Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria

NCT03580044 | Terminated Phase 3 Results DMC FDA Drug

• 3 other identifiers: C36010092017-004544-38ASSEMBLE
• Study Type: interventional
• Target: 15
• Locations: 12 countries
• Sites: 42

Brief Summary

Phase 3 study to determine the efficacy, safety, and tolerability of aztreonam- avibactam (ATM- AVI) versus best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections (cIAI), nosocomial pneumonia (NP) including hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), complicated urinary tract infections (cUTI), or bloodstream infections (BSI) due to metallo-β-lactamase (MBL)- producing Gram-negative bacteria.

Conditions

Serious Bacterial Infection

Keywords

Serious bacterial infection; cIAI; HAP/(VAP; cUTI; BSI; MBL

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Clinical Cure at the Test of Cure (TOC) Visit -Microbiological Intent to Treat (Micro-ITT) Analysis Set

  Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% confidence interval (CI) was calculated using Jeffrey's method.

  Day 28

Secondary Outcomes (19)

• Percentage of Participants With Clinical Cure at the TOC Visit-Microbiologically Evaluable (ME) Analysis Set

  Day 28

• Percentage of Participants With Clinical Cure at the End of Treatment (EOT) Visit- Micro-ITT Analysis Set

  Up to 24 hours after the last infusion on Day 14

• Percentage of Participants With Clinical Cure at the EOT Visit- ME Analysis Set

  Up to 24 hours after the last infusion on Day 14

• Percentage of Participants With a Favorable Per Participant Microbiological Response at EOT Visit-Micro-ITT Analysis Set

  Up to 24 hours after the last infusion on Day 14

• Percentage of Participants With a Favorable Per Participant Microbiological Response at TOC Visit-Micro-ITT Analysis Set

  Day 28

Study Arms (2)

ATM- AVI Aztreonam- Avibactam (ATM-AVI) Active Treatment Arm

EXPERIMENTAL

Combination Product: ATM-AVI

Best Available Therapy (BAT) Comparator Treatment Arm

ACTIVE COMPARATOR

Drug: BAT

Interventions

ATM-AVI COMBINATION_PRODUCT

ATM-AVI doses (loading, extended loading and maintenance) and the dosing frequency of the maintenance dose are dependent on renal function. Subjects will be given a loading dose of 500 mg ATM plus 167 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 30 minutes. This treatment will immediately be followed by an extended loading dose of 1500 mg ATM plus 500 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 3 hours. Then there will be a 3 hour or 5 hour gap. Subjects will receive a maintenance dose of 1500 mg ATM plus 500 mg AVI every 6 hours or 750 mg ATM plus 250 mg AVI every 6 hours, or 675 mg ATM plus 225 mg AVI every 8 hours. Subjects with cIAI will also receive Metronidazole (MTZ) 500 mg IV q8h over 60 minutes. The first dose of MTZ will be started immediately after the extended loading dose of ATM-AVI has completed and treatment will be continued until the end of the treatment period.

Also known as: Aztreonam- Avibactam

ATM- AVI Aztreonam- Avibactam (ATM-AVI) Active Treatment Arm

BAT DRUG

The comparator treatment in this study is best available therapy (BAT) based upon site practice and local epidemiology. The choice of BAT (monotherapy or combination) for each subject must be recorded prior to randomization. If the chosen BAT does not provide adequate anaerobic coverage for cIAI subjects MTZ is to be administered as a co therapy. BAT dose, frequency, dose adjustments with renal impairment will be based on per local package inserts.

Also known as: Best Available Therapy

Best Available Therapy (BAT) Comparator Treatment Arm

Eligibility Criteria

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

You may qualify if:

• Subject must be ≥18 years of age.
• Evidence of a personally signed and dated informed consent document indicating that the subject or a legally acceptable representative has been informed of all pertinent aspects of the study.
• Subjects must have a confirmed diagnosis of serious bacterial infection, specifically cIAI, HAP/VAP, cUTI, or BSI requiring administration of IV antibacterial therapy.
• Subjects must have an MBL- positive Gram- negative bacteria (an Enterobacteriaceae and/or Stenotrophomonas maltophilia for which the imipenem or meropenem MIC is ≥ 4 µg/mL), that was isolated from an appropriate specimen obtained within 7 days prior to screening.
• Female subject of childbearing potential must have a negative serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL.
• Subjects who have received more than 48 hours of an appropriate prior systemic antibiotic\[s\] for a carbapenem non -susceptible pathogen may be enrolled if they demonstrate worsening or lack of improvement of objective symptoms or signs of infection (Note: antibiotic\[s\] is considered appropriate if microbiological susceptibility test results show that all carbapenem non -susceptible pathogens are susceptible to the systemic antibiotic\[s\] received).
• Subject must have a specimen obtained from an abdominal source during a surgical intervention within 7 days prior to screening from which a study qualifying pathogen was isolated upon culture. Surgical intervention includes open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery.
• The subject has at least 1 of the following diagnosed during the surgical intervention:
• Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall;
• Diverticular disease with perforation or abscess;
• Appendiceal perforation or peri-appendiceal abscess;
• Acute gastric or duodenal perforations, only if operated on \>24 hours after diagnosis;
• Traumatic perforation of the intestines, only if operated on \>12 hours after diagnosis;
• Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis associated with cirrhosis or chronic ascites);
• Intra abdominal abscess (including of the liver and spleen provided that there is extension beyond the organ with evidence of intra peritoneal involvement).

You may not qualify if:

• History of serious allergic reaction (anaphylaxis, angioedema, bronchospasm, hypersensitivity) to any systemic antibacterial allowed per protocol.
• Subject has a concurrent infection that may interfere with the evaluation of response to the study antibiotics.
• Subject has a need for effective concomitant systemic antibacterials in addition to those allowed per protocol for the diagnoses under study.
• Estimated CrCL ≤15 mL/min or anticipated requirement for dialysis during the study.
• Subject has infections limited to the hollow viscous, such as simple cholecystitis, gangrenous cholecystitis without rupture, and simple appendicitis, or has acute suppurative cholangitis, infected necrotizing pancreatitis, or pancreatic abscess.
• Subject has abdominal wall abscess or small bowel obstruction without perforation or ischemic bowel without perforation.
• Subject has a cIAI managed by staged abdominal repair (STAR), or "open abdomen" technique, or marsupialization. This criterion is intended to exclude subjects in whom the abdomen is left open, particularly those for whom re operation is planned.
• \. Any recent history of trauma to the pelvis or urinary tract.
• \. Subject has a prosthetic cardiac valve or synthetic endovascular graft. 2. Subject has a suspected or documented medical condition with well-defined requirement for prolonged antibiotic treatment (eg, infectious endocarditis, osteomyelitis/septic arthritis, undrainable/undrained abscess, unremoveable/unremoved prosthetic associated infection).

Sponsors & Collaborators

• Pfizer: lead
• Allergan: collaborator

Study Sites (42)

Banner University Medical Center Tucson

Tucson, Arizona, 85719, United States

Location

Hospital San Roque

Córdoba, 5000, Argentina

Location

The First Affiliated Hospital of Shantou University Medical College

Shantou, Guangdong, 515041, China

Location

Hunan Province People's Hospital

Changsha, Hunan, 410005, China

Location

Baotou Central Hospital

Baotou, Inner Mongolia, 014000, China

Location

Huashan Hospital Fudan University

Shanghai, Shanghai Municipality, 200040, China

Location

The First Hospital of Kunming

Kunming, Yunnan, 650034, China

Location

The First Hospital of Kunming

Kunming, China

Location

General Hospital of Athens "Evangelismos"

Athens, 10676, Greece

Location

General and Chest Diseases Hospital "Sotiria"

Athens, 11527, Greece

Location

General Hospital of Athens "Laiko",

Athens, 11527, Greece

Location

University General Hospital "ATTIKON", Medicine and Infectious Diseases

Athens, 12462, Greece

Location

University General Hospital of Heraklion

Heraklion, Crete, 71110, Greece

Location

University General Hospital of Larissa

Larissa, 41110, Greece

Location

Government medical College

Kozhikode, Kerala, 673008, India

Location

Deenanath Mangeshkar Hospital And Research Centre

Pune, Maharashtra, 411004, India

Location

S.R.Kalla Memorial Gastro & General Hospital

Jaipur, Rajasthan, 302001, India

Location

Apollo Hospitals Enterprise Limited

Chennai, Tamil Nadu, 600006, India

Location

Victoria Hospital, Bangalore Medical College and Research Institute

Bangalore, 560002, India

Location

Hospital Kuala Lumpur

Kuala Lumpur, Kuala Lumpur, 50586, Malaysia

Location

University Malaya Medical Centre

Kuala Lumpur, 59100, Malaysia

Location

Hospital Civil de Guadalajara "Fray Antonio Alcalde"

