A Study to Determine the Efficacy, Safety and Tolerability of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem (MER) ± Colistin (COL) for the Treatment of Serious Infections Due to Gram Negative Bacteria. (REVISIT)

A PHASE 3 PROSPECTIVE, RANDOMIZED, MULTICENTER, OPEN-LABEL, CENTRAL ASSESSOR-BLINDED, PARALLEL GROUP, COMPARATIVE STUDY TO DETERMINE THE EFFICACY, SAFETY AND TOLERABILITY OF AZTREONAM-AVIBACTAM (ATM-AVI) ±METRONIDAZOLE (MTZ) VERSUS MEROPENEM±COLISTIN (MER±COL) FOR THE TREATMENT OF SERIOUS INFECTIONS DUE TO GRAM NEGATIVE BACTERIA, INCLUDING METALLO-Β-LACTAMASE (MBL) - PRODUCING MULTIDRUG RESISTANT PATHOGENS, FOR WHICH THERE ARE LIMITED OR NO TREATMENT OPTIONS

A Phase 3 comparative study to determine the efficacy, safety and tolerability of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) versus Meropenem (MER) ± Colistin (COL) for the treatment of serious infections due to Gram negative bacteria.

Study Overview

• Status: Completed
• Conditions: Ventilator Associated Pneumonia; Complicated Intra-abdominal Infection; Hosptial Acquired Pneumonia
• Intervention / Treatment: Drug: ATM-AVI; Drug: MTZ; Drug: MER; Drug: COL

Detailed Description

A Phase 3 Prospective, Randomized, Multicenter, Open Label, Central Assessor Blinded, Parallel Group, Comparative Study To Determine The Efficacy, Safety And Tolerability Of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem±Colistin (MER±COL) For The Treatment Of Serious Infections Due To Gram Negative Bacteria, Including Metallo Β Lactamase (MBL) - Producing Multidrug Resistant Pathogens, For Which There Are Limited Or No Treatment Options

• Study Type: Interventional
• Enrollment (Actual): 422
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Córdoba, Argentina, 5000
    • Hospital San Roque
  • Santa FE
    • Rosario, Santa FE, Argentina, 2000
      • Sanatorio Britanico
    • Santo Tome, Santa FE, Argentina, S3016
      • Sanatorio Servicios Medicos SM
• Bulgaria
  • Sofia, Bulgaria, 1431
    • University Hospital Alexandrovska, Clinic of Anesthesiology and Intensive Care
  • Sofia, Bulgaria, 1527
    • University Hospital Queen Joanna ISUL, Clinic of Surgery
  • Stara Zagora, Bulgaria, 6003
    • University Multiprofile Hospital for Active Treatment ''Prof.Dr Stoyan Kirkovich''AD
• China
  • Beijing, China, 100044
    • Peking University People's Hospital
  • Jiangyin, China, 214400
    • Jiangyin People's Hospital
  • Tianjin, China, 300000
    • Tianjin Union Medical Center
  • Beijing
    • Beijing, Beijing, China, 100191
      • Peking University Third Hospital
  • Fujian
    • Zhangzhou, Fujian, China, 363000
      • Zhangzhou Municipal Hospital of Fujian Province
  • Guangdong
    • Guangzhou, Guangdong, China, 510280
      • Zhujiang Hospital of Southern Medical University
    • Shantou, Guangdong, China, 515041
      • The First Affiliated Hospital of Shantou University Medical College
    • Shenzhen, Guangdong, China, 518035
      • The second people's Hospital of Shenzhen
  • Guangxi
    • Guilin, Guangxi, China, 541001
      • Affiliated Hospital of Guilin Medical University
  • Guangxi Zhuang Autonomous Region
    • Nanning, Guangxi Zhuang Autonomous Region, China, 530022
      • Nanning First People's Hospital
  • Hunan
    • Changsha, Hunan, China, 410005
      • Hunan Province People's Hospital
    • Changsha, Hunan, China, 410000
      • Changsha Third Hospital
  • Inner Mongolia Autonomous Region
    • Baotou, Inner Mongolia Autonomous Region, China, 014000
      • Baotou Central Hospital
  • Jiangsu
    • Jiangyin, Jiangsu, China, 214400
      • Jiangyin People's Hospital
    • Zhenjiang, Jiangsu, China, 212001
      • Affiliated Hospital of Jiangsu University
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital Fudan University
    • Shanghai, Shanghai, China, 200433
      • Shanghai Pulmonary Hospital
  • Yunnan
    • Kunming, Yunnan, China, 650034
      • The First people's Hospital of Kunming
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • The First Affiliated Hospital of College of Medicine, Zhejiang University
    • Linhai, Zhejiang, China, 317000
      • Taizhou Hospital of Zhejiang Province
    • Lishui, Zhejiang, China, 323000
      • Lishui People's Hospital
    • Quzhou, Zhejiang, China, 324000
      • Quzhou People's Hospital
• Croatia
  • Osijek, Croatia, 31000
    • University Hospital Centre Osijek
  • Slavonski Brod, Croatia, 35000
    • General Hospital "Dr. Josip Benčević" Slavonski Brod
  • Zagreb, Croatia, 10000
    • Clinical Hospital Dubrava
  • GRAD Zagreb
    • Zagreb, GRAD Zagreb, Croatia, 10000
      • Klinička Bolnica Merkur
  • Primorsko-goranska Zupanija
    • Rijeka, Primorsko-goranska Zupanija, Croatia, 51000
      • Klinicki bolnicki centar Rijeka
• Czechia
  • Brno, Czechia, 625 00
    • Fakultni nemocnice Brno
  • Decin, Czechia, 40599
    • Krajska zdravotni, a.s. - Nemocnice Decin, o.z.
  • Decin, Czechia, 40599
    • Lekarna Nemocnice Decin, Krajska zdravotni, a.s.- Nemocnice Decin, o.z.
  • Kolin III, Czechia, 280 02
    • Public Hospital Kolin, a.s.
  • Kyjov, Czechia, 697 01
    • Nemocnice Kyjov, prispevkova organizace
  • Praha 10, Czechia, 100 34
    • Fakultni nemocnice Kralovske Vinohrady
• Greece
  • Athens, Greece, 11527
    • General Hospital of Athens "LAIKO"
  • Athens, Greece, 12462
    • University General Hospital "Attikon"
  • Athens, Greece, 10676
    • General Hospital of Athens "Evangelismos"
  • Athens, Greece, 11527
    • General and Chest Diseases Hospital "Sotiria"
  • Heraklion, Crete, Greece, 71110
    • University General Hospital of Heraklion
  • Larissa, Greece, 41110
    • University General Hospital of Larissa
  • Larissa, Greece, 41221
    • Koutlimbaneio and Triantafylleio General Hospital of Larissa
• India
  • Ludhiana, India, 141001
    • Dayanand Medical College and Hospital
  • Pune, India
    • Sahyadri Specialty Hospital
  • Pune, India, 411004
    • Sahyadri Clinical Research & Development Center
  • Andhra Pradesh
    • Visakhapatnam, Andhra Pradesh, India, 530002
      • King George Hospital
  • Karnataka
    • Bangalore, Karnataka, India, 560054
      • M S Ramaiah Medical College and Hospitals
    • Bangalore, Karnataka, India, 560002
      • Victoria Hospital, Bangalore Medical College And Research Institute
