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NCT03032380: APEKS-NP

Clinical Study of Cefiderocol (S-649266) for the Treatment of Nosocomial Pneumonia Caused by Gram-negative Pathogens

Completed Phase 3 Results posted Last updated 13 November 2020
What this trial tests

Phase 3 trial testing Cefiderocol in Healthcare-associated Pneumonia (HCAP) in 300 participants. Completed in 1 April 2019.

Timeline
24 October 2017
Primary endpoint
26 February 2019
1 April 2019

Quick facts

Lead sponsorShionogi
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingtriple
Primary purposetreatment
Enrollment300
Start date24 October 2017
Primary completion26 February 2019
Estimated completion1 April 2019
Sites119 locations across Japan, Taiwan, Philippines, Russia, Belgium, Estonia, United States, Latvia

Drugs / interventions tested

Conditions studied

Sponsor

Shionogi — full company profile →

Who can join

18 and older, any sex, with Healthcare-associated Pneumonia (HCAP) or Hospital Acquired Pneumonia (HAP). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

All-cause Mortality Rate at Day 14 Primary · From first dose of study drug to Day 14

The all-cause mortality (ACM) rate at Day 14 was calculated as the percentage of participants in each treatment group who experienced mortality, regardless of the cause, from the first infusion of study drug up to Day 14. The Modified Intent-to-Treat Population included all randomized participants who met either of the following criteria: * Evidence of Gram-negative infection of the lower respiratory tract based on a culture, Gram-stain, or other diagnostic test * Evidence of a lower respiratory tract infection but culture or other diagnostic tests did not provide a microbiologic diagnosis

GroupValue95% CI
Cefiderocol12.4
Meropenem11.6
Percentage of Participants With Microbiologic Eradication at Test of Cure (TOC) Secondary · Test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21)

Lower respiratory tract specimens (eg, sputum, endotracheal aspiration \[ETA\], endobronchial culture specimens collected by bronchoalveolar lavage \[BAL\], or protected specimen brush \[PSB\], lung biopsy tissue, pleural effusions, etc) were sent to the local microbiology laboratory for isolation and identification of pathogens. Microbiological outcome by Baseline pathogen at TOC was determined by the sponsor as either Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline p

GroupValue95% CI
Cefiderocol47.6
Meropenem48.0
Percentage of Participants With Clinical Cure at Test of Cure Secondary · Test of cure (7 days after the end of treatment; equivalent to Study Day 14 to 21)

Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.

GroupValue95% CI
Cefiderocol64.8
Meropenem66.7
Percentage of Participants With Clinical Cure at Early Assessment (EA) Secondary · Early assessment (Day 3-4 after the start of treatment)

Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.

GroupValue95% CI
Cefiderocol82.8
Meropenem83.0
Percentage of Participants With Clinical Cure at End of Treatment (EOT) Secondary · End of treatment (Day 7 to 14)

Clinical outcome was assessed by the investigator as either Clinical Cure, Clinical Failure, or Indeterminate. Clinical Cure: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia, including a reduction in Sequential Organ Failure Assessment (SOFA) and Clinical Pulmonary Infection Score (CPIS) scores, and improvement or lack of progression of chest radiographic abnormalities such that no additional antibacterial therapy was required for the treatment of the current infection.

GroupValue95% CI
Cefiderocol77.2
Meropenem81.0
Percentage of Participants With Sustained Clinical Cure at Follow-up (FU) Secondary · Follow-up (14 days after the end of treatment; Day 21 to 28)

Clinical outcome was assessed by the investigator at follow-up as either Sustained Clinical Cure, Relapse, or Indeterminate. Sustained Clinical Cure: Continued resolution or substantial improvement of Baseline signs and symptoms of pneumonia, such that no antibacterial therapy was required for the treatment of pneumonia in a participant assessed as cured at TOC.

