Approach for Optimizing Meropenem Therapy in Intubated and Mechanically-Ventilated, Adult Patients With Severe Gram-Negative Lower Respiratory Tract Infection (MON4STRAT)

Prospective, Randomized, Open, Controlled, Multicenter Study to Evaluate the Safety and Efficacy of the MON4STRAT Approach for Optimizing Meropenem Therapy in Intubated and Mechanically-Ventilated, Adult Patients With Severe Gram-Negative Lower Respiratory Tract Infection MON4STRAT Study

Antibacterial drugs are facing increasing limitations in terms of effectiveness due to emergence resistance. Improved antibacterial drug monitoring approaches are particularly needed in nosocomial infections occurring in ICU patients, including ventilator-associated pneumonia and ventilator-associated tracheobronchitis, where decreased susceptibility of the etiological organisms is observed worldwide and pharmacokinetic alterations frequently observed.

No routine drug monitoring is available for betalactams at the point of care in a useful time frame (i.e., within a few hours after having collected the blood specimens).

The purpose of this study is to compare MON4STRAT approach for reaching and maintaining a meropenem pre-determined PK-PD target when compared to conventional meropenem dose.

Study Overview

• Status: Terminated
• Conditions: Lower Respiratory Tract Infection
• Intervention / Treatment: Device: MON4STRAT Strategy; Other: Control group

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium
    • Université libre de Bruxelles
• France
  • Paris, France, 75013
    • Pitié Salpêtrière hospital
• Spain
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and non-pregnant, non-lactating females, 18 years of age or older
2. Currently intubated and mechanically-ventilated subjects in the ICU
3. Suspicion of lower respiratory tract infection
4. Presence of Gram-negative organism(s) by Gram stain OR by culture of pre-therapy respiratory specimen (eg, endotracheal aspirate [ETA], bronchoalveolar lavage [BAL], or mini-BAL) OR previous colonization 48 h before screening.
5. Initial empiric antimicrobial meropenem regimen
6. At least two risk factors for multidrug-resistant organisms
7. Provision of written informed consent by the subject or a family member or a close relative or waiver of consent.

Exclusion Criteria:

1. Subjects who have received antibiotic therapy for Gram-negative LRT infection for ≥ 36 hours at the time of randomization
2. Subjects with known or suspected type 1 hypersensitivity to beta-lactam and/or cephalosporin
3. Subjects taking valproic acid for a seizure disorder
4. Subjects who have had a left hemisphere stroke within five days and there is an increased risk of fatal brain oedema
5. Subjects who have cystic fibrosis, human immunodeficiency virus (HIV) infection with CD4 count <100 cell/mm3 or invasive fungal infection of the lung
6. Neutropenia (ANC < 103 neutrophils/mm3)
7. Bone marrow transplant.
8. Subjects who have been on mechanical ventilation for >28 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: MON4STRAT Strategy	Device: MON4STRAT Strategy; Meropenem infusion guided by daily Therapeutic Drug Monitoring (adjusted in order to reach predetermined PK/PD targets) using MON4STRAT device.
Active Comparator: Group 2: Conventional treatment	Other: Control group; Meropenem 1 gram infused every 8 hours over 30 minutes, consistent with standard-of-care treatment and published guidelines. Meropenem doses will be modified according to SmPC recommendations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To document the superiority of the MON4STRAT approach for reaching and maintaining a meropenem pre-determined PK-PD target when compared to conventional therapies.	The proportion of time from day 1 after randomization to end of therapy (EOT) in which the free meropenem trough concentration in serum was maintained above 8 mg/L or above 4 x MIC if antibiotic MIC > 2 and ≤ 8 mg/L, without exceeding 140 mg/L at peak level, as determined by a method of reference (HPLC).	During meropenem treatment: Day1 to Day 7

Secondary Outcome Measures

Outcome Measure	Time Frame
Clinical and microbiological response rates	Test of cure (TOC) visit (7 to 10 days after last study drug infusion)
Time to LRT bacterial eradication, as assessed by follow-up cultures of ETA	Days 3, 5, 7 of treatment and at the end of treatment (EOT) visit
All-cause mortality	Day 14 and day 28
ICU and hospital length of stay	Up to day 28
Number of mechanical ventilation-free days, defined as the number of days of unassisted breathing	Up to day 28

Collaborators and Investigators

• Sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Study record dates

Study Major Dates

• Study Start (Actual): February 18, 2019
• Primary Completion (Actual): July 8, 2019
• Study Completion (Actual): July 29, 2019

Study Registration Dates

• First Submitted: April 3, 2019
• First Submitted That Met QC Criteria: April 12, 2019
• First Posted (Actual): April 16, 2019

Study Record Updates

• Last Update Posted (Actual): February 17, 2020
• Last Update Submitted That Met QC Criteria: February 13, 2020
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Meropenem; Antibiotic Resistance; MON4STRAT; Treatment Drug Monitoring; Beta-Lactams Resistance; Health Care-Asociated Infection
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Infections; Communicable Diseases; Respiratory Tract Infections
• Other Study ID Numbers: MON4STRAT; 2018-000450-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No