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

Phase 4CompletedNCT04882085

Pfizer60 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Urinary Tract Infection Acute Pyelonephritis Hospital Acquired Pneumonia Ventilator-associated Pneumonia

Interventions

Zavicefta, Ceftazidime-AvibactamDRUG

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.

Best Available TreatmentDRUG

main treatment expected to be used as either monotherapy or in combination are colistin, tigecycline, fosfomycin, amikacin, and meropenem

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (37)

The First Affiliated Hospital of Bengbu Medical

Bengbu, Anhui, China

The First Affiliated Hospital of Bengbu Medical College

Bengbu, Anhui, China

Chizhou People's Hospital

Chizhou, Anhui, China

Fuyang People's Hospital

Fuyang, Anhui, China

Peking University Third Hospital

Beijing, Beijing Municipality, China

Outcomes

Primary Outcomes

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.

Time frame: At TOC visit (From Day 21 up to Day 24)

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: From first dose of study treatment (Day 1) until TOC (Up to Day 24)