GroupValue95% CI
Cefiderocol57.9
Meropenem57.8
Percentage of Participants With Microbiologic Eradication at Early Assessment Secondary · Early Assessment, Days 3 to 4

Microbiological outcome by Baseline pathogen at Early Assessment was determined by the sponsor as either Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical ou

GroupValue95% CI
Cefiderocol41.9
Meropenem53.5
Percentage of Participants With Microbiologic Eradication at End of Treatment Secondary · End of treatment, Day 7 to 14

Microbiological outcome by Baseline pathogen at End of Treatment was determined by the sponsor as either: Eradication, Persistence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture, and the participant had a successful clinical o

GroupValue95% CI
Cefiderocol63.7
Meropenem66.9
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up Secondary · Follow-up (14 days after the end of treatment, Days 21 to 28)

Microbiological outcome by Baseline pathogen at Follow-up was determined by the sponsor as either Sustained Eradication, Persistence, Recurrence, or Indeterminate. Overall per-participant microbiological outcome was determined based on the individual microbiological outcomes for each Baseline pathogen. Sustained eradication: Absence of all Baseline Gram-negative pathogens from an appropriate clinical specimen (sputum, tracheal aspirate, BAL fluid, protected specimen brush, pleural fluid, or lung biopsy) after TOC. If it was not possible to obtain an appropriate clinical culture and the partic

GroupValue95% CI
Cefiderocol43.5
Meropenem38.6
All-cause Mortality Rate at Day 28 Secondary · From first dose of study drug to Day 28

The all-cause mortality (ACM) rate at Day 28 was calculated as the percentage of participants who experienced mortality, regardless of the cause, from the first dose of study drug up to Day 28.

GroupValue95% CI
Cefiderocol21.0
Meropenem20.5
All-cause Mortality Rate at the End of Study Secondary · From first dose of study drug through end of study (28 days after end of treatment, up to 42 days)

The all-cause mortality rate during both the treatment and follow-up period (up to the end of study \[EOS\] visit) was calculated as the percentage of participants who experienced mortality, regardless of the cause, from the first infusion of study drug up to EOS. If a participant discontinued from the study before EOS and survival information was not available, then the survival status for this endpoint for the participant was considered unknown.

GroupValue95% CI
Cefiderocol26.8
Meropenem23.3
Total Hospitalization Time Secondary · From first dose of study drug to test of cure (7 days after end of treatment; equivalent to Study Day 14 to 21) and to follow-up (14 days after the end of treatment; Day 21 to 28)

The length of hospital stay attributable to the study-qualifying infection.

Test of Cure
GroupValue95% CI
Cefiderocol11.54± 7.81
Meropenem11.47± 7.32
Follow-up
GroupValue95% CI
Cefiderocol13.49± 10.06
Meropenem12.98± 9.59

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study drug through the end of study, up to 42 days.. Reporting threshold: 2%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cefiderocol
Serious: 54/148 (36%)
Deaths: 39/148
Meropenem
Serious: 45/150 (30%)
Deaths: 35/150

Serious adverse events (97 terms)

ReactionSystemCefiderocolMeropenem
Cardiac arrestCardiac disorders
PneumoniaInfections and infestations
Acute respiratory failureRespiratory, thoracic and mediastinal disorders
Hepatic enzyme increasedInvestigations
Brain oedemaNervous system disorders
Multiple organ dysfunction syndromeGeneral disorders
Septic shockInfections and infestations
Cardiac failureCardiac disorders
Cardio-respiratory arrestCardiac disorders
SepsisInfections and infestations
Acute kidney injuryRenal and urinary disorders
Pneumonia aspirationRespiratory, thoracic and mediastinal disorders
Pulmonary artery thrombosisRespiratory, thoracic and mediastinal disorders
Respiratory failureRespiratory, thoracic and mediastinal disorders
CoagulopathyBlood and lymphatic system disorders
Haemorrhagic anaemiaBlood and lymphatic system disorders
ThrombocytopeniaBlood and lymphatic system disorders
Acute myocardial infarctionCardiac disorders
Cardiac failure acuteCardiac disorders
Left ventricular dysfunctionCardiac disorders
Urinary tract infectionInfections and infestations
Liver function test increasedInvestigations
Cerebrovascular accidentNervous system disorders
Intracranial pressure increasedNervous system disorders
Pulmonary oedemaRespiratory, thoracic and mediastinal disorders
Other adverse events (51 terms — click to expand)