    • Manipal, Karnataka, India, 576104
      • Kasturba Medical College and Hospital
    • Mysuru, Karnataka, India, 570004
      • JSS Hospital
  • Kerala
    • Kochi, Kerala, India, 682041
      • Amrita Institute Of Medical Sciences & Research Centre
    • Kozhikode, Kerala, India, 673008
      • Government Medical College, Kozhikode
  • Maharashtra
    • Pune, Maharashtra, India, 411004
      • Sahyadri Super Specialty Hospital
    • Pune, Maharashtra, India, 411004
      • Sahyadri Super Speciality Hospital
    • Pune, Maharashtra, India, 411004
      • Deenanath Mangeshkar Hospital and Research Centre
  • Rajasthan
    • Jaipur, Rajasthan, India, 302001
      • S.R. Kalla Memorial Gastro & General Hospital
  • Tamil NADU
    • Chennai, Tamil NADU, India, 600006
      • Apollo Hospitals
  • Uttar Pradesh
    • Lucknow, Uttar Pradesh, India, 226003
      • King George's Medical University
• Israel
  • Ashdod, Israel, 7747629
    • Assuta Ashdod University Hospital
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus
  • Jerusalem, Israel, 9112001
    • Hadassah Medical Organization, Hadassah Medical Center, Ein-Karem
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center, Beilinson Hospital
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
  • Tel-Hashomer, Israel, 5265601
    • The Chaim Sheba Medical Center
  • Zerifin, Israel, 7030000
    • Shamir Medical Center, Infectious Diseases Unit
• Italy
  • Foggia, Italy, 71122
    • Azienda Ospedaliero-Universitaria Ospedali Riuniti
  • Modena, Italy, 41124
    • Azienda Ospedaliero Universitaria di Modena
  • Modena, Italy, 41124
    • Farmacia Ospedaliera - Direzione Assistenza Farmaceutica
  • Modena, Italy, 41124
    • SC di Radiologia - Azienda Ospedaliera Universitaria di Modena
  • Pisa, Italy, 56100
    • Azienda Ospedaliero-Universitaria Pisana Ospedale Cisanello
  • Pisa, Italy, 56100
    • UO Radiognastostica 2 Azienda Ospedaliero-Universitaria Pisana Ospedale Cisanello
  • Pisa, Italy, 56126
    • UO Farmaceutica Azienda Ospedaliero-Universitaria Pisana
  • Udine, Italy, 33100
    • Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Presidio Ospedaliero Universitario Santa
  • Milan
    • Milano, Milan, Italy, 20122
      • Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 07441
    • Hallym University Kangnam Sacred Heart Hospital
  • Seoul, Korea, Republic of, 03312
    • The Catholic University of Korea, Eunpyeong St. Mary's Hospital
  • Incheon Gwang'yeogsiv
    • Incheon, Incheon Gwang'yeogsiv, Korea, Republic of, 21565
      • Gachon University Gil Medical Center - Infectious Disease
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
  • Pulau Pinang
    • Seberang Jaya, Pulau Pinang, Malaysia, 13700
      • Hospital Seberang Jaya
  • Terengganu
    • Kuala Terengganu, Terengganu, Malaysia, 20400
      • Hospital Sultanah Nur Zahirah
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Hospital Civil Fray Antonio Alcalde
  • Nuevo LEON
    • Monterrey, Nuevo LEON, Mexico, 64460
      • Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
• Philippines
  • Baguio City, Philippines, 2600
    • Baguio General Hospital and Medical Center
  • Davao City, Philippines, 8000
    • Davao Doctors Hospital
  • Iloilo City, Philippines, 5000
    • West Visayas State University Medical Center
  • Iloilo City, Philippines, 5000
    • St. Paul's Hospital of Iloilo, Inc.
  • Makati City, Philippines, 1229
    • Makati Medical Center
  • Manila, Philippines, 1000
    • Philippine General Hospital, Central Intensive Care Unit
  • Muntinlupa City, Philippines, 1780
    • Asian Hospital and Medical Center
  • Quezon City, Philippines, 1109
    • Quirino Memorial Medical Center
  • Quezon City, Philippines, 1112
    • St. Luke's Medical Center
  • Cavite
    • City Of Dasmarinas, Cavite, Philippines, 4114
      • De La Salle Medical and Health Sciences Institute
• Romania
  • Bucuresti, Romania, 021105
    • Institutul National de Boli Infectioase "Prof. Dr. Matei Bals"
  • Bucuresti, Romania, 030303
    • Spitalul Clinic de Boli Infectioase si Tropicale "Dr. Victor Babes"
  • Cluj-Napoca, Romania, 400348
    • Spitalul Clinic de Boli Infectioase Cluj-Napoca
  • Iasi, Romania, 700116
    • Spitalul Clinic de Boli Infectioase "Sf. Parascheva" Iasi
  • Timisoara, Romania, 300723
    • Spitalul Clinic Judetean de Urgenta "Pius Brinzeu"
• Russian Federation
  • Chelyabinsk, Russian Federation, 454048
    • Private Healthcare Institution "Clinical Hospital 'Russian Railroad Medicine, Chelyabinsk'"
  • Krasnodar, Russian Federation, 350012
    • State Budgetary Healthcare Institution "Regional Clinical Hospital No. 2" of the Ministry of Health
