Session Type: 1-hour Mini Oral Flash
Session Title: 1-hour Mini Oral Flash
Authors(s): L.F. Hill (1, 2), M. Clements (3), M.A. Turner (4), D. Donà (1), P.T. Heath (1), I. Lutsar (5), E. Jacqz-Aigrain (6), E. Roilides (7), L. Rawcliffe (8), B. Bafadal (8), A.S. Walker (3), M. Sharland (1)
Authors Affiliations(s): (1) 1. Paediatric Infectious Diseases Research Group, Institute for Infection & Immunity, St George’s, University of London, UK, United Kingdom, (2) 2. UCL Great Ormond Street Institute for Child Health, London, UK, United Kingdom, (3) 3. MRC Clinical Trials Unit at UCL, London, UK, United Kingdom, (4) 4. Institute of Translational Medicine, University of Liverpool, Liverpool, UK, United Kingdom, (5) 5. University of Tartu, Tartu, Estonia, Estonia, (6) 6. Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France, France, (7) 7. 3rd Department of Pediatrics, Aristotle University, Thessaloniki, Greece, Greece, (8) 8. Therakind Ltd., London, UK, United Kingdom
Third Party Affiliation: on behalf of the NeoVanc Consortium
Background:
Vancomycin has been used to treat Gram-positive sepsis for >50 years, however, robust data supporting infant dosing regimens are lacking. NeoVanc (NCT02790996) was a European, multicentre, phase IIb, non-inferiority randomised controlled trial (RCT) trialling an optimised dosing regimen, derived from pre-clinical studies, in infants up to 90 days of age with confirmed/suspected Gram-positive late-onset sepsis.
Methods:Participants with clinical sepsis (≥3 clinical/laboratory criteria) or confirmed Gram-positive sepsis with ≥1 clinical/laboratory criterion were enrolled from 22 neonatal units. Randomisation was 1:1 to the optimised regimen (loading dose [25 mg/kg] followed by 5±1 days of 15 mg/kg q12h or q8h dependent on postmenstrual age [PMA]) or the standard regimen (no loading dose; 10±2 day course at 15 mg/kg q24h, q12h, or q8h dependent on PMA). The primary endpoint was successful outcome at the end of vancomycin therapy without clinically/microbiologically significant relapse/new infection requiring specific anti-staphylococcal antibiotic treatment within 10 days of stopping vancomycin.
Secondary endpoints included safety.
Results describe the per-protocol population (participants receiving the loading dose as randomised and ≥48h of study vancomycin) unless specified.
NeoVanc was stopped at 242 participants when it became apparent that the sample size of 300 would not be met within the trial timelines.
Results:A successful outcome was achieved in 64/90 (71%) in the optimised and 73/92 (79%) in the standard arm (95% confidence-interval of difference: (-15%, 2%)); non-inferiority was not confirmed on a non-inferiority margin of –10%. Failure in the optimised arm was associated with inadequate resolution of clinical/laboratory signs at 5±1 days of vancomycin therapy.
Abnormal hearing in the intention to treat population was twice as high in the optimised arm (25/84; 30%) as the standard arm (12/79; 15%. P=0.03), although hearing data was not available for all participants. Abnormal renal function was rare in both arms.
Conclusions:NeoVanc is the largest infant vancomycin efficacy RCT ever conducted. A potential ototoxic safety signal was identified with a loading dose, emphasising the importance of RCTs in infants for commonly prescribed drugs; long-term follow-up is planned to further assess this signal. As non-inferiority was not met the optimised regimen would not be recommended.
Keyword(s): neonate, antibiotic duration, ototoxicitySession Type: 1-hour Mini Oral Flash
Session Title: 1-hour Mini Oral Flash
Authors(s): L.F. Hill (1, 2), M. Clements (3), M.A. Turner (4), D. Donà (1), P.T. Heath (1), I. Lutsar (5), E. Jacqz-Aigrain (6), E. Roilides (7), L. Rawcliffe (8), B. Bafadal (8), A.S. Walker (3), M. Sharland (1)
Authors Affiliations(s): (1) 1. Paediatric Infectious Diseases Research Group, Institute for Infection & Immunity, St George’s, University of London, UK, United Kingdom, (2) 2. UCL Great Ormond Street Institute for Child Health, London, UK, United Kingdom, (3) 3. MRC Clinical Trials Unit at UCL, London, UK, United Kingdom, (4) 4. Institute of Translational Medicine, University of Liverpool, Liverpool, UK, United Kingdom, (5) 5. University of Tartu, Tartu, Estonia, Estonia, (6) 6. Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France, France, (7) 7. 3rd Department of Pediatrics, Aristotle University, Thessaloniki, Greece, Greece, (8) 8. Therakind Ltd., London, UK, United Kingdom
Third Party Affiliation: on behalf of the NeoVanc Consortium
Background:
Vancomycin has been used to treat Gram-positive sepsis for >50 years, however, robust data supporting infant dosing regimens are lacking. NeoVanc (NCT02790996) was a European, multicentre, phase IIb, non-inferiority randomised controlled trial (RCT) trialling an optimised dosing regimen, derived from pre-clinical studies, in infants up to 90 days of age with confirmed/suspected Gram-positive late-onset sepsis.
Methods:Participants with clinical sepsis (≥3 clinical/laboratory criteria) or confirmed Gram-positive sepsis with ≥1 clinical/laboratory criterion were enrolled from 22 neonatal units. Randomisation was 1:1 to the optimised regimen (loading dose [25 mg/kg] followed by 5±1 days of 15 mg/kg q12h or q8h dependent on postmenstrual age [PMA]) or the standard regimen (no loading dose; 10±2 day course at 15 mg/kg q24h, q12h, or q8h dependent on PMA). The primary endpoint was successful outcome at the end of vancomycin therapy without clinically/microbiologically significant relapse/new infection requiring specific anti-staphylococcal antibiotic treatment within 10 days of stopping vancomycin.
Secondary endpoints included safety.
Results describe the per-protocol population (participants receiving the loading dose as randomised and ≥48h of study vancomycin) unless specified.
NeoVanc was stopped at 242 participants when it became apparent that the sample size of 300 would not be met within the trial timelines.
Results:A successful outcome was achieved in 64/90 (71%) in the optimised and 73/92 (79%) in the standard arm (95% confidence-interval of difference: (-15%, 2%)); non-inferiority was not confirmed on a non-inferiority margin of –10%. Failure in the optimised arm was associated with inadequate resolution of clinical/laboratory signs at 5±1 days of vancomycin therapy.
Abnormal hearing in the intention to treat population was twice as high in the optimised arm (25/84; 30%) as the standard arm (12/79; 15%. P=0.03), although hearing data was not available for all participants. Abnormal renal function was rare in both arms.
Conclusions:NeoVanc is the largest infant vancomycin efficacy RCT ever conducted. A potential ototoxic safety signal was identified with a loading dose, emphasising the importance of RCTs in infants for commonly prescribed drugs; long-term follow-up is planned to further assess this signal. As non-inferiority was not met the optimised regimen would not be recommended.
Keyword(s): neonate, antibiotic duration, ototoxicity