Study to Evaluate the Efficacy and Safety of Intravenous Sulbactam-ETX2514 in the Treatment of Patients With Infections Caused by Acinetobacter Baumannii-calcoaceticus Complex

Study Overview
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Brief Summary
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This is a 2-part study, with Part A being the randomized, controlled portion of the study in patients with ABC hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or bacteremia. Part B is the single-group portion of the study and includes ABC infections that are resistant to or have failed colistin or polymyxin B treatment, as detailed in the inclusion criteria.

Official Title
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A Randomized, Active-controlled Study to Evaluate the Efficacy and Safety of Intravenous Sulbactam-ETX2514 in the Treatment of Patients With Infections Caused by Acinetobacter Baumannii-calcoaceticus Complex

Conditions
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Acinetobacter Baumannii-calcoaceticus Complex, Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, Bacteremia, Colistin Resistant ABC

Intervention / Treatment
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* Drug: Sulbactam
* Drug: Durlobactam
* Drug: Colistin
* Drug: Imipenem/Cilastatin 500 mg/500 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PART A A confirmed diagnosis of a serious infection that will require treatment with IV antibiotics; A known infection caused by ABC (bacteremia, HABP, VABP, VP, cUTI or AP, or surgical or post-traumatic wound infections) as either a single pathogen or member of a polymicrobial infection based on evidence from culture or, if available, rapid diagnostic test from a sample collected within 72 hours prior to randomization (HABP/VABP/VP patients), AND 1 of the following: Has received no more than 48 hrs of potentially effective (ie, Gram negative coverage) antimicrobial therapy prior to the first dose of study drug; Is clinically failing prior treatment regimens APACHE II score 10 and 30 inclusive, or SOFA score between 7 and 11 inclusive, at time of diagnosis Expectation, in the judgment of the Investigator, that the patient will benefit from effective antibiotic therapy and appropriate supportive care for the anticipated duration of the study Women of childbearing potential (ie, not post-menopausal or surgically sterilized) must have a negative highly sensitive urine or serum pregnancy test before randomization. Participating women of childbearing potential must be willing to consistently use one highly effective method of contraception (ie, condom, combined oral contraceptive, implant, injectable, indwelling intrauterine device, or a vasectomized partner) from Screening until at least 30 days after administration of the last dose of study drug. PART B 1. Has an infection (HABP, VABP, VP, bacteremia, cUTI, AP, or surgical or post-traumatic wound infections) caused by ABC organisms known to be resistant to colistin (defined as MIC ≥4 mg/L by a non-agar based method); Known to be resistant to colistin or polymyxin B; or Known intolerance to colistin; or Has myasthenia gravis or another neuromuscular syndrome(s) that contraindicates colistin and is not ventilated; or Has acute kidney injury and is receiving renal replacement therapy at study entry. Exclusion Criteria: Evidence of active concurrent pneumonia requiring additional antimicrobial treatment Presence of suspected or confirmed deep seated bacterial infections such as bacterial Gram negative osteomyelitis, endocarditis, or meningitis requiring prolonged therapy, as determined by history and/or physical examination; Sustained shock with persisting hypotension requiring vasopressors to maintain mean arterial pressure (MAP) ≥ 60 mmHg; Pregnant or breastfeeding women; Receiving peritoneal dialysis; Requirement for continuing treatment with probenecid, methotrexate, ganciclovir, valproic acid, or divalproex sodium during the study; Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis, hepatic cirrhosis, hepatic failure, chronic ascites, or hepatic encephalopathy;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - Group 1<br>Part A was the pivotal, assessor-blind, randomized, comparative portion of the study in patients with documented ABC hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), ventilated pneumonia (VP), or bacteremia. Part A - Group 1 (experimental): 1.0 g sulbactam/1.0 g durlobactam IV infused over 3 hours every 6 hours (q6h) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h | Drug: Sulbactam<br>* 1.0 g sulbactam IV infused over 3 hours every 6 hours (q6h).<br>Drug: Durlobactam<br>* 1.0 g durlobactam IV infused over 3 hours every 6 hours (q6h). Sulbactam-Durlobactam: Treatment for 7 days up to 14 days if clinically indicated.<br>* Other names: ETX2514;Drug: Imipenem/Cilastatin 500 mg/500 mg<br>* 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. Treatment for 7 days up to 14 days if clinically indicated.<br>|
| Active Comparator: Part A - Group 2<br>Part A - Group 2 (control group): 2.5 mg/kg colistin IV infused over 30 minutes every 12 hours (after an initial loading dose of colistin 2.5 to 5 mg/kg) plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. | Drug: Colistin<br>* Treatment for 7 days up to 14 days if clinically indicated.<br>* Other names: COLOMYCIN INJECTION 2 million IU/vial;Drug: Imipenem/Cilastatin 500 mg/500 mg<br>* 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. Treatment for 7 days up to 14 days if clinically indicated.<br>|
| Experimental: Part B - Group 3<br>Part B (Group 3) was the open-label, supportive portion of the study that included patients known to have HABP, VABP, VP, and/or bacteremia infections associated with ABC organisms resistant to colistin or polymyxin B, who failed a colistin or polymyxin B regimen prior to study entry or were on acute renal replacement therapy, and patients with infections due to colistin- or polymyxin B-resistant ABC with sources of infection other than HABP, VABP, VP, and/or bacteremia. Part B - Group 3: 1.0 g ETX2514/1.0 g sulbactam IV infused over 3 hours q6h plus 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. | Drug: Sulbactam<br>* 1.0 g sulbactam IV infused over 3 hours every 6 hours (q6h).<br>Drug: Durlobactam<br>* 1.0 g durlobactam IV infused over 3 hours every 6 hours (q6h). Sulbactam-Durlobactam: Treatment for 7 days up to 14 days if clinically indicated.<br>* Other names: ETX2514;Drug: Imipenem/Cilastatin 500 mg/500 mg<br>* 1.0 g imipenem/1.0 g cilastatin IV infused over 1 hour q6h. Treatment for 7 days up to 14 days if clinically indicated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With All-Cause Mortality in CRABC m-MITT Population | The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-MITT population in Part A. | 28 Days | 
| Proportion of Patients With Nephrotoxicity | The primary safety endpoint for the study is nephrotoxicity, as measured by the Risk-Injury-Failure-Loss-End-stage renal disease (RIFLE) criteria, in the MITT population in Part A. | 28 days |