  • Novosibirsk, Russian Federation, 630051
    • GBUZ of Novosibirsk region "City Clinical Hospital # 2"
  • Perm, Russian Federation, 614107
    • State autonomous institution of healthcare of the Perm Region" City clinical hospital #4"
  • Saint-Petersburg, Russian Federation, 197022
    • FGBOU VO "The First St. Petersburg state medical university n. a. I.P. Pavlova"
  • Smolensk, Russian Federation, 214018
    • OGBUZ "Smolensk Regional Clinical Hospital"
  • Smolensk, Russian Federation, 214019
    • FSBEI of HE "Smolensk State Medical University" of the Ministry of Health of the RF
  • Smolensk, Russian Federation, 214019
    • Scientific Research Institute of Antimicrobial Chemotherapy
• Spain
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 08003
    • Parc de Salut Mar- Hospital del Mar
  • Cordoba, Spain, 14004
    • Hospital Universitario Reina Sofía
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Malaga, Spain, 29010
    • Hospital Regional Universitario de Málaga
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol
    • Terrassa, Barcelona, Spain, 08221
      • Hospital Universitario Mutua de Terrassa
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36312
      • Complejo Hospitalario Universitario de Vigo. Area Sanitaria de Vigo. Hospital Alvaro Cunqueiro
• Taiwan
  • Kaohsiung, Taiwan, 81362
    • Kaohsiung Veterans General Hospital
  • Kaohsiung City, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taichung City, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Taipei, Taiwan, 116
    • Taipei Municipal Wanfang Hospital
  • Taipei City, Taiwan, 10002
    • National Taiwan University Hospital
  • Yunlin
    • Douliou, Yunlin, Taiwan, 64041
      • National Taiwan University Hospital Yun-Lin Branch
• Thailand
  • Bangkok
    • Bangkoknoi, Bangkok, Thailand, 10700
      • Faculty of Medicine Siriraj Hospital
  • Khon Kaen
    • Muang, Khon Kaen, Thailand, 40002
      • Srinagarind Hospital, Division of Infectious Disease and Tropical Medicine
  • Nonthaburi
    • Muang, Nonthaburi, Thailand, 11000
      • Bamrasnaradura Infectious Disease Institute (BIDI)
  • Songkhla
    • Hat Yai, Songkhla, Thailand, 90110
      • Songklanagarind Hospital, Prince of Songkla University
• Turkey
  • Ankara, Turkey, 06100
    • Hacettepe Universitesi Tip Fakultesi
  • Ankara, Turkey, 06230
    • Ankara University Faculty of Medicine
  • Ankara, Turkey, 06800
    • T.C. Saglik Bakanligi Ankara Sehir Hastanesi
  • Istanbul, Turkey, 34899
    • Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi
  • Istanbul, Turkey, 34303
    • Acibadem Atakent Hospital
  • Izmir, Turkey, 35040
    • Ege University Faculty of Medicine
  • Kocaeli, Turkey, 41380
    • Kocaeli University Medical Faculty
  • Trabzon, Turkey, 61080
    • Karadeniz Technical University Medical Faculty Farabi Hospital
• Ukraine
  • Chernivtsi, Ukraine, 58001
    • OKU "Chernivetska oblasna klinichna likarnia", khirurhichne viddilennia
  • Dnipro, Ukraine, 49005
    • KZ "Dnipropetrovska oblasna klinichna likarnia im. I.I. Mechnykova", viddilennia khirurhii №2
  • Dnipro, Ukraine, 49102
    • Komunalnyi zaklad "Miska klinichna likarnia No.4" Dniprovskoi miskoi rady, viddilennia profpatolohii
  • Ivano-Frankivsk, Ukraine, 76008
    • Oblasna klinichna likarnia, viddilennia anesteziolohii ta intensyvnoi terapii
  • Ivano-Frankivsk, Ukraine, 76018
    • Ivano-Frankivska tsentralna miska klin likarnia, viddilennia khirurhii,
  • Kharkiv, Ukraine, 61103
    • DU "Instytut zahalnoi ta nevidkladnoi khirurhii imeni V.T. Zaitseva Natsionalnoi akademii medychnykh
  • Kyiv, Ukraine, 02125
    • Kyivska miska klinichna likarnia No. 3, khirurhichne viddilennia
  • Kyiv, Ukraine, 03110
    • Kyivska miska klinichna likarnia #4, khirurhichne viddilennia #1
  • Lviv, Ukraine, 79010
    • Komunalne nekomertsiine pidpryiemstvo Lvivskoi oblasnoi rady Lvivska oblasna klinichna likarnia
  • Odesa, Ukraine, 65059
    • Odeska klinichna likarnia na zaliznychnomu transporti filii "Tsentr okhorony zdorovia" aktsionernoho
  • Poltava, Ukraine, 36039
    • Komunalne pidpryiemstvo "1-a miska klinichna likarnia Poltavskoi miskoi rady",
  • Vinnytsia, Ukraine, 21018
    • Vinnytska oblasna klinichna likarnia im. M.I. Pyrohova
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • Banner University Medical Center - Tucson
  • California
    • Torrance, California, United States, 90502
      • Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
    • Torrance, California, United States, 90509
      • Harbor-UCLA Medical Center
  • Illinois
    • Springfield, Illinois, United States, 62781
      • Memorial Medical Center
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

