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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ceftobiprole medocaril | Experimental | 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. |
|
| IV standard-of-care cephalosporin | Active Comparator | 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 methicillin-resistant Staphylococcus aureus (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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ceftobiprole medocaril | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Analysis of AEs assessed during the first 3 days of IV therapy and while on IV, a median of 7 days |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | At the test-of-cure (TOC) visit |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Marc Engelhardt, MD | Basilea Pharmaceutica | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Multiprofile Hospital for Active Treatment "Dr. Georgi Stranski" | Pleven | 5800 | Bulgaria | |||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34533489 | Derived | Rubino CM, Polak M, Schropf S, Munch HG, Smits A, Cossey V, Tomasik T, Kwinta P, Snariene R, Liubsys A, Gardovska D, Hornik CD, Bosheva M, Ruehle C, Litherland K, Hamed K. Pharmacokinetics and Safety of Ceftobiprole in Pediatric Patients. Pediatr Infect Dis J. 2021 Nov 1;40(11):997-1003. doi: 10.1097/INF.0000000000003296. | |
| 33480665 |
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All 138 randomized patients received treatment
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Nov 29, 2018 | Aug 19, 2020 |
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| IV standard-of-care cephalosporin | Drug | 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. |
|
| 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. | At the TOC visit |
| 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. | At Day 4 |
| 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. | At Day 4 |
| University Multiprofile Hospital for Active Treatment "Sveti Georgi" |
| Plovdiv |
| 4002 |
| Bulgaria |
| Multiprofile Hospital for Active Treatment | Rousse | 7002 | Bulgaria |
| University Multiprofile Hospital for Active Treatment "Aleksandrovska" | Sofia | 1431 | Bulgaria |
| Amtel Hospital First Clinical LLC | Tbilisi | 0144 | Georgia |
| LTD High Technology Medical Center University Clinic | Tbilisi | 0144 | Georgia |
| JSC Evex Hospitals 1 | Tbilisi | 0159 | Georgia |
| JSC Evex Hospitals 2 | Tbilisi | 0159 | Georgia |
| Tbilisi State Medical University G. Zhvania Pediatric Academic Clinic | Tbilisi | 0159 | Georgia |
| Ltd Tbilisi Pediatric Private Clinic | Tbilisi | 0191 | Georgia |
| Principal SMO Ltd. | Baja | 6500 | Hungary |
| Semmelweis University | Budapest | 1094 | Hungary |
| Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases | Budapest | 1097 | Hungary |
| Bekes County Central Hospital | Gyula | 5700 | Hungary |
| Kanizsai Dorottya Hospital | Nagykanizsa | 8800 | Hungary |
| Fejer County St. Gyorgy University Teaching Hospital | Székesfehérvár | 8000 | Hungary |
| Torokbalint Pulmonology Institute | Törökbálint | 2045 | Hungary |
| Alessandrescu-Rusescu National Institute for Mother and Child Health | Bucharest | 020395 | Romania |
| Sf. Maria" Children's Emergency Clinical Hospital | Iași | 700309 | Romania |
| Bosheva M, Gujabidze R, Karoly E, Nemeth A, Saulay M, Smart JI, Hamed KA. A Phase 3, Randomized, Investigator-blinded Trial Comparing Ceftobiprole With a Standard-of-care Cephalosporin, With or Without Vancomycin, for the Treatment of Pneumonia in Pediatric Patients. Pediatr Infect Dis J. 2021 Jun 1;40(6):e222-e229. doi: 10.1097/INF.0000000000003077. |
| IV Standard-of-care Cephalosporin |
Ceftriaxone was used as standard-of-care cephalosporin for the treatment of community-acquired pneumonia (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 hospital-acquired pneumonia (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 methicillin-resistant Staphylococcus aureus (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. |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Age, Continuous | Mean | Full Range | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Infection type | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Safety population: all randomized patients who received at least one dose of study drug, analyzed according to the first treatment actually received. | Posted | Count of Participants | Participants | Analysis of AEs assessed during the first 3 days of IV therapy and while on IV, a median of 7 days |
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| 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. | Intent-to-treat (ITT) population: all randomized patients, analyzed by treatment assigned. | Posted | Count of Participants | Participants | At the test-of-cure (TOC) visit |
| |||||||||||||||||||||||||||||||||
| 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. | 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. | Posted | Count of Participants | Participants | At the TOC visit |
| |||||||||||||||||||||||||||||||||
| 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. | Intent-to-treat (ITT) population: all randomized patients, analyzed by treatment assigned. | Posted | Count of Participants | Participants | At Day 4 |
| |||||||||||||||||||||||||||||||||
| 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. | 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. | Posted | Count of Participants | Participants | At Day 4 |
|
Relevant worsening of a patient's status after informed consent (before start of first study-drug infusion) was recorded in medical history. From start of first dosing to and including the last follow-up visit, 28 to 35 days after end-of-treatment, such worsening was recorded as an AE.
Once an AE was detected, it was proactively followed up at each visit (or more frequently if necessary) for any changes in severity, relationship to the study drug, interventions required for treatment, and the event's outcome. Serious adverse events (SAEs) were to be additionally reported and recorded on SAE report forms.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. | 0 | 94 | 7 | 94 | 8 | 94 |
| EG001 | 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. | 0 | 44 | 2 | 44 | 5 | 44 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA 22.1 | Systematic Assessment |
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| Pleurisy | Respiratory, thoracic and mediastinal disorders | MedDRA 22.1 | Systematic Assessment |
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| Hypersensitivity | Immune system disorders | MedDRA 22.1 | Systematic Assessment |
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| Seizure like phenomena | Nervous system disorders | MedDRA 22.1 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 22.1 | Systematic Assessment |
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| Pneumonia | Infections and infestations | MedDRA 22.1 | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA 22.1 | Systematic Assessment |
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| Pharyngitis streptococcal | Infections and infestations | MedDRA 22.1 | Systematic Assessment |
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| Tonsillitis streptococcal | Infections and infestations | MedDRA 22.1 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | MedDRA 22.1 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 22.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Project Physician | Basilea Pharmaceutica International Ltd. | +41 79 701 0551 | marc.engelhardt@basilea.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 2, 2020 | Aug 19, 2020 | SAP_001.pdf |
| ID | Term |
|---|---|
| D000098968 | Community-Acquired Pneumonia |
| D000077299 | Healthcare-Associated Pneumonia |
| ID | Term |
|---|---|
| D017714 | Community-Acquired Infections |
| D007239 | Infections |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D012140 | Respiratory Tract Diseases |
| D003428 | Cross Infection |
| D008171 | Lung Diseases |
| D007049 | Iatrogenic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C505439 | ceftobiprole medocaril |
| C443755 | ceftobiprole |
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| >=65 years |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Community-acquired pneumonia |
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| TEAE leading to death |
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| No TEAE |
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| While on IV therapy |
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