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

Phase 3

Completed

• Conditions: Hospital-acquired Bacterial Pneumonia; Acinetobacter Baumannii-calcoaceticus Complex; Bacteremia; Ventilator-associated Bacterial Pneumonia; Colistin Resistant ABC
• Interventions: Drug: Colistin; Drug: Sulbactam; Drug: Durlobactam; Drug: Imipenem/Cilastatin 500 mg/500 mg

• Registration Number: NCT03894046
• Lead Sponsor: Entasis Therapeutics

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-03-27
• Study First Submitted QC: 2019-03-27
• Study First Posted: 2019-03-28
• Study Start: 2019-09-05
• Primary Completion: 2021-07-26
• Study Completion: 2021-07-26
• Results First Submitted: 2022-11-07
• Status Verified: 2023-01
• Results First Submitted QC: 2023-01-05
• Last Update Submitted: 2023-01-05
• Results First Posted: 2023-02-01
• Last Update Posted: 2023-02-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 207

Inclusion Criteria

PART A

1. A confirmed diagnosis of a serious infection that will require treatment with IV antibiotics;

2. 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:

   1. Has received no more than 48 hrs of potentially effective (ie, Gram negative coverage) antimicrobial therapy prior to the first dose of study drug;
   2. Is clinically failing prior treatment regimens

3. APACHE II score 10 and 30 inclusive, or SOFA score between 7 and 11 inclusive, at time of diagnosis

4. 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

5. 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);

2. Known to be resistant to colistin or polymyxin B; or

3. Known intolerance to colistin; or

4. Has myasthenia gravis or another neuromuscular syndrome(s) that contraindicates colistin and is not ventilated; or

5. Has acute kidney injury and is receiving renal replacement therapy at study entry.

Exclusion Criteria

1. Evidence of active concurrent pneumonia requiring additional antimicrobial treatment
2. 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;
3. Sustained shock with persisting hypotension requiring vasopressors to maintain mean arterial pressure (MAP) ≥ 60 mmHg;
4. Pregnant or breastfeeding women;
5. Receiving peritoneal dialysis;
6. Requirement for continuing treatment with probenecid, methotrexate, ganciclovir, valproic acid, or divalproex sodium during the study;
7. Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis, hepatic cirrhosis, hepatic failure, chronic ascites, or hepatic encephalopathy;

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part A - Group 2	Colistin	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.
Part B - Group 3	Durlobactam	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.
Part A - Group 2	Imipenem/Cilastatin 500 mg/500 mg	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.
Part A - Group 1	Imipenem/Cilastatin 500 mg/500 mg	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
Part B - Group 3	Imipenem/Cilastatin 500 mg/500 mg	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.
Part A - Group 1	Sulbactam	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
Part A - Group 1	Durlobactam	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
Part B - Group 3	Sulbactam	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.

Primary Outcome Measures

Name	Time	Method
Proportion of Patients With Nephrotoxicity	28 days	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.
Proportion of Patients With All-Cause Mortality in CRABC m-MITT Population	28 Days	The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-MITT population in Part A.

Trial Locations

Locations (4)

Entasis Research Site 2; 🇹🇷 Ankara, Turkey

Entasis Research Site 3; 🇷🇺 Novosibirsk, Russian Federation

Entasis Research Site; 🇹🇷 Trabzon, Turkey

Entasis Research Site 1; 🇹🇷 Ankara, Turkey