All subjects:

1. Male or female from 18 years of age
2. Provision of informed consent
3. Confirmed diagnosis of HAP/VAP or cIAI requiring iv antibiotic treatment
4. Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met and negative pregnancy test

Additional for cIAI:

1. Diagnosis of cIAI, EITHER:

   Intra-operative/postoperative enrolment with visual confirmation of cIAI. OR Preoperative enrollment with evidence of systemic inflammatory response, physical and radiological findings consistent with cIAI; confirmation of cIAI at time of surgery within 24 hours of study entry

2. Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug

Additional for HAP/VAP:

1. Onset symptoms > 48h after admission to or <7 days after discharge from an inpatient care facility
2. New or worsening infiltrate on CXR or CT scan
3. Clinical signs and symptoms and laboratory findings consistent with HAP/VAP
4. Respiratory specimen obtained for Gram stain and culture following onset of symptoms and prior to randomisation

Exclusion criteria:

All subjects:

1. APACHE II score > 30
2. Confirmed or suspected infection caused by Gram-negative species not expected to respond to study drug, or Gram-positive species
3. Receipt of >24 hr systemic antibiotic within 48h prior to randomisation (exception in case of treatment failure)
4. History of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to aztreonam, carbapenem,monobactam or other β-lactam antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of the study drugs
5. Known Clostridium difficle associated diarrhoea
6. Requirement for effective concomitant systemic antibacterials or antifungals
7. Creatinine clearance ≤15 ml/min or requirement or expectation for renal replacement therapy
8. Acute hepatitis, cirrhosis, acute hepatic failure, chronic hepatic failure
9. Hepatic disease as indicated by AST or ALT >3 × ULN. Patients with AST and/or ALT up to 5 × ULN are eligible if acute and documented by the investigator as being directly related infectious process
10. Patient has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilbert's disease
11. ALP >3 × ULN. Patients with values >3 × ULN and <5 x ULN are eligible if acute and directly related to the infectious process being treated
12. Absolute neutrophil count <500/mm3
13. Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control.
14. Any other condition that may confound the results of the study or pose additional risks to the subject
15. Unlikely to comply with protocol
16. History of epilepsy or seizure disorders excluding febrile seizures of childhood

Additional for cIAI

1. Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours of diagnosis; perforation of gastroduodenal ulcer with surgery < 24 hours of diagnosis primary etiology is not likely to be infectious
2. Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess
3. Prior liver, pancreas or small-bowel transplant
4. Staged abdominal repair (STAR), open abdomen technique or marsupialisation

