Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria
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|ClinicalTrials.gov Identifier: NCT03580044|
Recruitment Status : Recruiting
First Posted : July 9, 2018
Last Update Posted : September 10, 2022
|Condition or disease||Intervention/treatment||Phase|
|Serious Bacterial Infection||Combination Product: ATM-AVI Drug: BAT||Phase 3|
This is a prospective, randomized, multicenter, open-label, parallel group, comparative study to determine the efficacy, safety, and tolerability of aztreonam- avibactam (ATM- AVI) versus best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections (cIAI), nosocomial pneumonia (NP) including hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), complicated urinary tract infections (cUTI), or bloodstream infections (BSI) due to metallo-β-lactamase (MBL)- producing Gram-negative bacteria.
The study will randomize approximately 60 subjects in a 2:1 randomization scheme (ATM-AVI: BAT) with infections due to MBL-producing Gram-negative bacteria. Molecular testing at the central microbiology laboratory will be performed to confirm the MBL status of the organism upon study completion or at pre-designated intervals.
The study will consist of a Screening Visit (Visit 1), a Baseline visit (Visit 2) on Day 1 of the study treatment, ongoing treatment visits (Visits 3 to 15) from Day 2 to Day 14, an End of Treatment (EOT) visit (Visit 16) within 24 hours after the last infusion, a Test of Cure (TOC) visit (Visit 17) on Day 28 (±3 days) and a Late Follow Up (LFU) visit (Visit 18) on Day 45 (±3 days).
Subjects will be stratified at randomization based on infection type (cIAI, HAP/VAP, cUTI or BSI). The number of subjects with cUTI will be no more than approximately 75% of the study population.
After obtaining written informed consent and confirming eligibility, subjects will be randomized in a 2:1 ratio to the ATM AVI treatment arm or the BAT treatment arm according to a central randomization schedule (approximately 40 (ATM AVI) and approximately 20 (BAT) subjects per group).
The duration of treatment is 5 to 14 days for cIAI, cUTI and BSI and 7 to 14 days for HAP/VAP. Each subject is expected to complete the study, including the LFU visit. The precise duration of treatment will be determined by the investigator based on the subject's severity of infection and subsequent response to treatment.
For subjects randomized to ATM AVI treatment arm, sparse blood samples will be collected for population pharmacokinetic (PK) assessments and PK/pharmacodynamic (PD) relationships will be evaluated in subjects where plasma samples and microbiological response data have been collected.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||60 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A PROSPECTIVE, RANDOMIZED,OPEN-LABEL, COMPARATIVE STUDY TO ASSESS THE EFFICACY, SAFETY AND TOLERABILITY OF AZTREONAM- AVIBACTAM (ATM-AVI) AND BEST AVAILABLE THERAPY FOR THE TREATMENT OF SERIOUS INFECTIONS DUE TO MULTI-DRUG RESISTANT GRAM- NEGATIVE BACTERIA PRODUCING METALLO -Β-LACTAMASE (MBL)|
|Actual Study Start Date :||December 25, 2020|
|Estimated Primary Completion Date :||February 20, 2023|
|Estimated Study Completion Date :||February 20, 2023|
|Experimental: ATM- AVI Aztreonam- Avibactam (ATM-AVI) Active Treatment Arm||
Combination Product: ATM-AVI
ATM-AVI doses (loading, extended loading and maintenance) and the dosing frequency of the maintenance dose are dependent on renal function. Subjects will be given a loading dose of 500 mg ATM plus 167 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 30 minutes. This treatment will immediately be followed by an extended loading dose of 1500 mg ATM plus 500 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 3 hours. Then there will be a 3 hour or 5 hour gap. Subjects will receive a maintenance dose of 1500 mg ATM plus 500 mg AVI every 6 hours or 750 mg ATM plus 250 mg AVI every 6 hours, or 675 mg ATM plus 225 mg AVI every 8 hours. Subjects with cIAI will also receive Metronidazole (MTZ) 500 mg IV q8h over 60 minutes. The first dose of MTZ will be started immediately after the extended loading dose of ATM-AVI has completed and treatment will be continued until the end of the treatment period.
Other Name: Aztreonam- Avibactam
|Active Comparator: Best Available Therapy (BAT) Comparator Treatment Arm||
The comparator treatments in this study are to be the best available therapy (BAT) based upon site practice and local epidemiology. The choice of BAT for each subject must be recorded prior to randomization. Acceptable BAT may include but not limit to the following Aminoglycoside; Colistin (or polymixin B if colistin not available/accessible); Fosfomycin; Meropenem; Tigecycline. If the chosen BAT does not provide adequate anaerobic coverage for cIAI subjects MTZ is to be administered as a co therapy. BAT dose, frequency, dose adjustments with renal impairment will be based on per local package inserts.
Other Name: Best Available Therapy
- Proportion of subjects with clinical cure in the microbiological Intent-To-Treat (micro-ITT) analysis set [ Time Frame: Up to 31 days ]Proportion of subjects with clinical cure at the TOC visit in the micro-ITT analysis set
- Proportion of subjects with clinical cure in the Microbiologically Evaluable (ME) analysis set [ Time Frame: up to 31 days ]Proportion of subjects with clinical cure at the TOC visit in the ME analysis set
- Proportion of subjects with clinical cure in the micro-ITT and ME analysis sets [ Time Frame: within 24 hours after the completion of the last infusion of IV study treatment ]Proportion of subjects with clinical cure at the EOT visit in the micro-ITT and ME analysis sets
- Proportion of subjects with a favorable per subject microbiological response in the micro ITT and ME analysis sets [ Time Frame: within 24 hours after the completion of the last infusion of IV study treatment and up to 31 days ]Proportion of subjects with a favorable (defined as eradication or presumed eradication) per subject microbiological response at the EOT and TOC visits in the micro-ITT and ME analysis sets
- Proportion of subjects with a favorable per pathogen microbiological response in the micro ITT and ME analysis sets [ Time Frame: within 24 hours after the completion of the last infusion of IV study treatment and up to 31 days ]Proportion of subjects with a favorable per pathogen microbiological response at the EOT and TOC visits in the micro- ITT and ME analysis sets
- Proportion of subjects who died on or before 28 days in the Intent-To-Treat (ITT) and micro-ITT analysis sets [ Time Frame: from randomization up to 31 days ]Proportion of subjects who died on or before 28 days from randomization in ITT and micro-ITT analysis sets
- Incidence and severity of adverse events [ Time Frame: from first dose up to 48 days ]Safety and tolerability as assessed by adverse events
- Incidence of abnormalities in physical examination [ Time Frame: from first dose up to 48 days ]Safety and tolerability as assessed by physical examination
- Incidence of vital sign abnormalities [ Time Frame: from first dose up to 48 days ]Safety and tolerability as assessed by vital sign assessments
- Incidence of ECG abnormalities [ Time Frame: from first dose up to 48 days ]Safety and tolerability as assessed by ECGs assessments
- Incidence of clinical laboratory abnormalities [ Time Frame: from first dose up to 48 days ]Safety and tolerability as assessed by clinical laboratory assessments
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03580044
|Contact: Pfizer CT.gov Call Center||1-800-718-1021||ClinicalTrials.gov_Inquiries@pfizer.com|
|Study Director:||Pfizer CT.gov Call Center||Pfizer|