TerminatedNCT01570192Updated Sep 29, 2017Results posted

Clinical Trials to Reduce the Risk of Antimicrobial Resistance

A Phase 2 interventional study of IV meropenem and I.V. Meropenem in Bacterial Pneumonia, sponsored by University of Florida. Terminated at 11 sites in 4 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-09-29.

Sponsored by University of Florida · Phase 2, Interventional, and Treatment

Why this study was terminated

NIAID terminated the study due to low subject enrollment

Phase: Phase 2
Study type: Interventional
Enrollment: 43
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study summary

The primary objective of this study is to demonstrate a low rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp during the treatment of hospitalized patients with pneumonia requiring mechanical ventilation treated with PD optimized meropenem administered as a prolonged infusion in combination with a parenteral aminoglycoside plus tobramycin by inhalation (Group 1) compared to therapy with meropenem alone (Group 2 - control arm).

Read the detailed description

The goal of this clinical study is to demonstrate that the application of pharmacodynamic dosing principles to the antibiotic treatment of hospitalized subjects with culture-documented pneumonia (including HABP, VABP and HCAP) requiring mechanical ventilation can inhibit the emergence of antibiotic-resistant organisms during treatment and therefore may improve the rate of a satisfactory clinical response. Antibiotic resistance is defined as an increase in meropenem or aminoglycoside MIC by two tube dilutions (fourfold) from baseline. In animal models of infection, the pharmacodynamic driver for bactericidal effect by β lactam antibiotics such as meropenem is the proportion of the dosing interval during which plasma drug levels are maintained above the MIC of the causative pathogen. The hypothesis of this study is that prolongation of time above MIC by increasing total meropenem dose and the duration of infusion will counter-select for the emergence of antimicrobial resistance during the treatment of hospitalized subjects with pneumonia (i.e. HABP, VABP and HCAP) caused by P.aeruginosa, Acinetobacter species (spp), or other pathogens with intermediate susceptibility to meropenem, and that the addition of parenteral aminoglycosides (amikacin, tobramycin or gentamicin) and nebulized aminoglycoside (tobramycin) given along optimal pharmacodynamic principles will further reduce the likelihood of resistance emergence, particularly among the non-fermenting Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp. The observed incidence of resistance emergence to meropenem will be compared across therapeutic regimens.

Conditions studied

Bacterial Pneumonia

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Keywords

gram negative pathogens
Pseudomonas aeruginosa
Acinetobacter
HCAP
VABP
HABP

In context

Pneumonia

2,044 studies on the registry are indexed under Pneumonia; 283 are open to participants now.

This study's enrollment of 43 is below the median of 106 across 1,247 interventional studies indexed under Pneumonia.

Browse Pneumonia studies →

Lead sponsor

University of Florida is the lead sponsor of 1,254 studies on the registry; 201 are open to participants now.

Of its 170 completed or terminated interventional studies of FDA-regulated products, 136 (80%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Written informed consent by the subject/subject's LAR.

Hospitalized males or females ≥ 18 yrs with respiratory failure requiring mechanical ventilation and clinical suspicion of HABP, HCAP or VABP.

Onset or exacerbation of pneumonia at least 48 hours after admission to any patient health care facility or onset of pneumonia in a nursing home or rehabilitation facility with subsequent transfer to an acute care facility

Women of childbearing potential if their pregnancy test is negative

Subjects who have received previous antibacterial therapy within 14 days of pre-treatment bronchoscopy entry may be entered only if the subject has not responded clinically.). While less than 24 hours of pre-treatment antibiotics is preferential, recovery of >104 CFU/ml in the quantitative Bronchoscopic BAL will be seen as primary evidence that the prior therapy was not efficacious and enrollment will be allowed.)

Patients should have clinical findings that support a diagnosis of HABP/VABP/HCAP:

Within 48 hours before starting empiric therapy a subject's chest radiograph should show the presence of a NEW or progressive infiltrate, cavitation, or effusion suggestive of pneumonia

Within 36 hours before the start of empiric study therapy, a quantitative culture of Bronchoscopic BAL fluid must be obtained.

Patients with VABP should have a Clinical Pulmonary Infection Score of >/= 5.

Exclusion criteria

Exclusion Criteria:

Subjects with pneumonia caused by pathogens resistant to meropenem (MIC greater than or equal to 16µg/ml) or a prior meropenem therapy failure.

Subjects with contra-indications to ANY study medication, in particular with known or suspected allergy or hypersensitivity.

Women who are pregnant or lactating.

