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

NCT03894046 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: CS2514-2017-0004
• Study Type: interventional
• Target: 207
• Locations: 17 countries
• Sites: 90

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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

Study Arms (3)

Part A - Group 1

EXPERIMENTAL

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; Drug: Durlobactam; Drug: Imipenem/Cilastatin 500 mg/500 mg

Part A - Group 2

ACTIVE COMPARATOR

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; Drug: Imipenem/Cilastatin 500 mg/500 mg

Part B - Group 3

EXPERIMENTAL

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; Drug: Durlobactam; Drug: Imipenem/Cilastatin 500 mg/500 mg

Interventions

Sulbactam DRUG

1.0 g sulbactam IV infused over 3 hours every 6 hours (q6h).

Part A - Group 1; Part B - Group 3

Durlobactam DRUG

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.

Also known as: ETX2514

Part A - Group 1; Part B - Group 3

Colistin DRUG

Treatment for 7 days up to 14 days if clinically indicated.

Also known as: COLOMYCIN INJECTION 2 million IU/vial

Part A - Group 2

Imipenem/Cilastatin 500 mg/500 mg DRUG

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.

Part A - Group 1; Part A - Group 2; Part B - Group 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• \. 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Entasis Therapeutics: lead

Study Sites (90)

Entasis Research Site

Chicago, Illinois, 60611, United States

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Entasis Research Site

Shreveport, Louisiana, 71101, United States

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Cincinnati, Ohio, 45219, United States

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Memphis, Tennessee, 38163, United States

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Houston, Texas, 77030, United States

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Brest, Belarus

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Grodno, Belarus

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Homyel, Belarus

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Minsk, Belarus

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Belo Horizonte, Brazil

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Campinas, Brazil

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Porto Alegre, Brazil

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Salvador, Brazil

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São José do Rio Preto, Brazil

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Entasis Research Site 1

Beijing, China

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Entasis Research Site 2

Beijing, China

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Entasis Research Site 3

Beijing, China

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Changsha, China

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Chongqing, China

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Guangzhou, China

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Hebei, China

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Hefei, China

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Entasis Research Site 2

Hefei, China

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Hubei, China

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Nanchang, China

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Nanjing, China

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Nanning, China

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Entasis Research Site 1

Shanghai, China

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Entasis Research Site 2

Shanghai, China

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Shenzhen, China

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Tianjin, China

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Wuhan, China

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Entasis Research Site 1

Athens, Greece

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Entasis Research Site 3

Athens, Greece

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Heraklion, Greece

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Larissa, Greece

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Thessaloniki, Greece

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Entasis Research Site 1

Budapest, Hungary

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Entasis Research Site 2

Budapest, Hungary

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Debrecen, Hungary

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Ahmedabad, India

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Belagavi, India

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Entasis Research Site 2

Gujrāt, 382 428, India

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Entasis Research Site 1

Gujrāt, 395002, India

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Hyderabad, India

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Kolkata, India

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Pune, India

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Holon, Israel

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Tel Aviv, Israel

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Tel Litwinsky, Israel

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Ẕerifin, Israel

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Kaunas, Lithuania

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Klaipėda, Lithuania

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Vilnius, Lithuania

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Entasis Research Site 1

Guadalajara, Mexico

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Entasis Research Site 2

Guadalajara, Mexico

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Entasis Research Site

Mexico City, Mexico

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Monterrey, Mexico

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San Luis Potosí City, Mexico

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Bellavista, Peru

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Cusco, Peru

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Lima, Peru

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San Isidro, Peru

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San Martín de Porres, Peru

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Ponce, Puerto Rico

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Arkhangelsk, Russia

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Krasnodar, Russia

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Entasis Research Site 1

Novosibirsk, Russia

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Entasis Research Site 2

Novosibirsk, Russia

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Entasis Research Site 3

Novosibirsk, Russia

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Entasis Research Site 2

Saint Petersburg, 192242, Russia

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Entasis Research Site

Smolensk, Russia

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Entasis Research Site 1

Tomsk, Russia

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Entasis Research Site 2

Tomsk, Russia

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Entasis Research Site

Gyeonggi-do, South Korea

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Entasis Research Site 1

Seoul, South Korea

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Entasis Research Site 2

Seoul, South Korea

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Entasis Research Site

Kaohsiung City, Taiwan

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Taichung, Taiwan

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Taipei, Taiwan

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Chiang Mai, Thailand

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Khon Kaen, Thailand

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Nakhon Ratchasima, Thailand

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Entasis Research Site

Nonthaburi, Thailand

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Entasis Research Site 1

Ankara, Turkey (Türkiye)

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Entasis Research Site 2

Ankara, Turkey (Türkiye)

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Entasis Research Site

Eskişehir, Turkey (Türkiye)

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Entasis Research Site

Kocaeli, Turkey (Türkiye)

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Entasis Research Site

Küçükçekmece, Turkey (Türkiye)

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Entasis Research Site

Trabzon, Turkey (Türkiye)

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Related Publications (1)

• Kaye KS, Shorr AF, Wunderink RG, Du B, Poirier GE, Rana K, Miller A, Lewis D, O'Donnell J, Chen L, Reinhart H, Srinivasan S, Isaacs R, Altarac D. Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK). Lancet Infect Dis. 2023 Sep;23(9):1072-1084. doi: 10.1016/S1473-3099(23)00184-6. Epub 2023 May 11.

  PMID: 37182534 DERIVED

MeSH Terms

Conditions

Bacteremia

Interventions

Sulbactam; durlobactam; Colistin; Imipenem; Cilastatin

Condition Hierarchy (Ancestors)

Bacterial Infections; Bacterial Infections and Mycoses; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Polymyxins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Antimicrobial Cationic Peptides; Peptides; Amino Acids, Peptides, and Proteins; Antimicrobial Peptides; Pore Forming Cytotoxic Proteins; Membrane Proteins; Proteins; Thienamycins; Carbapenems; Cyclopropanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids

Results Point of Contact

• Title: Dr. David Altarac - Chief Medical Officer
• Organization: Entasis Therapeutics

david.altarac@entasistx.com

+1 781 810 0120

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 27, 2019
• First Posted: March 28, 2019
• Study Start: September 5, 2019
• Primary Completion: July 26, 2021
• Study Completion: July 26, 2021
• Last Updated: February 1, 2023
• Results First Posted: February 1, 2023

Record last verified: 2023-01

Locations

IN (7); TW (3); TH (4); US (5); GR (5); IL (4); PE (5); CN (18); HU (3); PR (1); TU (6); KR (3); BE (4); ME (5); BR (5); LI (3); RU (9)