharmacologic Actions; Amikacin; Mechanical ventilation; Therapeutic Uses; Pneumonia, Bacterial; Anti-Bacterial Agents; Fosfomycin; Gram-negative pneumonia; Aerosol antibiotics
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Pneumonia; Pneumonia, Bacterial; Anti-Infective Agents; Anti-Bacterial Agents; Pharmaceutical Solutions; Amikacin; Fosfomycin
• Other Study ID Numbers: CAP-01-103