Efficacy and Safety of CAZ-AVI in the Treatment of Infections Due to Carbapenem-resistant G- Pathogens in Chinese Adults

AN OPEN-LABEL, RANDOMIZED, MULTI-CENTER, ACTIVE-CONTROLLED STUDY TO ESTIMATE THE EFFICACY AND SAFETY OF CEFTAZIDIME-AVIBACTAM (CAZ-AVI) VERSUS BEST AVAILABLE TREATMENT (BAT) IN THE TREATMENT OF INFECTIONS DUE TO CARBAPENEM-RESISTANT GRAM-NEGATIVE PATHOGENS IN CHINESE ADULTS

This is an open-label, randomized, multi-center, interventional, active-controlled Phase 4 study to evaluate the efficacy and safety of CAZ-AVI versus BAT in the treatment of infected participants with selected infection types (Hospital Acquired Pneumonia [HAP] (including Ventilator-Associated Pneumonia [VAP]); Complicated Urinary-Tract Infection [cUTI]; Complicated Intra-Abdominal Infection [cIAI]; Bloodstream Infection [BSI]) due to carbapenem-resistant Gram-negative pathogens in China.This study will be an estimation study. The statistical inference will be based on point estimate and confidence interval.

Study Overview

• Status: Completed
• Conditions: Bacteremia; Urinary Tract Infection; Intra-abdominal Infection; Hospital Acquired Pneumonia; Acute Pyelonephritis; Ventilator-associated Pneumonia
• Intervention / Treatment: Drug: Zavicefta, Ceftazidime-Avibactam; Drug: Best Available Treatment

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Jiangyin, China, 214400
    • Jiangyin People's Hospital
  • Shanghai, China, 200240
    • Shanghai Fifth People's Hospital, Fudan University
  • Anhui
    • Bengbu, Anhui, China, 233004
      • The First Affiliated Hospital of Bengbu Medical College
    • Bengbu, Anhui, China, 233000
      • The First Affiliated Hospital of Bengbu Medical
    • Chizhou, Anhui, China, 247000
      • Chizhou People's Hospital
    • Fuyang, Anhui, China, 236000
      • Fuyang People's Hospital
  • Beijing
    • Beijing, Beijing, China, 100191
      • Peking University Third Hospital
  • Fujian
    • Xiamen, Fujian, China, 361004
      • Zhongshan Hospital Xiamen University
  • Guangdong
    • Guangzhou, Guangdong, China, 510180
      • Guangzhou First People's Hospital
    • Qingyuan, Guangdong, China, 511518
      • Qingyuan People's Hospital
    • Shenzhen, Guangdong, China, 518020
      • ShenZhen People's Hospital
    • Shenzhen, Guangdong, China, 518035
      • The Second People's Hospital of Shenzhen
    • Zhanjiang, Guangdong, China, 524000
      • Affiliated Hospital Of Guangdong Medical University
  • Guangxi
    • Guilin, Guangxi, China, 541001
      • Affiliated Hospital of Guilin Medical College
  • Guizhou
    • Zunyi, Guizhou, China, 563000
      • Affiliated Hospital of Zunyi Medical University
  • Hebei
    • Baoding, Hebei, China, 071000
      • Affiliated Hospital of Hebei University
  • Henan
    • Luoyang, Henan, China, 471009
      • Luoyang Central Hospital
    • Nanyang, Henan, China, 473000
      • Nanyang Central Hospital
    • Zhengzhou, Henan, China, 450003
      • Henan Provincial People's Hospital
    • Zhengzhou, Henan, China, 450000
      • Henan Provincial People's Hospital
  • Inner Mongolia Autonomous Region
    • Baotou, Inner Mongolia Autonomous Region, China, 014000
      • Baotou Central Hospital
  • Jiangsu
    • Jiangyin, Jiangsu, China, 214400
      • Jiangyin People's Hospital
    • Xuzhou, Jiangsu, China, 221006
      • Affiliated Hospital of Xuzhou Medical University
    • Yangzhou, Jiangsu, China, 225001
      • Subei People's Hospital of Jiangsu province
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Jiangxi Provincial People's Hospital
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital, Fudan University
  • Sichuan
    • Chengdu, Sichuan, China, 610055
      • Chengdu Xinhua Hospital
  • Tianjin
    • Tianjin, Tianjin, China, 300222
      • Tianjin Chest Hospital
  • Yunnan
    • Kunming, Yunnan, China, 650034
      • The First People's Hospital of kunming
    • Kunming, Yunnan, China, 650034
      • The First People's Hospital of Kunming (South Hospital)
    • Kunming, Yunnan, China, 650224
      • The First People's Hospital of Kunming Ganmei Hospital (North Hospital)
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310014
      • Zhejiang Provincial People's Hospital
    • Hangzhou, Zhejiang, China, 310013
      • Zhejiang Hospital
    • Lishui, Zhejiang, China, 323000
      • Lishui People's Hospital
    • Taizhou, Zhejiang, China, 317000
      • Taizhou Hospital of Zhejiang Province
    • Wenzhou, Zhejiang, China, 325035
      • The 2nd Affiliated Hospital of WMU
    • Wenzhou, Zhejiang, China, 325099
      • Wenzhou Central Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Male or female >18 years of age
• Participant must have a diagnosis of an infection (HAP/VAP, cUTI, cIAI, BSI) due to confirmed carbapenem-resistant aerobic Gram-negative pathogens, requiring administration of IV antibacterial therapy
• Participant who had received appropriate prior empiric antibacterial therapy for a carbapenem-resistant pathogen must meet at least 1 of the following criteria: no or no more than 24h; worsening of objective symptoms or signs after at least 48 hours of antibacterial therapy; no change of objective symptoms or signs after at least 72 hours of antibacterial therapy.
• Capable of giving signed informed consent

