Efficacy and Safety of CAZ-AVI in the Treatment of Infections Due to Carbapenem-resistant G- Pathogens in Chinese Adults
- Conditions
- Hospital Acquired PneumoniaAcute PyelonephritisIntra-abdominal InfectionBacteremiaUrinary Tract InfectionVentilator-associated Pneumonia
- Interventions
- Drug: Zavicefta, Ceftazidime-AvibactamDrug: Best Available Treatment
- Registration Number
- NCT04882085
- Lead Sponsor
- Pfizer
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 60
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description CAZ-AVI Zavicefta, Ceftazidime-Avibactam ceftazidime 2g plus avibactam 0.5g Best Available Treatment Best Available Treatment Based on investigative site practice and local epidemiology and guideline
- Primary Outcome Measures
Name Time Method Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit - Microbiologically Modified Intent-to-Treat (mMITT) Analysis Set At TOC visit (From Day 21 up to Day 24) 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Clinical Cure at TOC Visit - Microbiologically Evaluable (ME) Analysis Set At TOC visit (From Day 21 up to Day 24) 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.
Percentage of Participants With Clinical Cure at End of Treatment (EOT) Visit -mMITT Analysis Set At EOT visit (up to 24 hours after the last infusion on Day 14) 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.
Percentage of Participants With Clinical Cure at EOT Visit - ME Analysis Set At EOT visit (up to 24 hours after the last infusion on Day 14) 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.
Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit - mMITT Analysis Set At TOC visit (From Day 21 up to Day 24) 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.
Percentage of Participants With Favorable Per-Participant Microbiological Response at TOC Visit - ME Analysis Set At TOC visit (From Day 21 up to Day 24) 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.
Percentage of Participants With Favorable Per-Participant Microbiological Response at EOT Visit - mMITT Analysis Set At EOT visit (Up to 24 hours after last infusion on Day 14) 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.
Percentage of Participants With Favorable Per-Participant Microbiological Response at EOT Visit - ME Analysis Set At EOT visit (Up to 24 hours after last infusion on Day 14) 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.
Percentage of Participants With Favorable Per-Pathogen Microbiological Response at TOC Visit - mMITT Analysis Set At TOC visit (From Day 21 up to Day 24) 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.
Percentage of Participants With Favorable Per-Pathogen Microbiological Response at EOT Visit - mMITT Analysis Set At EOT visit (Up to 24 hours after last infusion on Day 14) 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.
Percentage of Participants Who Died Due to Any Cause Until Day 28 From first dose of study intervention (Day 1) up to 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.
Number of Participants With Treatment-Emergent Adverse Events From start of study treatment on Day 1 up to 32 days after the last dose of study intervention (Up to 46 days) 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.
Number of Participants With Discontinuation Due to Adverse Events 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 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.
Number of Participants With Potentially Clinically Significant Post-baseline Hematology Values From first dose of study treatment (Day 1) until TOC (Up to Day 24) 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.
Number of Participants With Potentially Clinically Significant Post-baseline Clinical Chemistry Values From first dose of study treatment (Day 1) until TOC (Up to Day 24) 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.
Trial Locations
- Locations (35)
Chizhou People's Hospital
🇨🇳Chizhou, Anhui, China
Shenzhen People's Hospital
🇨🇳Shenzhen, Guangdong, China
The First Affiliated Hospital of Bengbu Medical
🇨🇳Bengbu, Anhui, China
The First Affiliated Hospital of Bengbu Medical College
🇨🇳Bengbu, Anhui, China
Guangzhou First People's Hospital
🇨🇳Guangzhou, Guangdong, China
Qingyuan People's Hospital
🇨🇳Qingyuan, Guangdong, China
Huashan Hospital, Fudan University
🇨🇳Shanghai, Shanghai, China
Chengdu Xinhua Hospital
🇨🇳Chengdu, Sichuan, China
The First People's Hospital of Kunming (South Hospital)
🇨🇳Kunming, Yunnan, China
The First people's Hospital of Kunming
🇨🇳Kunming, Yunnan, China
Zhejiang Hospital
🇨🇳Hangzhou, Zhejiang, China
Fuyang People's Hospital
🇨🇳Fuyang, Anhui, China
Peking University Third Hospital
🇨🇳Beijing, Beijing, China
Zhongshan Hospital Xiamen University
🇨🇳Xiamen, Fujian, China
The Second People's Hospital of Shenzhen
🇨🇳Shenzhen, Guangdong, China
Affiliated Hospital of Guangdong Medical University
🇨🇳Zhanjiang, Guangdong, China
Affiliated Hospital of Guilin Medical College
🇨🇳Guilin, Guangxi, China
Affiliated Hospital of Zunyi Medical University
🇨🇳Zunyi, Guizhou, China
Affiliated Hospital of Hebei University
🇨🇳Baoding, Hebei, China
Luoyang Central Hospital
🇨🇳Luoyang, Henan, China
Jiangyin People's Hospital
🇨🇳Jiangyin, China
NanYang central hospital
🇨🇳Nanyang, Henan, China
Henan provincial people's hospital
🇨🇳Zhengzhou, Henan, China
Baotou Central Hospital
🇨🇳Baotou, Inner Mongolia Autonomous Region, China
Jiangxi Provincial People's Hospital
🇨🇳Nanchang, Jiangxi, China
Affiliated Hospital of Xuzhou Medical University
🇨🇳Xuzhou, Jiangsu, China
Subei People's Hospital of Jiangsu province
🇨🇳Yangzhou, Jiangsu, China
Tianjin Chest Hospital
🇨🇳Tianjin, Tianjin, China
The First People's Hospital of Kunming Ganmei Hospital (North Hospital)
🇨🇳Kunming, Yunnan, China
Lishui People's Hospital
🇨🇳Lishui, Zhejiang, China
Taizhou Hospital of Zhejiang Province
🇨🇳Taizhou, Zhejiang, China
Zhejiang Provincial People's Hospital
🇨🇳Hangzhou, Zhejiang, China
The 2nd Affiliated Hospital of WMU
🇨🇳Wenzhou, Zhejiang, China
Shanghai Fifth People's Hospital, Fudan University
🇨🇳Shanghai, China
Wenzhou Central Hospital
🇨🇳Wenzhou, Zhejiang, China