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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 422
- 试验地点
- 156
- 主要终点
- Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: Intent-To-Treat (ITT) Analysis Set
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
An independent adjudication committee (central blinded assessor) will be convened at regular intervals during the study. The adjudication committee will be blinded to study treatment and will review the clinical response assessments at each visit. In case of a discrepancy with the Investigator's assignment of clinical response, the adjudication committee's assessment will prevail.
In addition, for cIAI subjects classified as a clinical failure, and all cIAI subjects classified as a cure who undergo another procedure (eg, another surgical procedure) subsequent to randomization, the expert panel will review the adequacy of the surgical source control.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All subjects:
- •Male or female from 18 years of age
- •Provision of informed consent
- •Confirmed diagnosis of HAP/VAP or cIAI requiring iv antibiotic treatment
- •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:
- •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
- •Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug
- •Additional for HAP/VAP:
- •Onset symptoms > 48h after admission to or <7 days after discharge from an inpatient care facility
- •New or worsening infiltrate on CXR or CT scan
- •Clinical signs and symptoms and laboratory findings consistent with HAP/VAP
- •Respiratory specimen obtained for Gram stain and culture following onset of symptoms and prior to randomisation
- •Exclusion criteria:
- •All subjects:
- •APACHE II score > 30
- •Confirmed or suspected infection caused by Gram-negative species not expected to respond to study drug, or Gram-positive species
- •Receipt of >24 hr systemic antibiotic within 48h prior to randomisation (exception in case of treatment failure)
- •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
- •Known Clostridium difficle associated diarrhoea
- •Requirement for effective concomitant systemic antibacterials or antifungals
- •Creatinine clearance ≤15 ml/min or requirement or expectation for renal replacement therapy
- •Acute hepatitis, cirrhosis, acute hepatic failure, chronic hepatic failure
- •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
- •Patient has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilbert's disease
- •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
- •Absolute neutrophil count <500/mm3
- •Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control.
- •Any other condition that may confound the results of the study or pose additional risks to the subject
- •Unlikely to comply with protocol
- •History of epilepsy or seizure disorders excluding febrile seizures of childhood
- •Additional for cIAI
- •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
- •Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess
- •Prior liver, pancreas or small-bowel transplant
- •Staged abdominal repair (STAR), open abdomen technique or marsupialisation
- •Additional for HAP/VAP
- •APACHE II score < 10
- •Known or high likelihood of Gram-positive monomicrobial infection
- •Lung abscess, pleural empyema, post-obstructive pneumonia
- •Lung or heart transplant
- •Myasthenia gravis
排除标准
- 未提供
研究组 & 干预措施
Aztreonam-Avibactam ± Metronidazole
All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover
干预措施: ATM-AVI (Drug)
Aztreonam-Avibactam ± Metronidazole
All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover
干预措施: MTZ (Drug)
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
干预措施: MER (Drug)
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
干预措施: COL (Drug)
结局指标
主要结局
Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: Intent-To-Treat (ITT) Analysis Set
时间窗: At TOC visit (Day 28)
Clinical cure was defined as improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by the Independent Clinical Adjudication Committee. 95% confidence interval (CI) was based on Jeffrey's method.
Percentage of Participants With Clinical Cure at TOC Visit: Clinically Evaluable (CE) Analysis Set
时间窗: At TOC visit (Day 28)
Clinical cure = improvement in baseline signs and symptoms such that after study treatment, no further antimicrobial treatment for the index infection (i.e., cIAI or HAP/VAP) was required. Additionally for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. Clinical cure was determined by Independent Clinical Adjudication Committee. 95% CI was based on Jeffrey's method. CE analysis set:all participants in ITT analysis set; met criteria for cIAI, or HAP/VAP; received at least 48 hours of study treatment or \<48 hours of treatment before discontinuing study drug due to AE; no concomitant antibiotics for any baseline pathogens between first dose and TOC (except protocol-allowed antibiotics); no prior antibiotics other than allowed per protocol; no important protocol deviations; no clinical outcome of indeterminate at TOC; no monomicrobial infections due to non-eligible pathogens and did not have only Gram-positive pathogens.