Subjects taking anticonvulsant medications for a known seizure disorder.Patients with a history of seizures, AND who are stabilized on anti-seizure medication, may be enrolled into the study at the discretion of the site investigator.

Subjects with known or suspected community acquired bacterial pneumonia (CABP) or viral pneumonia; or Subjects with acute exacerbation of chronic bronchitis without evidence of pneumonia.

Subjects with primary lung cancer or another malignancy metastatic to the lungs.

Subjects who were previously enrolled in this study.

Subjects who have had an investigational drug or have used an investigational device within 30 days prior to entering the study.

Subjects with another focus of infection requiring concurrent antibiotics that would interfere with evaluation of the response to study drug.

Subjects with cystic fibrosis, AIDS with a CD4 lymphocyte count \<200 cells/µl, neutropenia (absolute neutrophil count \<500 cells/ml), known or suspected active tuberculosis.

Subjects with little chance of survival for the duration of study therapy.

Subjects with an APACHE II score >35.

Subjects with underlying condition(s) which would make it difficult to interpret response to the study drugs.

Subjects with hypotension or acidosis despite attempts at fluid resuscitation. Subjects requiring ongoing treatment with vasopressors will be eligible for the study if their hypotension is controlled and acidosis has resolved. Subjects with intractable septic shock are not eligible for enrollment.

Subjects who have undergone bone marrow transplantation.

Subjects with profound hypoxia as defined by a PaO2/FiO2 ratio \<100.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Double (Participant, Investigator)
Enrollment: 43 participants (actual)

Study arms

Experimental
IV meropenem; parenteral aminoglycoside
Subjects assigned to this group will receive: * IV meropenem (2 g infused over 3 hrs q 8 hr); * a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) * tobramycin nebulization Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens.
Drug: IV meropenem · Drug: Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h · Drug: Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage. · Device: tobramycin nebulization
Active comparator
I.V. Meropenem
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens. \*\*NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion.
Drug: I.V. Meropenem · Drug: Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage.

Interventions

DrugIV meropenem
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
Also known as: Merrem I.V.
DrugI.V. Meropenem
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage
Also known as: Merrem I.V.
DrugParenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h
a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)
DrugLinezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage.
Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.
Devicetobramycin nebulization
tobramycin nebulization 600mg/day

What researchers measure

Primary outcomes

Number of Participants With Suppression and Emergence of Resistance
The emergence of resistance is defined as a change of meropenem MIC or aminoglycoside MIC by two tube dilutions (fourfold) from baseline when assessed at the second BAL procedure on day 5/early extubation. Patients are evaluable for this endpoint IF they had baseline BAL and Day 5/early extubation and if they had positive cultures on baseline and Day/EE.
Time frame: up to 28 days after enrollment

Secondary outcomes

Clinical Response
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time frame: End of treatment - up to 28 days after enrollment
Clinical Response in Subjects Who Received Prior Antibiotics
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time frame: End of treatment - up to 28 days after enrollment
Overall Microbiologic Response
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time frame: End of treatment - up to 28 days after enrollment
Pretreatment Pathogen Response
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time frame: End of treatment - up to 28 days after enrollment
Suppression of the Emergence of Resistance in Other Gram-negative Pathogens
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time frame: Day 5/Early Extubation
Occurrence of Repeat Negative Cultures
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time frame: Day 5/Early Extubation
Mortality
Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)
Time frame: 14 days
Mortality
Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)
Time frame: 28 days

Results

Posted Apr 20, 2017

Participant flow

We had 8 clinical sites: recruitment into the study began September 2010 and ended April 10, 2015.

Participant flow — Overall Study
Milestone	IV Meropenem; Parenteral Aminoglycoside	I.V. Meropenem
Started	13	30
Completed	6	17
Not completed	7	13
Withdrew: No qualifying organism	6	12
Withdrew: Changed to palliative care	1	0
Withdrew: Physician decision	0	1

Outcome measures

PrimaryNumber of Participants With Suppression and Emergence of Resistance

The emergence of resistance is defined as a change of meropenem MIC or aminoglycoside MIC by two tube dilutions (fourfold) from baseline when assessed at the second BAL procedure on day 5/early extubation. Patients are evaluable for this endpoint IF they had baseline BAL and Day 5/early extubation and if they had positive cultures on baseline and Day/EE.

Time frame:: up to 28 days after enrollment
Reported as:: Number · participants

Number of Participants With Suppression and Emergence of Resistance
participants	IV Meropenem; Parenteral Aminoglycoside	I.V. Meropenem
suppression of emergence of resistance	—	5
emergence of resistance	—	1

SecondaryClinical Response