Clinical trial NCT01969799: Aerosolized Amikacin and Fosfomycin in Mechanically Ventilated Patients With Gram-negative Pneumonia
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pneumonia, Bacterial
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
Lead sponsor: Cardeas Pharma
Sponsor class: INDUSTRY
First posted: 2013-10-25
Enrollment: 143
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: 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 .
timeFrame: 10 day treatment period.
Secondary outcomes:
measure: Composite Endpoint of Mortality and Clinical Cure
timeFrame: Day 1 - Day 28
measure: Composite Endpoint of Mortality and Ventilator-free Days
timeFrame: Day 1- Day 28
measure: Number of Days Free of Mechanical Ventilation From Day 1 Through Day 28
timeFrame: Day 1 - Day 28
measure: Number of ICU Days From Day 1 Through Day 28
timeFrame: Day 1 - Day 28
measure: Microbiological Response Rates in Patients Positive for Multi-drug Resistant Gram-negative Bacteria
timeFrame: Day 14
measure: Mortality From Day 1 Through Day 28
timeFrame: Day 1 - Day 28
measure: Clinical Relapse Rate
timeFrame: Day 11 - Day 28
Other outcomes:
Locations:
city: Los Angeles
country: United States
state: California
city: Gainesville
country: United States
state: Florida
city: Jacksonville
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Hazard
country: United States
state: Kentucky
city: Lexington
country: United States
state: Kentucky
city: Boston
country: United States
state: Massachusetts
city: Burlington
country: United States
state: Massachusetts
city: Springfield
country: United States
state: Massachusetts
city: Detroit
country: United States
state: Michigan
city: Saint Louis
country: United States
state: Missouri
city: Omaha
country: United States
state: Nebraska
city: Oklahoma City
country: United States
state: Oklahoma
city: Knoxville
country: United States
state: Tennessee
city: El Paso
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Limoges
country: France
state: Limousin
city: Orléans
country: France
state: Loiret
city: Vandoeuvre les Nancy
country: France
state: Meurthe-et-Moselle
city: Tours
country: France
city: Colombes
country: France
state: Île-de-France
city: Alexandroupoli
country: Greece
state: Evros
city: Athens
country: Greece
city: Athens
country: Greece
city: Athens
country: Greece
city: Athens
country: Greece
city: Ioannina
country: Greece
city: Larisa
country: Greece
city: Debrecen
country: Hungary
state: Hajdú-Bihar
city: Debrecen
country: Hungary
state: Hajdú-Bihar
city: Budapest
country: Hungary
city: Budapest
country: Hungary
city: San Juan
country: Puerto Rico
city: Palma de Majorca
country: Spain
state: Baleares
city: Getafe
country: Spain
state: Comunidad de Madrid
city: Barcelona
country: Spain
city: Anakara
country: Turkey
state: Ankara
city: Ankara
country: Turkey
city: Istanbul
country: Turkey
city: Istanbul
country: Turkey
city: Trabzon
country: Turkey
Study officials:
affiliation: Washington University School of Medicine
name: Marin Kollef, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.