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

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)

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.

Study Overview

• Status: Completed
• Conditions: Pneumonia, Bacterial
• Intervention / Treatment: 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 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

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Tours, France, 37044
  • Limousin
    • Limoges, Limousin, France, 87042
  • Loiret
    • Orléans, Loiret, France, 45000
  • Meurthe-et-Moselle
    • Vandoeuvre les Nancy, Meurthe-et-Moselle, France, 54500
  • Île-de-France
    • Colombes, Île-de-France, France, 92701
• Greece
  • Athens, Greece, 11527
  • Athens, Greece, 12462
  • Athens, Greece, 10676
  • Athens, Greece, 15227
  • Ioannina, Greece, 45500
  • Larisa, Greece, 41334
  • Evros
    • Alexandroupoli, Evros, Greece, 68100
• Hungary
  • Budapest, Hungary, 1125
  • Budapest, Hungary, 1081
  • Hajdú-Bihar
    • Debrecen, Hajdú-Bihar, Hungary, 4012
    • Debrecen, Hajdú-Bihar, Hungary, 4043
• Puerto Rico
  • San Juan, Puerto Rico, 00921
• Spain
  • Barcelona, Spain, 08036
  • Baleares
    • Palma de Majorca, Baleares, Spain, 07010
  • Comunidad de Madrid
    • Getafe, Comunidad de Madrid, Spain, 28905
• Turkey
  • Ankara, Turkey, 06110
  • Istanbul, Turkey, 34760
  • Istanbul, Turkey, 34098
  • Trabzon, Turkey, 61080
  • Ankara
    • Anakara, Ankara, Turkey, 06100
• United States
  • California
    • Los Angeles, California, United States, 90033
  • Florida
    • Gainesville, Florida, United States, 32610
    • Jacksonville, Florida, United States, 32209
  • Illinois
    • Chicago, Illinois, United States, 60612
  • Kentucky
    • Hazard, Kentucky, United States, 41701
    • Lexington, Kentucky, United States, 21686
  • Massachusetts
    • Boston, Massachusetts, United States, 02119
    • Burlington, Massachusetts, United States, 01805
    • Springfield, Massachusetts, United States, 01199
  • Michigan
    • Detroit, Michigan, United States, 48202
  • Missouri
    • Saint Louis, Missouri, United States, 63110
  • Nebraska
    • Omaha, Nebraska, United States, 60198
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
  • Texas
    • El Paso, Texas, United States, 79905
    • Houston, Texas, United States, 77030

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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

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 twice daily for 10 days to be administered by aerosol via the eFlow 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 eFlow Inline System; Other Names: eFlow Inline System; Amikacin fosfomycin inhalation system (AFIS)
PLACEBO_COMPARATOR: Aerosolized placebo; Aerosolized placebo twice daily for 10 days administered using the eFlow Inline System	Drug: Aerosolized placebo; Placebo twice daily for 10 days to be administered by aerosol 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 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

Collaborators and Investigators

• Sponsor: Cardeas Pharma
• Investigators: Principal Investigator: Marin Kollef, M.D., Washington University School of Medicine

Publications and helpful links

General Publications

• Kollef MH, Ricard JD, Roux D, Francois B, Ischaki E, Rozgonyi Z, Boulain T, Ivanyi Z, Janos G, Garot D, Koura F, Zakynthinos E, Dimopoulos G, Torres A, Danker W, Montgomery AB. A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia: IASIS Trial. Chest. 2017 Jun;151(6):1239-1246. doi: 10.1016/j.chest.2016.11.026. Epub 2016 Nov 24.

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: December 1, 2013
• Primary Completion (ACTUAL): March 1, 2016
• Study Completion (ACTUAL): April 1, 2016

Study Registration Dates

• First Submitted: October 22, 2013
• First Submitted That Met QC Criteria: October 22, 2013
• First Posted (ESTIMATE): October 25, 2013

Study Record Updates

• Last Update Posted (ACTUAL): July 2, 2017
• Last Update Submitted That Met QC Criteria: June 4, 2017
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Respiratory Tract Diseases; Anti-Infective Agents; 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; Amikacin; Fosfomycin
• Other Study ID Numbers: CAP-01-102; 2013-002855-13 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED