Clinical trial NCT02790996: Neonatal Vancomycin Trial
Official title: Multi-centre, Randomised, Open Label, Phase IIb Study to Compare the Efficacy, Safety and Pharmacokinetics (PK) of an Optimised Dosing to a Standard Dosing Regimen of Vancomycin in Neonates and Infants Aged ≤ 90 Days With Late Onset Bacterial Sepsis Known or Suspected to be Caused by Gram-positive Microorganisms
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Late Onset Neonatal Sepsis
Keywords: sepsis
neonate
vancomycin
Lead sponsor: PENTA Foundation
Sponsor class: NETWORK
Collaborators: name: St George's, University of London
name: Hopital Universitaire Robert-Debre
name: University of Tartu
name: Consorzio per Valutazioni Biologiche e Farmacologiche
name: University of Liverpool
name: Therakind limited
name: Bambino Gesù Hospital and Research Institute
name: Servicio Madrileño de Salud, Madrid, Spain
name: Aristotle University Of Thessaloniki
name: Cardiff University
name: SYNAPSE Research Management Partners S.L
name: European Commission
First posted: 2016-06-06
Enrollment: 242
Sex: ALL
Minimum age (years): 72
Maximum age (years): 90
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study aims to compare the efficacy, safety and pharmacokinetics (PK) of an optimised dosing to a standard dosing regimen of vancomycin in neonates and infants aged ≤ 90 days with late onset bacterial sepsis known or suspected to be caused by Gram-positive microorganisms

Detailed description: Detailed objectives of the study are:

* 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.
* 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. vancomycin-resistant enterococci (VRE)) and Candida spp. by allocation group at baseline, TOC and short-term follow-up
* To validate across multiple centres a host biomarker panel to allow improved diagnosis of bacterial sepsis and monitor response to antibacterial therapy

Eligibility criteria: Inclusion Criteria:

* Postnatal age ≤ 90 days AND
* Postnatal age ≥ 72 hours at onset of sepsis AND
* Clinical sepsis as defined by presence of any three clinical or laboratory criteria from the list below 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

* hyper- 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 or \> 20 x 109 cells/L
* immature to total neutrophil ratio (I/T) \> 0.2
* platelet count \< 100 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

Exclusion Criteria:

* Administration of any systemic antibiotic regimen for more than 24 hours prior to randomisation, unless the change is driven by the apparent lack of efficacy of the original regimen
* Treatment with vancomycin for ≥ 24 hours at any time within 7 days of enrolment
* Known toxicity, hypersensitivity or intolerance to vancomycin
* Known renal impairment with 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
* 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 participant found to have Gram-negative or fungal sepsis, osteomyelitis, septic arthritis, UTI, meningitis or S. aureus (MSSA or MRSA) bacteraemia after randomisation will be excluded from analysis. Participants who have received at least one dose of study vancomycin will be followed up for safety

Primary outcomes:
measure: Successful outcome at Test of Cure visit
timeFrame: 10±1 days after End of Actual Vancomycin Therapy
Secondary outcomes:
measure: Clinically or microbiologically significant relapse or new infection requiring treatment with any other antibiotic for more than 24 hours
timeFrame: 10±1 days after the End of Actual Vancomycin Treatment
measure: Successful outcome at Visit 4 or End of Actual Vancomycin Therapy including total duration of vancomycin therapy
timeFrame: Day 5±1 or Day 10±2
measure: Abnormal renal function tests at the Short-term Follow-Up Visit
timeFrame: 30±5 days post-initiation of vancomycin therapy
measure: Abnormal hearing screening test
timeFrame: By Day 90 post-initiation of vancomycin therapy
measure: Comparative safety of vancomycin (relating to the number of treatment-related adverse events other than those associated with renal function and hearing) at Short Term Follow-Up Visit
timeFrame: 30±5 days post-initiation of vancomycin therapy
measure: Pharmacokinetic parameters of vancomycin using population PK modelling by allocation group
timeFrame: Up to 2 years (final data collection date for outcome measure)
measure: Probability of target attainment (PTA) with different study regimens
timeFrame: Up to 2 years (final data collection date for outcome measure)
measure: Relationship between CoNS species and duration of treatment and CRP response
timeFrame: Day 5±1 or Day 10±1
measure: Gut colonisation by vancomycin resistant organisms at baseline, Test of Cure Visit and Short-term Follow-Up Visit
timeFrame: Baseline, 10±1 days after end of vancomycin therapy, 30±5 days post-initiation of vancomycin therapy
measure: Skin colonisation and resistance patterns before and after vancomycin treatment
timeFrame: Baseline, 10±1 days after end of vancomycin therapy, 30±5 days post-initiation of vancomycin therapy
measure: Assessment of changes in host biomarker panel profiles from baseline to End of Actual Vancomycin Therapy and the relationship between host biomarker and duration of treatment
timeFrame: Day 3 and Day 5±1, Day 10±1 (standard arm only)
Other outcomes:
Locations:
city: Tallinn
country: Estonia
facility: Tallinn's Children's Hospital
city: Tartu
country: Estonia
facility: Paediatric Intensive Care Unit, Clinicum of the University of Tartu
city: Athens
country: Greece
facility: Aghia Sophia Children's Hospital (A)
city: Athens
country: Greece
facility: Aghia Sophia Children's Hospital (B)
city: Athens
country: Greece
facility: Aghia Sophia Children's Hospital (C)
city: Athens
country: Greece
facility: Kyriakou Children's Hospital
city: Chaïdári
country: Greece
facility: General University Hospital Attikon
city: Thessaloniki
country: Greece
facility: Hippokration Hospital - Department of Neonatology
city: Thessaloniki
country: Greece
facility: Papageorgiou 2nd Department of Neonatology
city: Bari
country: Italy
facility: Ospedale "Di Venere" - Carbonara di Bari
city: Milan
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Pavia
country: Italy
facility: Policlinico San Matteo
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesu'
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Materno Infantil, La Paz
city: Manchester
country: United Kingdom
facility: St Mary's Hospital
Study officials:
affiliation: St George's, University of London
name: Mike Sharland, MD, FRCPCH
role: STUDY_CHAIR
References:
citation: Hill LF, Turner MA, Lutsar I, Heath PT, Hardy P, Linsell L, Jacqz-Aigrain E, Roilides E, Sharland M; NeoVanc Consortium. An optimised dosing regimen versus a standard dosing regimen of vancomycin for the treatment of late onset sepsis due to Gram-positive microorganisms in neonates and infants aged less than 90 days (NeoVanc): study protocol for a randomised controlled trial. Trials. 2020 Apr 15;21(1):329. doi: 10.1186/s13063-020-4184-8.
citation: Hill LF, Clements MN, Turner MA, Dona D, Lutsar I, Jacqz-Aigrain E, Heath PT, Roilides E, Rawcliffe L, Alonso-Diaz C, Baraldi E, Dotta A, Ilmoja ML, Mahaveer A, Metsvaht T, Mitsiakos G, Papaevangelou V, Sarafidis K, Walker AS, Sharland M; NeoVanc Consortium. Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial. Lancet Child Adolesc Health. 2022 Jan;6(1):49-59. doi: 10.1016/S2352-4642(21)00305-9. Epub 2021 Nov 26.