次要结局
- Percentage of Participants With Clinical Cure at TOC Visit: Microbiological Intent-To-Treat (Micro-ITT) Analysis Set(At TOC visit (Day 28))
- Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Evaluable (ME) Analysis Set(At TOC visit (Day 28))
- Percentage of Participants With Clinical Cure at TOC Visit by Type of Infection: ITT Analysis Set(At TOC visit (Day 28))
- Percentage of Participants With Clinical Cure at TOC Visit by Type of Infection: CE Analysis Set(At TOC visit (Day 28))
- Percentage of Participants With Clinical Cure in Participants With Metallo-beta-lactamase (MBL) Positive Pathogen at TOC Visit: Micro-ITT Analysis Set(At TOC visit (Day 28))
- Percentage of Participants With Clinical Cure in Participants With MBL Positive Pathogen at TOC Visit: ME Analysis Set(At TOC visit (Day 28))
- Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit: Micro- ITT Analysis Set(At TOC visit day (28))
- Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit: ME Analysis Set(At TOC Visit (Day 28))
- Percentage of Participants Who Died on or Before 28 Days After Randomization: ITT Analysis Set(From randomization up to 28 days)
- Percentage of Participants Who Died on or Before 28 Days After Randomization: Micro-ITT Analysis Set(From randomization up to 28 days)
- Plasma Concentration of Aztreonam(Anytime between 25 to 30 minutes, 3.25 to 3.5 hours, 5.5 to 6.5 hours, 7.5 to 8.5 hours post start of infusion on Day 1; 2.75 to 3 hours, 3.5 to 4.5 hours, 5 to 6 and 7 to 8 hours post start of infusion on Day 4)
- Plasma Concentration of Avibactam(Anytime between 25 to 30 minutes, 3.25 to 3.5 hours, 5.5 to 6.5 hours, 7.5 to 8.5 hours post start of infusion on Day 1; 2.75 to 3 hours, 3.5 to 4.5 hours, 5 to 6 and 7 to 8 hours post start of infusion on Day 4)
- Maximum Plasma Concentration for a Dosing Interval at Steady-State (Cmax, ss) According to Clinical Response by Infection Type at TOC: Aztreonam(At TOC (Day 28))
- Percentage of Time That Free Plasma Concentrations Are Above the Minimum Inhibitory Concentration Over a Dosing Interval (%fT>MIC Aztreonam (ATM) of 8 mg/L) According to Clinical Response by Infection Type at TOC: Aztreonam(At TOC (Day 28))
- Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss ) According to Clinical Response by Infection Type at TOC: Aztreonam(0 to 24 hours at TOC (Day 28))
- Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss) According to Microbiological Response by Infection Type at TOC: Aztreonam(At TOC (Day 28))
- Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Microbiological Response by Infection Type at TOC: Aztreonam(0 to 24 hours at TOC (Day 28))
- Percentage of Time That Free Plasma Concentrations Are Above the Minimum Inhibitory Concentration Over a Dosing Interval (%fT>MIC Aztreonam (ATM) of 8 mg/L) According to Microbiological Response by Infection Type at TOC: Aztreonam(At TOC (Day 28))
- Percent of Time That Free Plasma Concentrations Are Above the Threshold Concentration Over a Dosing Interval (%fT>CT of 2.5mg/L) According to Clinical Response by Infection Type at TOC: Avibactam(At TOC (Day 28))
- Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Clinical Response by Infection Type at TOC: Avibactam(0 to 24 hours at TOC (Day 28))
- Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss ) According to Clinical Response by Infection Type at TOC: Avibactam(At TOC (Day 28))
- Area Under the Plasma Concentration-time Curve Over 24 Hours at Steady-state (AUC24,ss) According to Microbiological Response by Infection Type at TOC: Avibactam(0 to 24 hours At TOC (Day 28))
- Maximum Plasma Concentration for a Dosing Interval at Steady-state (Cmax,ss (mg/L)) According to Microbiological Response by Infection Type at TOC: Avibactam(At TOC (Day 28))
- Percent of Time That Free Plasma Concentrations Are Above the Threshold Concentration Over a Dosing Interval; (%fT>CT of 2.5 mg/L) According to Microbiological Response by Infection Type at TOC: Avibactam(At TOC (Day 28))
- Number of Participants With Adverse Events (AEs) and Serious AEs(From start of study treatment until end of late follow-up (Up to Day 45))
- Number of Participants With Potentially Clinically Significant Hematology Abnormalities(From start of study treatment until TOC visit (Up to Day 28))
- Number of Participants With Abnormalities in Vital Signs(From start of study treatment until TOC visit (Up to Day 28))
- Number of Participants With Potentially Clinically Significant Clinical Chemistry Abnormalities(From start of study treatment until At TOC visit (Up to Day 28))
- Number of Participants With Abnormal Physical Examination Finding(Screening, End of treatment (up to 24 hours post infusion on Day 14) and Test of Cure (Day 28))
- Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings(Baseline (latest non-missing value before start of treatment) and Day 3)