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HABP/VABP Trial—REPROVE

HABP/VABP Phase 3 trial vs meropenem1

STUDY DESIGN1

Type of Trial

Phase 3, multinational, multicenter, double-blind, randomized, noninferiority trial

Study Population

870 hospitalized adults with HABP/VABP; the ITT population included all randomized patients who received study drug. The micro-ITT population included all patients with at least one Gram-negative pathogen.

The median age was 66 years and 74.1% were male. The median APACHE II score was 14. The majority of patients were from China (33.1%) and Eastern Europe (25.5%). There were no patients enrolled within the United States. Overall, 43.6% of patients were ventilated at enrollment, including 33.3% with VABP and 10.2% with ventilated HABP. Bacteremia at baseline was present in 4.8% of patients.

Comparative Agents

AVYCAZ® 2.5 g (ceftazidime 2 grams and avibactam 0.5 grams) IV every 8 hours

Meropenem 1 gram intravenously every 8 hours

Study medication dosages were adjusted per renal function.

The protocol allowed for administration of prior and concomitant systemic antibacterial therapy.

Treatment Duration

7 to 14 days

Primary Endpoints

The primary efficacy endpoint was 28-day all-cause mortality evaluated in the ITT population (28 to 32 days after randomization).

ITT, intent-to-treat.

micro-ITT, microbiological intent-to-treat.

APACHE II, Acute Physiology and Chronic Health Evaluation II.

IV, intravenous.

Clinical efficacy in HABP/VABP demonstrated in a Phase 3 trial vs meropenem1

  • AVYCAZ was noninferior to meropenem with regard to the primary endpoint (28-day all-cause mortality in the ITT population)1

28-DAY ALL-CAUSE MORTALITY RATES (ITT)1

28-DAY ALL-CAUSE MORTALITY RATES (micro-ITT)1

  • The control group mortality rates were lower than that observed in other HABP/VABP trials which may impact generalizability of results. However, review of patient characteristics reflecting disease severity indicates the study enrolled a representative HABP/VABP population1

CLINICAL CURE RATES AT TOC (ITT)*1

chart showing 28-day All-cause mortality

*A quantitative estimate of treatment effect has not been established for the clinical cure endpoint.

Clinical cure was defined as resolution or significant improvement in signs and symptoms associated with pneumonia and cessation of antibacterial treatment for HABP/VABP.1

The TOC visit occurred 21 to 25 days from randomization.1

ITT, intent-to-treat.

micro-ITT, microbiological intent-to-treat.

CI, confidence interval.

TOC, test of cure.

Subset populations

Clinical efficacy in patients who received potentially effective prior or concomitant antibacterial therapy1

The administration of prior or concomitant Gram-negative antibacterial therapy can confound the assessment of trial results. However, a subgroup analysis of 28-day all-cause mortality in subjects who received 24 hours or less of potentially effective antibacterial therapy prior to randomization and 72 hours or less of concomitant potentially effective antibacterial therapy following randomization produced results similar to the overall ITT population (AVYCAZ mortality 10.0% [20/200], meropenem 6.2% [12/195] [difference 3.8%; 95% CI: -1.6% to 9.5%]). In the subset of patients who received more than 24 hours of potentially effective antibacterial therapy prior to randomization or more than 72 hours of concomitant potentially effective antibacterial therapy following randomization, results were similar to the overall ITT population (AVYCAZ 9.7% [25/258], meropenem 10.5% [28/266] [difference -0.08%; 95% CI: -6.1% to 4.4%]).1

Clinical efficacy in HABP/VABP in patients with bacteremia (micro-ITT)1

  • Of the 382 patients in the micro-ITT population, 36 were bacteremic at baseline1
    • 95.2% (20/21) in the AVYCAZ® arm and 86.7% (13/15) in the meropenem arm survived through the day-28 follow-up visit1
    • 61.9% (13/21) of patients in the AVYCAZ arm and 60.0% (9/15) of patients in the meropenem arm had a clinical cure at the TOC visit1

micro-ITT, microbiological intent-to-treat.

TOC, test of cure.

ITT, intent-to-treat.

Clinical efficacy in HABP/VABP caused by ceftazidime-NS Gram-negative pathogens1

  • At baseline, 28.3% (108/382) of patients in the micro-ITT population had Gram-negative isolates that were not susceptible to ceftazidime, including 53 patients with K. pneumoniae and 28 patients with P. aeruginosa isolates1

CEFTAZIDIME-NS SUBSET POPULATION; 28-DAY ALL-CAUSE MORTALITY (micro-ITT)1

chart showing CEFTAZIDIME-NS POPULATION; 28-DAY ALL-CAUSE MORTALITY (micro-ITT)

CEFTAZIDIME-NS SUBSET POPULATION: CLINICAL CURE RATES AT TOC (micro-ITT)1

chart showing Ceftazidime-NS subset population: clinical cure rates at TOC

NS, nonsusceptible.

micro-ITT, microbiological intent-to-treat.

TOC, test of cure.

Mortality data by pathogen

28-DAY ALL-CAUSE MORTALITY BY BASELINE PATHOGEN (micro-ITT)

28-DAY ALL-CAUSE MORTALITY BY BASELINE PATHOGEN (micro-ITT)

micro-ITT, microbiological intent-to-treat.

Clinical cure data by pathogen

CLINICAL CURE RATES AT TOC BY BASELINE PATHOGEN (micro-ITT)1

chart Clinical cure rates at TOC by baseline pathogen

TOC, test of cure.

micro-ITT, microbiological intent-to-treat.

INDICATIONS AND USAGE

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

AVYCAZ® (ceftazidime and avibactam) is indicated for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae in patients 18 years or older.

Complicated Intra-Abdominal Infections (cIAI)

AVYCAZ, in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa in patients 18 years or older.

Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

AVYCAZ is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa in patients 18 years or older.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactam-containing products, or other members of the cephalosporin class.

WARNINGS AND PRECAUTIONS

  • In a Phase 3 cIAI trial, clinical cure rates were lower in a subgroup of patients with baseline creatinine clearance (CrCl) of 30 to less than or equal to 50 mL/min compared to those with CrCl greater than 50 mL/min. The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl of 30 to less than or equal to 50 mL/min. Clinical cure rate in patients with normal renal function/mild renal impairment (CrCl greater than 50 mL/min) was 85% (322/379) with AVYCAZ plus metronidazole vs 86% (321/373) with meropenem, and clinical cure rate in patients with moderate renal impairment (CrCl 30 to less than or equal to 50 mL/min) was 45% (14/31) with AVYCAZ plus metronidazole vs 74% (26/35) with meropenem. The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials or the Phase 3 HABP/VABP trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly.
  • Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs.
  • Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs. If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible.
  • Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on CrCl.
  • Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS

The most common adverse reactions in cIAI patients (≥ 5% when used with metronidazole) were diarrhea (8%), nausea (7%), and vomiting (5%). The most common adverse reactions in cUTI patients (3%) were diarrhea and nausea. The most common adverse reactions in HABP/VABP patients (≥ 5%) were diarrhea (15%) and vomiting (6%).