Community-acquired Pneumonia (CAP), Hospital-acquired Pneumonia (HAP)
Conditions
Brief summary
This was a study of the safety and efficacy of ceftobiprole medocaril compared with intravenous (IV) standard-of-care cephalosporin treatment with or without vancomycin in pediatric patients with either hospital-acquired bacterial pneumonia (HAP) or community-acquired bacterial pneumonia (CAP) requiring hospitalization, and requiring intravenous (IV) antibiotic therapy.
Detailed description
This was a randomized, investigator-blind, active-controlled multi-center study to evaluate the safety, tolerability, pharmacokinetics and efficacy of ceftobiprole medocaril compared with IV standard-of-care cephalosporin treatment with or without vancomycin in pediatric patients aged 3 months to less than 18 years with HAP or CAP requiring hospitalization and therapy with IV antibiotics. Randomization was stratified by four age groups (3 months to \< 2 years; 2 years to \< 6 years; 6 years to \< 12 years; 12 years to \< 18 years), and by diagnosis of HAP or CAP.
Interventions
Ceftobiprole medocaril was administered at age-adjusted doses (10, 15 or 20 mg/kg) and infusion durations (2 or 4 hours) every 8 hours. The maximum dose, regardless of body weight, was 500 mg ceftobiprole every 8 hours (maximum total daily dose of 1500 mg ceftobiprole). After a minimum of 3 days of IV treatment, patients with sufficient improvement in disease signs and symptoms could be switched to an age-appropriate oral antibiotic to complete a total minimum of 7 days and a total maximum of 14 days' antibiotic treatment.
DRUGIV standard-of-care cephalosporin
Ceftriaxone was administered at 50 to 80 mg/kg IV as a single daily dose, up to a maximum dose of 2 g/day. The actual dose of ceftriaxone within this dose range was determined by the blinded investigator prior to first study drug administration and was not modified during subsequent study days. After a minimum of 3 days of IV treatment, patients with sufficient improvement in disease signs and symptoms could be switched to an age-appropriate oral antibiotic to complete a total minimum of 7 days and a total maximum of 14 days' antibiotic treatment. At the discretion of the blinded investigator, patients received vancomycin at a dose of 10 to 15 mg/kg IV every 6 hours, up to a maximum dose of 2 g/day, in addition to the IV standard-of-care cephalosporin when MRSA was suspected or confirmed.
Sponsors
Basilea Pharmaceutica
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
* Male of female aged 3 months to \< 18 years with a body weight of at least 5 kg * Diagnosis of either hospital-acquired pneumonia or community-acquired pneumonia requiring hospitalization and administration of IV antibiotic therapy * New or progressive imaging findings consistent with bacterial pneumonia * Requirement for IV antibacterial treatment for pneumonia * Other inclusion criteria may apply
Exclusion criteria
* Known resistance of the causative pathogen to ceftobiprole or IV standard-of-care cephalosporin treatment (± vancomycin) * On mechanical ventilation * Chest trauma with severe lung contusion or flail chest * Acute respiratory distress syndrome * Empyema or lung abscess * Anatomical bronchial obstruction * Active or currently treated pulmonary tuberculosis * Atypical bacterial pneumonia, or viral pneumonia without bacterial superinfection, or need for antibiotic coverage with a macrolide * Pertussis, chemical pneumonitis, or cystic fibrosis * Severe immunodeficiency * Significant laboratory abnormalities including: Hematocrit \<20%; absolute neutrophil count \<0.5x10⁹/L; platelet count \<50x10⁹/L; alanine aminotransferase, aspartate aminotransferase, or bilirubin \>5 times the age-specific upper limit of normal; * Creatinine clearance \<50 mL/min/1.73 m² * Use of systemic antimicrobial therapy for more than 24 hours in the 48 hours before randomization * History of a previous clinically-relevant hypersensitivity or serious adverse reaction to beta lactam antibiotics or to vancomycin * Poorly controlled seizure disorder * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | Analysis of AEs assessed during the first 3 days of IV therapy and while on IV, a median of 7 days | Reported are adverse events (AEs) during the first 3 days of IV therapy and while patients were on IV therapy irrespective of when they switched to oral antibiotic treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Clinical Cure in the Intent-to-treat Population (ITT) | At the test-of-cure (TOC) visit | Comparison of clinical cure rates (signs and symptoms of pneumonia normalized or improved such that no further antibiotic therapy was necessary, and stabilization or improvement of chest X-ray findings if these were available) in the ITT population between ceftobiprole and the comparator at the TOC visit. |
| Proportion of Patients With Clinical Cure in the Clinically Evaluable (CE) Population | At the TOC visit | Comparison of clinical cure rates (signs and symptoms of pneumonia normalized or improved such that no further antibiotic therapy was necessary, and stabilization or improvement of chest X-ray findings if these were available) in the CE population between ceftobiprole and the comparator at the TOC visit. |
| Proportion of Patients With Early Clinical Response in the Intent-to-treat (ITT) Population | At Day 4 | Comparison of early clinical response rates in the ITT population between ceftobiprole and the comparator at Day 4. |
| Proportion of Patients With Early Clinical Response in the Clinically Evaluable (CE) Population | At Day 4 | Comparison of early clinical response rates in the CE population between ceftobiprole and the comparator at Day 4. |
Countries
Bulgaria, Georgia, Hungary, Romania
Participant flow
Pre-assignment details
All 138 randomized patients received treatment
Participants by arm
| Arm | Count |
|---|---|
| Ceftobiprole Medocaril Ceftobiprole medocaril is the water-soluble prodrug of ceftobiprole, an advanced-generation cephalosporin developed for IV administration. Ceftobiprole is characterized by potent, broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative pathogens. | 94 |
| IV Standard-of-care Cephalosporin Ceftriaxone was used as standard-of-care cephalosporin for the treatment of CAP. It is a third-generation cephalosporin with activity against typical bacterial pathogens of CAP requiring hospitalization, and is widely used for the treatment of various bacterial infections in neonates, infants, children, and adults.
Ceftazidime was used as standard-of-care cephalosporin for the treatment of HAP. It is also a third-generation cephalosporin, but with broader activity against Gram-negative aerobic bacilli, including Pseudomonas aeruginosa.
Vancomycin is a glycopeptide antibiotic that is active against staphylococci, including MRSA. At the discretion of the blinded investigator, patients received vancomycin in addition to the IV standard-of-care cephalosporin when MRSA was suspected or confirmed. | 44 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other reasons | 1 | 0 |
Baseline characteristics
| Characteristic | Ceftobiprole Medocaril | IV Standard-of-care Cephalosporin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 94 Participants | 44 Participants | 138 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 6.81 years | 6.95 years | 6.86 years |
| Infection type Community-acquired pneumonia | 89 Participants | 41 Participants | 130 Participants |
| Infection type Hospital-acquired pneumonia | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 94 Participants | 43 Participants | 137 Participants |
| Sex: Female, Male Female | 41 Participants | 23 Participants | 64 Participants |
| Sex: Female, Male Male | 53 Participants | 21 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 94 | 0 / 44 |
| other Total, other adverse events | 8 / 94 | 5 / 44 |
| serious Total, serious adverse events | 7 / 94 | 2 / 44 |
Outcome results
Primary
Adverse Events
Reported are adverse events (AEs) during the first 3 days of IV therapy and while patients were on IV therapy irrespective of when they switched to oral antibiotic treatment.