Exclusion Criteria:

• Other medical or psychiatric condition may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
• Participant is expected to require more than 21 days of treatment
• Participants who need more than 3 systemic antibiotics as part of best available treatment (BAT)
• Previous administration with an investigational drug within 30 days or 5 half lives preceding the first dose of study intervention used in this study (whichever is longer).
• Participant is pregnant or breastfeeding.
• Acute Physiology and Chronic Health Evaluation (APACHE) II score >30 or <10 using the most recent available data.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CAZ-AVI; ceftazidime 2g plus avibactam 0.5g	Drug: Zavicefta, Ceftazidime-Avibactam; CAZ-AVI 2.5 g (2 g ceftazidime + 0.5 g avibactam) administered IV as a 2 hour infusion every 8 hours. Dose adjustments are available for participants with CrCL ≤50 mL/min.
Active Comparator: Best Available Treatment; Based on investigative site practice and local epidemiology and guideline	Drug: Best Available Treatment; main treatment expected to be used as either monotherapy or in combination are colistin, tigecycline, fosfomycin, amikacin, and meropenem

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit - Microbiologically Modified Intent-to-Treat (mMITT) 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, complicated intra-abdominal infection [cIAI], complicated urinary-tract infection [cUTI], hospital-acquired pneumonia/ventilator-associated pneumonia [HAP/VAP] or bloodstream infection [BSI]) after study treatment. Also, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response was assessed by the independent adjudication committee. 95 percent (%) confidence interval (CI) was calculated using Jeffrey's method.	At TOC visit (From Day 21 up to Day 24)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Clinical Cure at TOC Visit - Microbiologically Evaluable (ME) Analysis Set	Clinical cure: improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for 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 initial procedure. 95% CI based on Jeffrey's method. ME analysis set (sub-set of mMITT): participants who received 3 days of study intervention, or received study intervention for >=48 hours with >= 80% compliance, or for <48 hours before discontinuation due to adverse event, no concomitant antibiotics against baseline carbapenem-resistant gram negative pathogens between first dose and TOC (excluding participants with failed study therapy requiring additional antibiotics), had baseline organisms genetically confirmed by central microbiological testing, no indeterminate clinical outcome at end of treatment (EOT) or TOC visits, no important protocol deviations that affect assessment of efficacy.	At TOC visit (From Day 21 up to Day 24)
Percentage of Participants With Clinical Cure at End of Treatment (EOT) Visit -mMITT 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 was assessed by the independent adjudication committee. 95% CI was calculated using Jeffrey's method.	At EOT visit (up to 24 hours after the last infusion on Day 14)
Percentage of Participants With Clinical Cure at EOT Visit - ME Analysis Set	Clinical cure: improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for 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 initial procedure. 95% CI based on Jeffrey's method. ME analysis set (sub-set of mMITT): participants who received 3 days of study intervention, or received study intervention for >=48 hours with >= 80% compliance, or for <48 hours before discontinuation due to adverse event, no concomitant antibiotics against baseline carbapenem-resistant gram negative pathogens between first dose and TOC (excluding participants with failed study therapy requiring additional antibiotics), had baseline organisms genetically confirmed by central microbiological testing, no indeterminate clinical outcome at EOT or TOC visits, no important protocol deviations that affect assessment of efficacy.	At EOT visit (up to 24 hours after the last infusion on Day 14)
Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit - mMITT Analysis Set	Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 colony forming units per milliliter [CFU/mL] for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/ clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). 95% CI was calculated using Jeffrey's method.	At TOC visit (From Day 21 up to Day 24)
Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit - ME Analysis Set	Favorable microbiological response=eradication: absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from appropriately obtained specimen at site of infection or presumed eradication: repeat culture of specimens were not performed/clinically indicated in participant who had clinical cure (specific to cIAI,HAP/VAP participants). 95% CI was calculated using Jeffrey's method. ME analysis set: participants received 3 days of study intervention,or received study intervention for >= 48 hours with >=80% compliance or for <48 hours before discontinuation due to adverse event, no concomitant antibiotics against baseline carbapenem-resistant gram negative pathogens between first dose and TOC (excluding participants with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing, no indeterminate clinical outcome at EOT/TOC, no important protocol deviations that affect assessment of efficacy.	At TOC visit (From Day 21 up to Day 24)
Percentage of Participants With Favorable Per-Participant Microbiological Response at EOT Visit - mMITT Analysis Set	Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). 95% CI was calculated using Jeffrey's method.	At EOT visit (Up to 24 hours after last infusion on Day 14)
Percentage of Participants With Favorable Per-Participant Microbiological Response at EOT Visit - ME Analysis Set	Favorable microbiological response=eradication: absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from appropriately obtained specimen at site of infection or presumed eradication: repeat culture of specimens were not performed/clinically indicated in participant who had clinical cure (specific to cIAI,HAP/VAP participants). 95% CI was calculated using Jeffrey's method. ME analysis set: participants received 3 days of study intervention,or received study intervention for >= 48 hours with >=80% compliance or for <48 hours before discontinuation due to adverse event, no concomitant antibiotics against baseline carbapenem-resistant gram negative pathogens between first dose and TOC (excluding participants with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing, no indeterminate clinical outcome at EOT/TOC, no important protocol deviations that affect assessment of efficacy.	At EOT visit (Up to 24 hours after last infusion on Day 14)
Percentage of Participants With Favorable Per-Pathogen Microbiological Response at TOC Visit - mMITT Analysis Set	Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). 95% CI was calculated using Jeffrey's method.	At TOC visit (From Day 21 up to Day 24)
Percentage of Participants With Favorable Per-Pathogen Microbiological Response at EOT Visit - mMITT Analysis Set	Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). 95% CI was calculated using Jeffrey's method.	At EOT visit (Up to 24 hours after last infusion on Day 14)
Percentage of Participants Who Died Due to Any Cause Until Day 28	Percentage of participants who died due to any cause up to Day 28 was reported in this outcome measure. The 95% CI was calculated using the Jeffrey's method.	From first dose of study intervention (Day 1) up to Day 28
Number of Participants With Treatment-Emergent Adverse Events	An adverse event (AE) was any untoward medical occurrence in a study participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment-emergent adverse event (TEAE) was any AE that started after the study intervention start date and time.	From start of study treatment on Day 1 up to 32 days after the last dose of study intervention (Up to 46 days)
Number of Participants With Discontinuation Due to Adverse Events	Number of participants who discontinued the study due to adverse events were reported in this outcome measure. Discontinuations from study due to TEAEs included all participants with an AE record indicating that the AE caused permanent discontinuation from the study. Permanent discontinuations from any study intervention due to TEAEs included participants with an AE record indicating that action taken with study treatment was drug withdrawn but AE did not cause the participant to be discontinued from study.	From start of study treatment on Day 1 up to 32 days after the last dose of study intervention (Up to 46 days)
Number of Participants With Potentially Clinically Significant Post-baseline Hematology Values	Potentially clinically significant hematology parameters included Hemoglobin (gram/deciliter), Hematocrit (%), Erythrocytes (10^12/Liter [L]): value < 0.8*lower limit of normal (LLN) and change (Chg) > 20% decrease, value > 1.3*upper limit of normal (ULN) and Chg > 30% increase. Platelets (10^9/L): Value < 0.65*LLN and Chg > 50% decrease, Value > 1.5*ULN and Chg > 100% increase. Leukocytes (10^9/L): Value < 0.65*LLN and Chg > 60% decrease, Value > 1.6*ULN and Chg > 100% increase. Lymphocytes (10^9/L): Value < 0.25*LLN and Chg > 75% decrease, Value > 1.5*ULN and Chg > 100% increase. Neutrophils (10^9/L): Value < 0.65*LLN and Chg > 75% decrease, Value > 1.6*ULN and Chg > 100% increase. Basophils (10^9/L), Eosinophils (10^9/L), Monocytes (10^9/L): Value > 4.0*ULN and Chg > 300% increase. Number of participants with potentially clinically significant values for any hematology parameters were reported in this outcome measure.	From first dose of study treatment (Day 1) until TOC (Up to Day 24)
Number of Participants With Potentially Clinically Significant Post-baseline Clinical Chemistry Values	Potentially clinically significant criteria included Bilirubin(mg/dL): >2.0*ULN and Chg >150% increase (inc).Aspartate Aminotransferase,Alanine Aminotransferase(Units/Liter[U/L]):>3.0*ULN and Chg >200% inc.Alkaline Phosphatase(U/L):<0.5*LLN and Chg >80% decrease (dec),> 2.0*ULN and Chg >100% inc.Protein,Albumin(g/dL):<0.5*LLN and Chg >50% dec,>1.5*ULN and Chg >50% inc.Blood Urea Nitrogen(mg/dL):<0.2*LLN and Chg >100% dec, >3.0*ULN and Chg >200% inc.Creatinine(mg/dL):>2.0*ULN and Chg >100% inc.Sodium(milliequivalent[mEq]/L):<0.85*LLN and Chg >10% dec, >1.1*ULN and Chg >10% inc.Potassium,Chloride(mEq/L):<0.8*LLN and Chg >20% dec, >1.2*ULN and Chg >20% inc.Calcium(mg/dL):<0.7*LLN and Chg >30% dec,> 1.3*ULN and Chg >30% inc.Bicarbonate(mEq/L):<0.7*LLN and Chg >40% dec, >1.3*ULN and Chg >40% inc.Glucose(mg/dL):<0.6*LLN and Chg >40% dec, >3.0*ULN and Chg >200% inc.Number of participants with potentially clinically significant values for any clinical chemistry parameters were reported.	From first dose of study treatment (Day 1) until TOC (Up to Day 24)

Collaborators and Investigators

• Sponsor: Pfizer
• 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): August 26, 2021
• Primary Completion (Actual): August 31, 2023
• Study Completion (Actual): August 31, 2023

Study Registration Dates

• First Submitted: April 27, 2021
• First Submitted That Met QC Criteria: May 10, 2021
• First Posted (Actual): May 11, 2021

Study Record Updates

• Last Update Posted (Actual): October 21, 2024
• Last Update Submitted That Met QC Criteria: August 1, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Kidney Diseases; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Cross Infection; Iatrogenic Disease; Sepsis; Nephritis; Nephritis, Interstitial; Pyelitis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Infections; Communicable Diseases; Healthcare-Associated Pneumonia; Pneumonia; Intraabdominal Infections; Bacteremia; Urinary Tract Infections; Pneumonia, Ventilator-Associated; Pyelonephritis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Third Generation Cephalosporins; Beta Lactam Antibiotics; Avibactam; Ceftazidime; Avibactam, ceftazidime drug combination
• Other Study ID Numbers: C3591033

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