E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neonatal late onset sepsis |
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E.1.1.1 | Medical condition in easily understood language |
Infection of the blood in babies who are more than 3 days but less than 91 days old |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053598 |
E.1.2 | Term | Late onset neonatal sepsis |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of an optimised vancomycin dosing regimen to a standard vancomycin dosing regimen in patients with late onset bacterial sepsis, known or suspected to be caused by Gram-positive microorganisms |
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E.2.2 | Secondary objectives of the trial |
To compare the safety of vancomycin (including renal and hearing safety) by allocation group in the intention to treat (ITT) population. To describe the PK parameters according to vancomycin dosing regimen and outcome using population PK modelling in the ITT population. To describe PK/PD in terms of the probability of target attainment (PTA) with different vancomycin dosing regimens in the ITT and per protocol (PP) populations. To describe outcomes and duration of therapy at the end of vancomycin treatment and at the short term follow-up visit by allocation group in the ITT and PP populations. To compare the clinical outcome to the antibacterial susceptibility of infecting organisms. To compare colonisation by resistant microorganisms [e.g. vancomycinresistant enterococci (VRE) and Candida spp.] by allocation group at baseline, TOC and short-term follow-up. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Postnatal age less or equal to 90 days at randomisation AND Postnatal age 72 hours and above at onset of sepsis AND Clinical sepsis as defined by presence of any three clinical or laboratory criteria, in the 24 hours before randomisation OR Confirmed, significant bacterial sepsis as defined by positive culture with a Gram-positive bacterium from a normally sterile site and at least one clinical or one laboratory criterion from the list below, in the 24 hours before randomisation
Clinical criteria: - Hyperthermia or hypothermia - Hypotension or impaired peripheral perfusion or mottled skin - Apnoea or increased oxygen requirement or increased requirement for ventilatory support - Bradycardic episodes or tachycardia - Worsening feeding intolerance or abdominal distension - Lethargy or hypotonia or irritability
Laboratory criteria: - White blood cell (WBC) count < 4,000 or > 20,000 x 109 cells/L - Immature to total neutrophil ratio (I/T) > 0.2 - Platelet count < 100,000 x 109/L - C-reactive protein (CRP) > 10 mg/L - Glucose intolerance as defined by a blood glucose value > 180 mg/dL (> 10 mmol/L) when receiving normal glucose amounts (8 – 15 g/kg/day) - Metabolic acidosis as defined by a base excess (BE) < –10 mmol/L (–10 mEq/L) or a blood lactate value > 2 mmol/L |
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E.4 | Principal exclusion criteria |
- Administration of any systemic antibiotic regimen for more than 24 hours prior to randomisation - Known toxicity, hypersensitivity or intolerance to vancomycin - Known acute renal impairment as defined by urinary output < 0.7 ml/kg/hour for 24 hours or a creatinine value ≥ 100 µmol/L (1.13 mg/dL) - Patient receiving (or planned to receive) haemofiltration, haemodialysis, peritoneal dialysis, extracorporeal membrane oxygenation (ECMO) or cardiopulmonary bypass - Severe congenital malformations where the infant is not expected to survive for more than 3 months - Treatment with vancomycin for ≥ 24 hours at any time within 7 days of enrolment - Patient known to have S. aureus (MSSA or MRSA) bacteraemia - Patient with osteomyelitis, septic arthritis, urinary tract infection (UTI) or meningitis - Patient with high suspicion of/confirmed sepsis caused by Gram-negative organisms or fungi - Other situations where the treating physician considers a different empiric antibiotic regimen necessary - Current participation in any other clinical study of an investigational medicinal product (IMP)
Post-randomisation exclusions - Any patient found to have osteomyelitis, septic arthritis, urinary tract infection (UTI), meningitis or S. aureus (MSSA or MRSA) after randomisation will be excluded from analysis. Any participant who has received at least one dose of study vancomycin will be followed up for safety |
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E.5 End points |
E.5.1 | Primary end point(s) |
Successful outcome at test of cure visit (TOC)
Successful outcome at TOC: - Patient is alive AND - Successful outcome at end of vancomycin therapy (EVT) AND - Patient has not had a significant relapse or new infection within 10 days of EVT |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Test of Cure Visit: 10 +/- 1 days after the end of actual vancomycin treatment |
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E.5.2 | Secondary end point(s) |
EVALUATION OF EFFICACY 1. Clinically or microbiologically significant relapse or new infection within 10 days of End of Actual Vancomycin Therapy (EVT) requiring treatment with any other antibiotic for more than 24 hours 2. Successful outcome at Visit 4 or EVT visit including total duration of vancomycin treatment 3. Clinically or microbiologically significant relapse or new infection at short-term follow-up (FU) visit EVALUATION OF SAFETY 4. Abnormal renal function tests at the short-term FU visit 5. Abnormal hearing screening test 6. Comparative safety of vancomycin (related to all other parameters other than renal and hearing safety) at short-term FU visit PK/PD EVALUATION 7. PK parameters of vancomycin using population PK modelling by allocation group 8. Probability of target attainment (PTA) with different study regimens MICROBIOLOGICAL EVALUATION 9. Relationship between CoNS species and duration of treatment and CRP response 10. Gut colonisation by vancomycin resistant organisms at baseline, TOC and short-term FU visit 11. Skin colonisation and resistance patterns before and after vancomycin treatment 12. Bacterial DNA PCR analysis in babies < 29 weeks postmenstrual age (PMA) BIOMARKER EVALUATION 13. Assessment of changes in host biomarker panel profiles from baseline to EVT and the relationship between host biomarker and duration of treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 10±1 days after the end of vancomycin therapy 2. Day 5±1 or Day 10±2 3. 30±5 days post-initiation of vancomycin therapy 4. 30±5 days post-initiation of vancomycin therapy 5. By Day 90 post-initiation of vancomycin therapy 6. 30±5 days post-initiation of vancomycin therapy 7. End of Trial 8. End of Trial 9. Day 5±1 or Day 10±2 10. Day 0, 10±1 days after end of vancomycin therapy, 30±5 days post-initiation of therapy 11. 30±5 days post-initiation of therapy 12. Day 3 (measured retrospectively in batches; no realtime data available) 13. Day 5±1 or Day 10±2 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Same medicinal product but different dosing regimen |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is the date that the database is locked down, this is when all queries have been solved and the database can be released for statistical analyses. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |