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

• ClinicalTrials.gov Identifier: NCT03894046
• Recruitment Status: Completed
• First Posted: March 28, 2019
• Results First Posted: February 1, 2023
• Last Update Posted: February 1, 2023
• Sponsor: Entasis Therapeutics
• Information provided by (Responsible Party): Entasis Therapeutics

Tracking Information

• First Submitted Date: March 27, 2019
• First Posted Date: March 28, 2019
• Results First Submitted Date: November 7, 2022
• Results First Posted Date: February 1, 2023
• Last Update Posted Date: February 1, 2023
• Actual Study Start Date: September 5, 2019
• Actual Primary Completion Date: July 26, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 5, 2023)

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

Original Primary Outcome Measures (submitted: March 27, 2019)

• CRABC m-MITT (Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex Microbiologically Modified Intent-to-Treat Population) [ Time Frame: 28 Days ]
  The primary efficacy endpoint for the study is 28-day all-cause mortality in the CRABC m-MITT population in Part A.
• MITT (Modified Intent To Treat population containing all patients who received any amount of study drug) [ Time Frame: 28 days ]
  The primary safety endpoint for the study is the incidence of nephrotoxicity, as measured by the Risk-Injury-Failure-Loss-End-stage renal disease (RIFLE) criteria, in the MITT population in Part A.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Evaluate the Efficacy and Safety of Intravenous Sulbactam-ETX2514 in the Treatment of Patients With Infections Caused by Acinetobacter Baumannii-calcoaceticus Complex
• Official Title: 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:

Study drugs will not be masked due to logistical reasons, every attempt will be made to maintain the blind for patients, all staff at the site, and the Sponsor or its designees, except for the treatment physician and other immediate healthcare providers.

Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Sulbactam
  1.0 g sulbactam IV infused over 3 hours every 6 hours (q6h).
• Drug: Durlobactam

  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.

  Other Name: ETX2514
• Drug: Colistin
  Treatment for 7 days up to 14 days if clinically indicated.
  Other Name: COLOMYCIN INJECTION 2 million IU/vial
• Drug: Imipenem/Cilastatin 500 mg/500 mg
  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.

Study Arms

• Experimental: Part A - Group 1

  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

  Interventions:

  • Drug: Sulbactam
  • Drug: Durlobactam
  • Drug: Imipenem/Cilastatin 500 mg/500 mg
• Active Comparator: Part A - Group 2
  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.
  Interventions:

  • Drug: Colistin
  • Drug: Imipenem/Cilastatin 500 mg/500 mg
• Experimental: Part B - Group 3

  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.

  Interventions:

  • Drug: Sulbactam
  • Drug: Durlobactam
  • Drug: Imipenem/Cilastatin 500 mg/500 mg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 13, 2021): 207
• Original Estimated Enrollment (submitted: March 27, 2019): 80
• Actual Study Completion Date: July 26, 2021
• Actual Primary Completion Date: July 26, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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);

1. Known to be resistant to colistin or polymyxin B; or
2. Known intolerance to colistin; or
3. Has myasthenia gravis or another neuromuscular syndrome(s) that contraindicates colistin and is not ventilated; or
4. 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;

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belarus, Brazil, China, Greece, Hungary, India, Israel, Korea, Republic of, Lithuania, Mexico, Peru, Puerto Rico, Russian Federation, Taiwan, Thailand, Turkey, United States

Administrative Information

• NCT Number: NCT03894046
• Other Study ID Numbers: CS2514-2017-0004
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Entasis Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Entasis Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Entasis Therapeutics
• Verification Date: January 2023