Additional for HAP/VAP

1. APACHE II score < 10
2. Known or high likelihood of Gram-positive monomicrobial infection
3. Lung abscess, pleural empyema, post-obstructive pneumonia
4. Lung or heart transplant
5. Myasthenia gravis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aztreonam-Avibactam ± Metronidazole; All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover	Drug: ATM-AVI; (Creatinine clearance > 50 mL/min) 6500 mg ATM/2167 mg (loading dose, extended loading dose and maintenance dose) by iv infusion on Day 1 followed by a total daily dose of 6000 mg ATM/2000 mg AVI (Creatinine clearance 31 - 50 mL/min) 4250 mg ATM/1417 mg AVI on Day 1 (loading dose, extended loading dose, maintenance dose) followed by total daily dose 3000 mg ATM/1000 mg AVI (Creatinine clearance 16 - 30 mL/min) 2700 mg ATM/900 mg AVI on Day 1 (loading dose, extended loading dose maintenance dose), followed by total daily dose 2025 mg ATM/675 mg AVI; Drug: MTZ; For cIAI only; 500 mg/100 mL metronidazole iv infusion over 1hr q8h
Active Comparator: Meropenem ± Colistin; All patients randomised to this arm will receive MER; addition of COL will be at investigator's discretion in line with local practice	Drug: MER; Where pathogen initially not suspected of being MER-resistant: (Creatinine clearance > 50 mL/min) 1000 mg meropenem by 30 min iv infusion q8h (Creatinine clearance 26 - 50 mL/min) 1000mg meropenem by 30 min iv infusion q12h (Creatinine clearance 16 - 25 mL/min) 500 mg meropenem by 30 min iv infusion q12h Where pathogen initially suspected of being MER-resistant (Creatinine clearance > 50 mL/min) 2000 mg meropenem by 180 min iv infusion q8h (Creatinine clearance 26 - 50 mL/min) 2000 mg meropenem by 180 min iv infusion q12h (Creatinine clearance 16 - 25 mL/min) 1000 mg meropenem by 180 min iv infusion q12h; Drug: COL; Loading dose 9 million IU by 30 -60 min iv infusion (6 million IU where weight < 60 kg) followed by one of the following maintenance doses: (Creatinine clearance > 50 mL/min) after a 12h interval, commence maintenance dosing 9 million IU daily in 2 or 3 divided doses by 30 -60 min iv infusions. (Creatinine clearance 31 - 50 mL/min) After a 24 hr interval, commence maintenance dosing of 6 million IU daily in 2 divided doses by 30 -60 min iv infusion (Creatinine clearance 21 - 30 mL/min) After a 24 hr interval, commence maintenance dosing 5 million IU daily in 2 divided doses by 30 -60 min iv infusion (Creatinine clearance 16 - 20 mL/min) after a 24 hr interval, commence maintenance dosing 4 million IU daily in 2 divided doses by 30 -60 min iv infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with clinical cure in the ITT and CE analysis sets	Proportion of subjects meeting the criteria for clinical cure	Test of Cure (TOC) visit, Day 28 +/- 3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with clinical cure in the m-ITT and ME analysis sets	Proportion of subjects meeting the criteria for clinical cure	Test of Cure (TOC) visit, Day 28 (+/- 3 days)
Proportion of subjects with clinical cure by infection type in the ITT and CE analysis sets.	Proportion of subjects meeting the criteria for clinical cure	Test of Cure (TOC) visit, Day 28 (+/- 3 days)
Proportion of subjects with clinical cure for subjects with MBL positive pathogens in the micro ITT and ME analysis sets.	Proportion of subjects meeting the criteria for clinical cure	Test of Cure (TOC) visit, Day 28 (+/- 3 days)
Proportion of subjects with a favorable per subject microbiological response in the micro ITT and ME analysis sets.	Proportion of subjects with a favourable microbiological response (aggregate of eradication + presumed eradication)	Test of Cure (TOC) visit, Day 28 (+/- 3 days)
Proportion of subjects who died	Daily mortality assessment	Day 28
PK of ATM	Plasma concentration of ATM	Days 1 and 4
PK/PD relationship between exposure and clinical response for ATM AVI±MTZ in the popPK analysis set	Correlation between plasma concentration of ATM and clinical cure	Test of Cure (TOC) visit, Day 28 (+/- 3 days)
PK of AVI	Plasma concentration of AVI	Days 1 and 4
PK/PD relationship between exposure and clinical response for ATM/AVI +/- MTZ in the popPK analysis set	Correlation between concentration of AVI and clinical cure	Test of Cure (TOC) days 28 (+/- 3 days)
PK/PD relationship between exposure and microbiological response for ATM/AVI+/-MTZ in the popPK analysis set	Correlation between plasma concentration of ATM and microbiological response	Test of Cure (TOC) visit, Days 28 (+/- 3 days)
PK/PD relationship between exposure and microbiological response for ATM/AVI+/-MTZ in the popPK analysis set	Correlation between plasma concentration of AVI and microbiological response	Test of Cure (TOC) visit, day 28 (+/- 3 days)
Description of safety in terms of adverse events	Descriptive summary of adverse events	Throughout study to Late Follow Up visit (Day 45 +/- 3 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with clinical cure in the ITT, micro ITT, CE and ME analysis sets	Proportion of subjects meeting the criteria for clinical cure	End of Treatment (EOT) visit (variable, between Days 1 and 15)
