Neonatal Vancomycin Trial (NeoVanc)

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

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

Study Overview

• Status: Terminated
• Conditions: Late Onset Neonatal Sepsis
• Intervention / Treatment: Drug: Vancomycin

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

• Study Type: Interventional
• Enrollment (Actual): 242
• Phase: Phase 2

Contacts and Locations

Study Locations

• Estonia
  • Tallinn, Estonia
    • Tallinn's Children's Hospital
  • Tartu, Estonia
    • Paediatric Intensive Care Unit, Clinicum of the University of Tartu
• Greece
  • Athens, Greece
    • Aghia Sophia Children's Hospital (A)
  • Athens, Greece
    • Aghia Sophia Children's Hospital (B)
  • Athens, Greece
    • Aghia Sophia Children's Hospital (C)
  • Athens, Greece
    • Kyriakou Children's Hospital
  • Chaïdári, Greece
    • General University Hospital Attikon
  • Thessaloniki, Greece
    • Hippokration Hospital - Department of Neonatology
  • Thessaloniki, Greece
    • Papageorgiou 2nd Department of Neonatology
• Italy
  • Bari, Italy
    • Ospedale "Di Venere" - Carbonara di Bari
  • Milan, Italy
    • Asst Grande Ospedale Metropolitano Niguarda
  • Padova, Italy
    • Azienda Ospedaliera di Padova
  • Pavia, Italy
    • Policlinico San Matteo
  • Rome, Italy
    • Ospedale Pediatrico bambino Gesu'
• Spain
  • Barcelona, Spain
    • Hospital Sant Joan de Déu
  • Madrid, Spain
    • Hospital 12 de Octubre
  • Madrid, Spain
    • Hospital Materno Infantil, La Paz
• United Kingdom
  • Manchester, United Kingdom
    • St Mary's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 days to 2 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vancomycin - Optimised Regimen; A single loading dose of 25 mg/kg followed by a maintenance dose of: Postmenstrual age ≤ 35 weeks - 15 mg/kg 12 hourly; Postmenstrual age > 35 weeks - 15 mg/kg 8 hourly	Drug: Vancomycin; Vancomycin is an antibiotic used to treat a number of bacterial infections.It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant S. aureus.
Active Comparator: Vancomycin - Standard Regimen; Postmenstrual age < 29 weeks - 15 mg/kg given 24 hourly; Postmenstrual age 29 - 35 weeks - 15 mg/kg 12 hourly; Postmenstrual age > 35 weeks - 15 mg/kg 8 hourly	Drug: Vancomycin; Vancomycin is an antibiotic used to treat a number of bacterial infections.It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant S. aureus.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful outcome at Test of Cure visit	Patient is alive AND has a successful outcome at the end of actual vancomycin therapy AND the patient has not had a clinically or microbiologically significant relapse or new infection.	10±1 days after End of Actual Vancomycin Therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinically or microbiologically significant relapse or new infection requiring treatment with any other antibiotic for more than 24 hours		10±1 days after the End of Actual Vancomycin Treatment
Successful outcome at Visit 4 or End of Actual Vancomycin Therapy including total duration of vancomycin therapy		Day 5±1 or Day 10±2
Abnormal renal function tests at the Short-term Follow-Up Visit		30±5 days post-initiation of vancomycin therapy
Abnormal hearing screening test		By Day 90 post-initiation of vancomycin therapy
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		30±5 days post-initiation of vancomycin therapy
Pharmacokinetic parameters of vancomycin using population PK modelling by allocation group	Area under the plasma concentration time curve - AUC (mg*hour/L)	Up to 2 years (final data collection date for outcome measure)
Probability of target attainment (PTA) with different study regimens	Different bacteriological targets will be tested, based on the MIC of different bacteria of interest with level of sensitivity. Simulations based on the vancomycin popPK model will be conducted to define the number of patients in the different allocation groups reaching the predefined targets when modifying the dose.	Up to 2 years (final data collection date for outcome measure)
Relationship between CoNS species and duration of treatment and CRP response		Day 5±1 or Day 10±1
Gut colonisation by vancomycin resistant organisms at baseline, Test of Cure Visit and Short-term Follow-Up Visit		Baseline, 10±1 days after end of vancomycin therapy, 30±5 days post-initiation of vancomycin therapy
Skin colonisation and resistance patterns before and after vancomycin treatment		Baseline, 10±1 days after end of vancomycin therapy, 30±5 days post-initiation of vancomycin therapy
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	Functional molecular units based on a multimarker panel - a set of 52 biomarkers will be performed as a classifier with high accuracy and specificity in predicting bacterial infection	Day 3 and Day 5±1, Day 10±1 (standard arm only)

Collaborators and Investigators

• Sponsor: PENTA Foundation
• Collaborators: Hopital Universitaire Robert-Debre; Cardiff University; Bambino Gesù Hospital and Research Institute; Aristotle University Of Thessaloniki; University of Liverpool; European Commission; St George's, University of London; University of Tartu; Servicio Madrileño de Salud, Madrid, Spain; Consorzio per Valutazioni Biologiche e Farmacologiche; Therakind limited; SYNAPSE Research Management Partners S.L
• Investigators: Study Chair: Mike Sharland, MD, FRCPCH, St George's, University of London

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2017
• Primary Completion (Actual): April 1, 2020
• Study Completion (Actual): April 1, 2020

Study Registration Dates

• First Submitted: April 7, 2016
• First Submitted That Met QC Criteria: May 31, 2016
• First Posted (Estimate): June 6, 2016

Study Record Updates

• Last Update Posted (Actual): September 9, 2020
• Last Update Submitted That Met QC Criteria: September 7, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: sepsis; vancomycin; neonate
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Sepsis; Neonatal Sepsis; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin
• Other Study ID Numbers: NeoVanc

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No