ReactionSystemCefiderocolMeropenem
HypokalaemiaMetabolism and nutrition disorders
Urinary tract infectionInfections and infestations
DiarrhoeaGastrointestinal disorders
AnaemiaBlood and lymphatic system disorders
HyponatraemiaMetabolism and nutrition disorders
Decubitus ulcerSkin and subcutaneous tissue disorders
Aspartate aminotransferase increasedInvestigations
Pleural effusionRespiratory, thoracic and mediastinal disorders
HypotensionVascular disorders
Alanine aminotransferase increasedInvestigations
HypomagnesaemiaMetabolism and nutrition disorders
HypoalbuminaemiaMetabolism and nutrition disorders
Atrial fibrillationCardiac disorders
ConstipationGastrointestinal disorders
HypertensionVascular disorders
ThrombocytopeniaBlood and lymphatic system disorders
HypoglycaemiaMetabolism and nutrition disorders
HydrothoraxRespiratory, thoracic and mediastinal disorders
PyrexiaGeneral disorders
PneumoniaInfections and infestations
Gamma-glutamyltransferase increasedInvestigations
Hepatic enzyme increasedInvestigations
DeliriumPsychiatric disorders
InsomniaPsychiatric disorders
ThrombocytosisBlood and lymphatic system disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
Clostridium difficile infectionInfections and infestations
Urinary tract infection fungalInfections and infestations
TracheobronchitisInfections and infestations
Transaminases increasedInvestigations
HyperglycaemiaMetabolism and nutrition disorders
HypocalcaemiaMetabolism and nutrition disorders
HyperkalaemiaMetabolism and nutrition disorders
HypoproteinaemiaMetabolism and nutrition disorders
Electrolyte imbalanceMetabolism and nutrition disorders
PhlebitisVascular disorders
Iron deficiency anaemiaBlood and lymphatic system disorders
BradycardiaCardiac disorders
Oedema peripheralGeneral disorders

Most-reported serious reactions: Cardiac arrest, Pneumonia, Acute respiratory failure, Hepatic enzyme increased, Brain oedema, Multiple organ dysfunction syndrome, Septic shock, Cardiac failure.

Data from ClinicalTrials.gov NCT03032380 adverse events section.

Sponsor's own description

The primary objective of this study is to compare all-cause mortality at Day 14 in participants receiving cefiderocol with participants receiving the comparator, meropenem, in adults with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by Gram-negative pathogens.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. NDM Metallo-β-Lactamases and Their Bacterial Producers in Health Care Settings.
    Wu W, Feng Y, Tang G, Qiao F, et al · · 2019 · cited 498× · PMID 30700432 · DOI 10.1128/cmr.00115-18
  2. Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections.
    Doi Y. · · 2019 · cited 405× · PMID 31724043 · DOI 10.1093/cid/ciz830
  3. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial.
    Wunderink RG, Matsunaga Y, Ariyasu M, Clevenbergh P, et al · · 2021 · cited 340× · PMID 33058798 · DOI 10.1016/s1473-3099(20)30731-3
  4. Bloodstream infections in critically ill patients: an expert statement.
    Timsit JF, Ruppé E, Barbier F, Tabah A, et al · · 2020 · cited 287× · PMID 32047941 · DOI 10.1007/s00134-020-05950-6
  5. Treatment of Infections Due to MDR Gram-Negative Bacteria.
    Bassetti M, Peghin M, Vena A, Giacobbe DR. · · 2019 · cited 209× · PMID 31041313 · DOI 10.3389/fmed.2019.00074
  6. Metallo-β-Lactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline.
    Boyd SE, Livermore DM, Hooper DC, Hope WW. · · 2020 · cited 206× · PMID 32690645 · DOI 10.1128/aac.00397-20
  7. Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?
    Domalaon R, Idowu T, Zhanel GG, Schweizer F. · · 2018 · cited 189× · PMID 29540434 · DOI 10.1128/cmr.00077-17
  8. Antibiotics in the clinical pipeline in October 2019.
    Butler MS, Paterson DL. · · 2020 · cited 174× · PMID 32152527 · DOI 10.1038/s41429-020-0291-8

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