Proportion of subjects with clinical cure by infection type in the ITT and CE analysis sets	Proportion of subjects meeting the criteria for clinical cure	End of Treatment (EOT) visit (variable, between Days 1 and 15)
Proportion of subjects with a favorable per subject microbiological response in the the micro ITT and ME analysis sets	Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)	End of Treatment (EOT) visit (variable, between Days 1 and 15)
Proportion of subjects with a favorable per pathogen microbiological response in the micro ITT and ME analysis sets	Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)	End of Treatment (EOT), (variable between Days 1 and 15)
Proportion of subjects with a favorable per subject microbiological response by pathogen resistance type (eg, ATM resistant, ESBL positive, carbapenamase positive, MBL positive) in the micro ITT and ME analysis sets	Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)	End of Treatment (EOT), (variable, between Days 1 and 15)
Proportion of subjects with a favorable per pathogen microbiological response by pathogen resistance type in the micro ITT and ME analysis sets	Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)	End of Treatment (EOT) visits, (variable between Days 1 and 15)
Proportion of subjects with clinical cure using objective clinical measures	Proportion of subjects with clinical cure	Test of Cure (TOC) visit, Day 28 +/- 3 days)
Proportion of subjects who died	Daily mortality assessment	Day 14
Health resource utilization in terms of length of hospital stay	Length of hospital stay (days), including any readmissions	Test of Cure (TOC), Day 28 +/- 3 days
Relationship between (as yet undetermined) biomarkers and liver transaminase elevations in response to exposure to ATM-AVI	Correlation between (yet to be determined) plasma biomarkers and elevated liver transaminases	Day 1 and 4
Proportion of subjects with a favorable per pathogen microbiological response in the micro ITT and ME analysis sets	Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)	Test of Cure (TOC) visit (Day 28 +/- 3 days)
Proportion of subjects with a favorable per subject microbiological response by pathogen resistance type (eg, ATM resistant, ESBL positive, carbapenamase positive, MBL positive) in the micro ITT and ME analysis sets	Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)	Test of Cure (TOC) visits, Day 28 +/- 3 days
Proportion of subjects with a favorable per pathogen microbiological response by pathogen resistance type in the micro ITT and ME analysis sets	Proportion of subjects with a favourable microbiological response (aggregate of eradication and presumed eradication)	Test of Cure (TOC) visits, Day 28 +/- 3 days
Health resource utilization in terms of treatment duration	Length of study treatment (days)	Test of Cure (TOC), Day 28 +/- 3 days
Health resource utilization in terms of length of ICU stay	Length of intensive care unit (ICU) stay (days)	Test of Cure (TOC), Day 28 +/- 3 days
Health resource utilization in terms of transfer to ICU	Transfer to the ICU (Yes/No)	Test of Cure (TOC), Day 28 +/- 3 days
Health resource utilization in terms of use of mechanical ventilation	Mechanical ventilation (Yes/No) for HAP/VAP subjects	Test of Cure (TOC), Day 28 +/- 3 days
Health resource utilization in terms of duration of mechanical ventilation	Length of mechanical ventilation (days) for HAP/VAP subjects	Test of Cure (TOC), Day 28 +/- 3 days
Health resource utilization in terms of subsequent unplanned surgical intervention	Subsequent unplanned surgical intervention (YES/NO) for cIAI subjects	Test of Cure (TOC), Day 28 +/- 3 days

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Biomedical Advanced Research and Development Authority; Innovative Medicines Initiative (IMI) COMBACTE-CARE (EU)
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2018
• Primary Completion (Actual): February 23, 2023
• Study Completion (Actual): February 23, 2023

Study Registration Dates

• First Submitted: October 6, 2017
• First Submitted That Met QC Criteria: October 27, 2017
• First Posted (Actual): November 1, 2017

Study Record Updates

• Last Update Posted (Actual): June 26, 2023
• Last Update Submitted That Met QC Criteria: June 23, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Complicated intra-abdominal infection; Hosptial acquired pneumonia; Ventilator associated pneumonia; Gram negative infections; Metallo-beta lactamase; Multi drug resistant pathogens
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Infections; Communicable Diseases; Pneumonia; Intraabdominal Infections; Pneumonia, Ventilator-Associated
• Other Study ID Numbers: C3601002; D4910C00004 (Other Identifier: Alias Study Number); 2017-002742-68 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No