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

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ClinicalTrials.gov Identifier: NCT01969799
Recruitment Status : Completed
First Posted : October 25, 2013
Results First Posted : July 2, 2017
Last Update Posted : July 2, 2017
Information provided by (Responsible Party):
Cardeas Pharma

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.

Condition or disease Intervention/treatment Phase
Pneumonia, Bacterial Drug: Amikacin fosfomycin inhalation solution Drug: Aerosolized placebo Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 143 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)
Study Start Date : December 2013
Actual Primary Completion Date : March 2016
Actual Study Completion Date : April 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

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:
  • Amikacin fosfomycin inhalation system (AFIS)
  • eFlow Inline System

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 Name: eFlow Inline System

Primary Outcome Measures :
  1. 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 . [ Time Frame: 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 Outcome Measures :
  1. Composite Endpoint of Mortality and Clinical Cure [ Time Frame: 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.

  2. Composite Endpoint of Mortality and Ventilator-free Days [ Time Frame: 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.

  3. Number of Days Free of Mechanical Ventilation From Day 1 Through Day 28 [ Time Frame: Day 1 - Day 28 ]
    Number of days free of mechanical ventilation from Day 1 through Day 28 mean days.

  4. Number of ICU Days From Day 1 Through Day 28 [ Time Frame: Day 1 - Day 28 ]
  5. Microbiological Response Rates in Patients Positive for Multi-drug Resistant Gram-negative Bacteria [ Time Frame: 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

  6. Mortality From Day 1 Through Day 28 [ Time Frame: Day 1 - Day 28 ]
    Mortality from Day 1 through Day 28, all causes, does not reflect just infection only

  7. Clinical Relapse Rate [ Time Frame: 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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01969799

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United States, California
Los Angeles, California, United States, 90033
United States, Florida
Gainesville, Florida, United States, 32610
Jacksonville, Florida, United States, 32209
United States, Illinois
Chicago, Illinois, United States, 60612
United States, Kentucky
Hazard, Kentucky, United States, 41701
Lexington, Kentucky, United States, 21686
United States, Massachusetts
Boston, Massachusetts, United States, 02119
Burlington, Massachusetts, United States, 01805
Springfield, Massachusetts, United States, 01199
United States, Michigan
Detroit, Michigan, United States, 48202
United States, Missouri
Saint Louis, Missouri, United States, 63110
United States, Nebraska
Omaha, Nebraska, United States, 60198
United States, Oklahoma
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Knoxville, Tennessee, United States, 37920
United States, Texas
El Paso, Texas, United States, 79905
Houston, Texas, United States, 77030
Limoges, Limousin, France, 87042
Orléans, Loiret, France, 45000
Vandoeuvre les Nancy, Meurthe-et-Moselle, France, 54500
Tours, France, 37044
Colombes, Île-de-France, France, 92701
Alexandroupoli, Evros, Greece, 68100
Athens, Greece, 10676
Athens, Greece, 11527
Athens, Greece, 12462
Athens, Greece, 15227
Ioannina, Greece, 45500
Larisa, Greece, 41334
Debrecen, Hajdú-Bihar, Hungary, 4012
Debrecen, Hajdú-Bihar, Hungary, 4043
Budapest, Hungary, 1081
Budapest, Hungary, 1125
Puerto Rico
San Juan, Puerto Rico, 00921
Palma de Majorca, Baleares, Spain, 07010
Getafe, Comunidad de Madrid, Spain, 28905
Barcelona, Spain, 08036
Anakara, Ankara, Turkey, 06100
Ankara, Turkey, 06110
Istanbul, Turkey, 34098
Istanbul, Turkey, 34760
Trabzon, Turkey, 61080
Sponsors and Collaborators
Cardeas Pharma
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Principal Investigator: Marin Kollef, M.D. Washington University School of Medicine
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Cardeas Pharma
ClinicalTrials.gov Identifier: NCT01969799    
Other Study ID Numbers: CAP-01-102
2013-002855-13 ( EudraCT Number )
First Posted: October 25, 2013    Key Record Dates
Results First Posted: July 2, 2017
Last Update Posted: July 2, 2017
Last Verified: March 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Cardeas Pharma:
Gram-negative pneumonia
Aerosol antibiotics
Mechanical ventilation
Pneumonia, Bacterial
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Additional relevant MeSH terms:
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Pneumonia, Bacterial
Respiratory Tract Infections
Lung Diseases
Respiratory Tract Diseases
Bacterial Infections
Bacterial Infections and Mycoses
Anti-Bacterial Agents
Anti-Infective Agents