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

Pneumonia, Bacterial Clinical Trial

— IASIS  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01969799
• Other study ID #: CAP-01-102
• Secondary ID: 2013-002855-13
• Status: Completed
• Phase: Phase 2
• First received: October 22, 2013
• Last updated: May 9, 2016
• Start date: December 2013
• Est. completion date: April 2016

Study information

• Verified date: March 2016
• Source: Cardeas Pharma
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: April 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Pneumonia
• Pneumonia, Bacterial

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Cardeas Pharma

Countries where clinical trial is conducted

United States,  France,  Greece,  Hungary,  Puerto Rico,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in Clinical Pulmonary Infection Score (CPIS) during the planned 10-day treatment period.	Daily CPIS will be determined by one blinded, central reviewer in order to minimize inter-observer variability.	10 day treatment period.	No
Secondary	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).	Day 1 - Day 28	No
Secondary	Composite endpoint of mortality and ventilator-free days	The hierarchical composite endpoint of mortality, then ventilator-free days.	Day 1- Day 28	No
Secondary	Number of days free of mechanical ventilation from Day 1 through Day 28		Day 1 - Day 28	No
Secondary	Number of ICU days from Day 1 through Day 28		Day 1 - Day 28	No
Secondary	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	Day 14	No
Secondary	Mortality from Day 1 through Day 28		Day 1 - Day 28	No
Secondary	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	No

External Links

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