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

NCT ID: NCT03894046

Last Updated: 2023-02-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 207 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-05
• Study Completion Date: 2021-07-26

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Sulbactam

Intervention Type: DRUG

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

Durlobactam

Intervention Type: 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.

Imipenem/Cilastatin 500 mg/500 mg

Intervention Type: 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 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.

Group Type: ACTIVE_COMPARATOR

Colistin

Intervention Type: DRUG

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

Imipenem/Cilastatin 500 mg/500 mg

Intervention Type: 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 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.

Group Type: EXPERIMENTAL

Sulbactam

Intervention Type: DRUG

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

Durlobactam

Intervention Type: 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.

Imipenem/Cilastatin 500 mg/500 mg

Intervention Type: 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.

Interventions

Sulbactam

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

Intervention Type: 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.

Intervention Type: DRUG

Colistin

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

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

ETX2514; COLOMYCIN INJECTION 2 million IU/vial

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;

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Entasis Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Entasis Research Site

Chicago, Illinois, United States

Entasis Research Site

Shreveport, Louisiana, United States

Entasis Research Site

Cincinnati, Ohio, United States

Entasis Research Site

Memphis, Tennessee, United States

Entasis Research Site

Houston, Texas, United States

Entasis Research Site

Brest, , Belarus

Entasis Research Site

Grodno, , Belarus

Entasis Research Site

Homyel, , Belarus

Entasis Research Site

Minsk, , Belarus

Entasis Research Site

Belo Horizonte, , Brazil

Entasis Research Site

Campinas, , Brazil

Entasis Research Site

Porto Alegre, , Brazil

Entasis Research Site

Salvador, , Brazil

Entasis Research Site

São José do Rio Preto, , Brazil

Entasis Research Site 1

Beijing, , China

Entasis Research Site 2

Beijing, , China

Entasis Research Site 3

Beijing, , China

Entasis Research Site

Changsha, , China

Entasis Research Site

Chongqing, , China

Entasis Research Site

Guangzhou, , China

Entasis Research Site

Hebei, , China

Entasis Research Site 1

Hefei, , China

Entasis Research Site 2

Hefei, , China

Entasis Research Site

Hubei, , China

Entasis Research Site

Nanchang, , China

Entasis Research Site

Nanjing, , China

Entasis Research Site

Nanning, , China

Entasis Research Site 1

Shanghai, , China

Entasis Research Site 2

Shanghai, , China

Entasis Research Site

Shenzhen, , China

Entasis Research Site

Tianjin, , China

Entasis Research Site

Wuhan, , China

Entasis Research Site 1

Athens, , Greece

Entasis Research Site 3

Athens, , Greece

Entasis Research Site

Heraklion, , Greece

Entasis Research Site

Larissa, , Greece

Entasis Research Site

Thessaloniki, , Greece

Entasis Research Site 1

Budapest, , Hungary

Entasis Research Site 2

Budapest, , Hungary

Entasis Research Site

Debrecen, , Hungary

Entasis Research Site

Ahmedabad, , India

Entasis Research Site

Belagavi, , India

Entasis Research Site 2

Gujrāt, , India

Entasis Research Site 1

Gujrāt, , India

Entasis Research Site

Hyderabad, , India

Entasis Research Site

Kolkata, , India

Entasis Research Site

Pune, , India

Entasis Research Site

Holon, , Israel

Entasis Research Site

Tel Aviv, , Israel

Entasis Research Site

Tel Litwinsky, , Israel

Entasis Research Site

Ẕerifin, , Israel

Entasis Research Site

Kaunas, , Lithuania

Entasis Research Site

Klaipėda, , Lithuania

Entasis Research Site

Vilnius, , Lithuania

Entasis Research Site 1

Guadalajara, , Mexico

Entasis Research Site 2

Guadalajara, , Mexico

Entasis Research Site

Mexico City, , Mexico

Entasis Research Site

Monterrey, , Mexico

Entasis Research Site

San Luis Potosí City, , Mexico

Entasis Research Site

Bellavista, , Peru

Entasis Research Site

Cusco, , Peru

Entasis Research Site

Lima, , Peru

Entasis Research Site

San Isidro, , Peru

Entasis Research Site

San Martín de Porres, , Peru

Entasis Research Site

Ponce, , Puerto Rico

Entasis Research Site

Arkhangelsk, , Russia

Entasis Research Site

Krasnodar, , Russia

Entasis Research Site 1

Novosibirsk, , Russia

Entasis Research Site 2

Novosibirsk, , Russia

Entasis Research Site 3

Novosibirsk, , Russia

Entasis Research Site 2

Saint Petersburg, , Russia

Entasis Research Site

Smolensk, , Russia

Entasis Research Site 1

Tomsk, , Russia

Entasis Research Site 2

Tomsk, , Russia

Entasis Research Site

Gyeonggi-do, , South Korea

Entasis Research Site 1

Seoul, , South Korea

Entasis Research Site 2

Seoul, , South Korea

Entasis Research Site

Kaohsiung City, , Taiwan

Entasis Research Site

Taichung, , Taiwan

Entasis Research Site

Taipei, , Taiwan

Entasis Research Site

Chiang Mai, , Thailand

Entasis Research Site

Khon Kaen, , Thailand

Entasis Research Site

Nakhon Ratchasima, , Thailand

Entasis Research Site

Nonthaburi, , Thailand

Entasis Research Site 1

Ankara, , Turkey (Türkiye)

Entasis Research Site 2

Ankara, , Turkey (Türkiye)

Entasis Research Site

Eskişehir, , Turkey (Türkiye)

Entasis Research Site

Kocaeli, , Turkey (Türkiye)

Entasis Research Site

Küçükçekmece, , Turkey (Türkiye)

Entasis Research Site

Trabzon, , Turkey (Türkiye)

Countries

United States; Belarus; Brazil; China; Greece; Hungary; India; Israel; Lithuania; Mexico; Peru; Puerto Rico; Russia; South Korea; Taiwan; Thailand; Turkey (Türkiye)

References

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.

Reference Type: DERIVED

PMID: 37182534 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

CS2514-2017-0004

Identifier Type: -

Identifier Source: org_study_id