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

NCT ID: NCT01969799

Last Updated: 2017-07-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 143 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2016-04-30

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

Conditions

Pneumonia, Bacterial

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Amikacin fosfomycin inhalation solution

Intervention Type: DRUG

300 mg of amikacin and 120 mg of fosfomycin twice daily for 10 days to be administered by aerosol via the eFlow Inline System

Aerosolized placebo

Aerosolized placebo twice daily for 10 days administered using the eFlow Inline System

Group Type: PLACEBO_COMPARATOR

Aerosolized placebo

Intervention Type: DRUG

Placebo twice daily for 10 days to be administered by aerosol the eFlow Inline System

Interventions

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

Intervention Type: DRUG

Aerosolized placebo

Placebo twice daily for 10 days to be administered by aerosol the eFlow Inline System

Intervention Type: DRUG

Other Intervention Names

Amikacin fosfomycin inhalation system (AFIS); eFlow Inline System; eFlow Inline System

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cardeas Pharma

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marin Kollef, M.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Los Angeles, California, United States

Gainesville, Florida, United States

Jacksonville, Florida, United States

Chicago, Illinois, United States

Hazard, Kentucky, United States

Lexington, Kentucky, United States

Boston, Massachusetts, United States

Burlington, Massachusetts, United States

Springfield, Massachusetts, United States

Detroit, Michigan, United States

St Louis, Missouri, United States

Omaha, Nebraska, United States

Oklahoma City, Oklahoma, United States

Knoxville, Tennessee, United States

El Paso, Texas, United States

Houston, Texas, United States

Limoges, Limousin, France

Orléans, Loiret, France

Vandœuvre-lès-Nancy, Meurthe-et-Moselle, France

Tours, , France

Colombes, Île-de-France Region, France

Alexandroupoli, Evros, Greece

Athens, , Greece

Athens, , Greece

Athens, , Greece

Athens, , Greece

Ioannina, , Greece

Larissa, , Greece

Debrecen, Hajdú-Bihar, Hungary

Debrecen, Hajdú-Bihar, Hungary

Budapest, , Hungary

Budapest, , Hungary

San Juan, , Puerto Rico

Palma de Majorca, Balearic Islands, Spain

Getafe, Madrid, Spain

Barcelona, , Spain

Ankara, Ankara, Turkey (Türkiye)

Ankara, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Trabzon, , Turkey (Türkiye)

Countries

United States; France; Greece; Hungary; Puerto Rico; Spain; Turkey (Türkiye)

References

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.

Reference Type: DERIVED

PMID: 27890714 (View on PubMed)

Related Links

http://www.nlm.nih.gov/medlineplus/antibiotics.html

MedlinePlus related topics: Antibiotics

http://www.nlm.nih.gov/medlineplus/pneumonia.html

MedlinePlus related topics: Pneumonia

http://druginfo.nlm.nih.gov/drugportal/ProxyServlet?mergeData=true&objectHandle=DBMaint&APPLICATION_NAME=drugportal&actionHandle=default&nextPage=jsp/drugportal/ResultScreen.jsp&TXTSUPERLISTID=0037517285&QV1=AMIKACIN

Drug Information available for amikacin

http://druginfo.nlm.nih.gov/drugportal/ProxyServlet?mergeData=true&objectHandle=DBMaint&APPLICATION_NAME=drugportal&actionHandle=default&nextPage=jsp/drugportal/ResultScreen.jsp&TXTSUPERLISTID=0023155024&QV1=FOSFOMYCIN

Drug information available for fosfomycin

http://www.clinicaltrials.gov/ct2/info/fdalinks

U.S. FDA Resources

Other Identifiers

2013-002855-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CAP-01-102

Identifier Type: -

Identifier Source: org_study_id