Time frame: Analysis of AEs assessed during the first 3 days of IV therapy and while on IV, a median of 7 days
Population: Safety population: all randomized patients who received at least one dose of study drug, analyzed according to the first treatment actually received.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Ceftobiprole Medocaril | Adverse Events | First 3 days of IV therapy | TEAE leading to death | 0 Participants |
| Ceftobiprole Medocaril | Adverse Events | While on IV therapy | Non-Serious TEAE | 17 Participants |
| Ceftobiprole Medocaril | Adverse Events | While on IV therapy | Serious TEAE | 2 Participants |
| Ceftobiprole Medocaril | Adverse Events | First 3 days of IV therapy | Non-Serious TEAE | 10 Participants |
| Ceftobiprole Medocaril | Adverse Events | While on IV therapy | TEAE leading to death | 0 Participants |
| Ceftobiprole Medocaril | Adverse Events | First 3 days of IV therapy | No TEAE | 83 Participants |
| Ceftobiprole Medocaril | Adverse Events | While on IV therapy | No TEAE | 75 Participants |
| Ceftobiprole Medocaril | Adverse Events | First 3 days of IV therapy | Serious TEAE | 1 Participants |
| IV Standard-of-care Cephalosporin | Adverse Events | While on IV therapy | No TEAE | 36 Participants |
| IV Standard-of-care Cephalosporin | Adverse Events | First 3 days of IV therapy | Serious TEAE | 0 Participants |
| IV Standard-of-care Cephalosporin | Adverse Events | While on IV therapy | Non-Serious TEAE | 8 Participants |
| IV Standard-of-care Cephalosporin | Adverse Events | First 3 days of IV therapy | Non-Serious TEAE | 5 Participants |
| IV Standard-of-care Cephalosporin | Adverse Events | First 3 days of IV therapy | TEAE leading to death | 0 Participants |
| IV Standard-of-care Cephalosporin | Adverse Events | First 3 days of IV therapy | No TEAE | 39 Participants |
| IV Standard-of-care Cephalosporin | Adverse Events | While on IV therapy | Serious TEAE | 0 Participants |
| IV Standard-of-care Cephalosporin | Adverse Events | While on IV therapy | TEAE leading to death | 0 Participants |
Secondary
Proportion of Patients With Clinical Cure in the Clinically Evaluable (CE) Population
Comparison of clinical cure rates (signs and symptoms of pneumonia normalized or improved such that no further antibiotic therapy was necessary, and stabilization or improvement of chest X-ray findings if these were available) in the CE population between ceftobiprole and the comparator at the TOC visit.
Time frame: At the TOC visit
Population: Clinically Evaluable (CE) population: all patients who had a valid clinical outcome assessment at TOC and no major protocol deviations such as non-study antibiotic therapies.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ceftobiprole Medocaril | Proportion of Patients With Clinical Cure in the Clinically Evaluable (CE) Population | 80 Participants |
| IV Standard-of-care Cephalosporin | Proportion of Patients With Clinical Cure in the Clinically Evaluable (CE) Population | 41 Participants |
Secondary
Proportion of Patients With Clinical Cure in the Intent-to-treat Population (ITT)
Comparison of clinical cure rates (signs and symptoms of pneumonia normalized or improved such that no further antibiotic therapy was necessary, and stabilization or improvement of chest X-ray findings if these were available) in the ITT population between ceftobiprole and the comparator at the TOC visit.
Time frame: At the test-of-cure (TOC) visit
Population: Intent-to-treat (ITT) population: all randomized patients, analyzed by treatment assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ceftobiprole Medocaril | Proportion of Patients With Clinical Cure in the Intent-to-treat Population (ITT) | 85 Participants |
| IV Standard-of-care Cephalosporin | Proportion of Patients With Clinical Cure in the Intent-to-treat Population (ITT) | 43 Participants |
Secondary
Proportion of Patients With Early Clinical Response in the Clinically Evaluable (CE) Population
Comparison of early clinical response rates in the CE population between ceftobiprole and the comparator at Day 4.
Time frame: At Day 4
Population: Clinically Evaluable (CE) population: all patients who had a valid clinical outcome assessment at TOC and no major protocol deviations such as non-study antibiotic therapies.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ceftobiprole Medocaril | Proportion of Patients With Early Clinical Response in the Clinically Evaluable (CE) Population | 84 Participants |
| IV Standard-of-care Cephalosporin | Proportion of Patients With Early Clinical Response in the Clinically Evaluable (CE) Population | 39 Participants |
Secondary
Proportion of Patients With Early Clinical Response in the Intent-to-treat (ITT) Population
Comparison of early clinical response rates in the ITT population between ceftobiprole and the comparator at Day 4.
Time frame: At Day 4
Population: Intent-to-treat (ITT) population: all randomized patients, analyzed by treatment assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ceftobiprole Medocaril | Proportion of Patients With Early Clinical Response in the Intent-to-treat (ITT) Population | 90 Participants |
| IV Standard-of-care Cephalosporin | Proportion of Patients With Early Clinical Response in the Intent-to-treat (ITT) Population | 41 Participants |