Guadalajara, Jalisco, 44280, Mexico

Location

Davao Doctors Hospital

Davao City, 8000, Philippines

Location

Makati Medical Center

Makati City, 1229, Philippines

Location

Manila Doctors Hospital

Manila, 1000, Philippines

Location

St. Luke's Medical Center

Quezon City, 1112, Philippines

Location

Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"

Bucharest, 021105, Romania

Location

Spitalul Clinic de Boli Infectioase si Tropicale "Dr. Victor Babes"

Bucharest, 030303, Romania

Location

Spitalul Clinic de Boli Infectioase Cluj Napoca

Cluj-Napoca, 400348, Romania

Location

Spitalul Clinic de Boli Infectioase "Sf. Parascheva" Iasi

Iași, 700116, Romania

Location

Spitalul Clinic Judetean de Urgenta "Pius Brinzeu"

Timișoara, 300723, Romania

Location

SBHI of the city of Moscow "N.I.Pirogov City Clinical Hospital # 1"

Moscow, 119049, Russia

Location

OGBUZ "Smolensk Regional Clinical Hospital"

Smolensk, 214018, Russia

Location

FSBEI of HE "Smolensk State Medical University" of the Ministry of Health of the RF

Smolensk, 214019, Russia

Location

SRI of Antimicrobial Chemotherapy

Smolensk, 214019, Russia

Location

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, 807, Taiwan

Location

Kaohsiung Veterans General Hospital

Kaohsiung City, 81362, Taiwan

Location

National Taiwan University Hospital

Taipei, 10002, Taiwan

Location

Faculty of Medicine Siriraj Hospital

Bangkoknoi, Bangkok, 10700, Thailand

Location

Bamrasnaradura Infectious Disease Institute (BIDI)

Muang, Changwat Nonthaburi, 11000, Thailand

Location

Songklanagarind Hospital, Prince of Songkla University

Hat Yai, Changwat Songkhla, 90110, Thailand

Location

Srinagarind Hospital, Division of lnfectious Disease and Tropical Medicine

Muang, Khonkaen, 40002, Thailand

Location

Related Publications (3)

• Raber SR, Xie R, Rogers H, Soto E, Arhin FF, Stone GG, Leister-Tebbe H, Chow JW. Microbiological, Clinical, and Pharmacokinetic/Pharmacodynamic Data to Support EUCAST Aztreonam-Avibactam Minimum Inhibitory Concentration Susceptibility Breakpoints Against Enterobacterales. Infect Dis Ther. 2026 Jan;15(1):183-195. doi: 10.1007/s40121-025-01267-3. Epub 2025 Nov 21.

  PMID: 41269522 DERIVED

• Xie R, Rogers H, Chow JW, Soto E, Raber SR. Population pharmacokinetic/pharmacodynamic modeling to optimize aztreonam-avibactam dose regimens for adult patients. Antimicrob Agents Chemother. 2025 Aug 6;69(8):e0195024. doi: 10.1128/aac.01950-24. Epub 2025 Jun 18.

  PMID: 40530972 DERIVED

• Das S, Riccobene T, Carrothers TJ, Wright JG, MacPherson M, Cristinacce A, McFadyen L, Xie R, Luckey A, Raber S. Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for Phase IIa and Phase III evaluation. Eur J Clin Pharmacol. 2024 Apr;80(4):529-543. doi: 10.1007/s00228-023-03609-x. Epub 2024 Jan 22.

  PMID: 38252170 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: June 4, 2018
• First Posted: July 9, 2018
• Study Start: December 25, 2020
• Primary Completion: January 23, 2023
• Study Completion: January 23, 2023
• Last Updated: February 2, 2024
• Results First Posted: February 2, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share

Locations

ME (1); TH (4); GR (6); US (1); RO (5); IN (5); CN (6); AR (1); RU (4); PH (4); MY (2); TW (3)