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Neonatal Vancomycin Trial (NeoVanc)

Primary Purpose

Late Onset Neonatal Sepsis

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Vancomycin
Sponsored by
PENTA Foundation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Late Onset Neonatal Sepsis focused on measuring sepsis, neonate, vancomycin

Eligibility Criteria

72 Hours - 90 Days (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Tallinn's Children's Hospital
  • Paediatric Intensive Care Unit, Clinicum of the University of Tartu
  • Aghia Sophia Children's Hospital (A)
  • Aghia Sophia Children's Hospital (B)
  • Aghia Sophia Children's Hospital (C)
  • Kyriakou Children's Hospital
  • General University Hospital Attikon
  • Hippokration Hospital - Department of Neonatology
  • Papageorgiou 2nd Department of Neonatology
  • Ospedale "Di Venere" - Carbonara di Bari
  • ASST Grande Ospedale Metropolitano Niguarda
  • Azienda Ospedaliera di Padova
  • Policlinico San Matteo
  • Ospedale Pediatrico Bambino Gesu'
  • Hospital Sant Joan de Deu
  • Hospital 12 de Octubre
  • Hospital Materno Infantil, La Paz
  • St Mary's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Vancomycin - Optimised Regimen

Vancomycin - Standard Regimen

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Clinically or microbiologically significant relapse or new infection requiring treatment with any other antibiotic for more than 24 hours
Successful outcome at Visit 4 or End of Actual Vancomycin Therapy including total duration of vancomycin therapy
Abnormal renal function tests at the Short-term Follow-Up Visit
Abnormal hearing screening test
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
Pharmacokinetic parameters of vancomycin using population PK modelling by allocation group
Area under the plasma concentration time curve - AUC (mg*hour/L)
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.
Relationship between CoNS species and duration of treatment and CRP response
Gut colonisation by vancomycin resistant organisms at baseline, Test of Cure Visit and Short-term Follow-Up Visit
Skin colonisation and resistance patterns before and after vancomycin treatment
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

Full Information

First Posted
April 7, 2016
Last Updated
September 7, 2020
Sponsor
PENTA Foundation
Collaborators
St George's, University of London, Hopital Universitaire Robert-Debre, University of Tartu, Consorzio per Valutazioni Biologiche e Farmacologiche, University of Liverpool, Therakind limited, Bambino Gesù Hospital and Research Institute, Servicio Madrileño de Salud, Madrid, Spain, Aristotle University Of Thessaloniki, Cardiff University, SYNAPSE Research Management Partners S.L, European Commission
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1. Study Identification

Unique Protocol Identification Number
NCT02790996
Brief Title
Neonatal Vancomycin Trial
Acronym
NeoVanc
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

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Terminated
Why Stopped
Planned interim analysis yielded different event rate affecting sample size and ability to recruit sufficient numbers within remaining trial time frame
Study Start Date
February 27, 2017 (Actual)
Primary Completion Date
April 1, 2020 (Actual)
Study Completion Date
April 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
PENTA Foundation
Collaborators
St George's, University of London, Hopital Universitaire Robert-Debre, University of Tartu, Consorzio per Valutazioni Biologiche e Farmacologiche, University of Liverpool, Therakind limited, Bambino Gesù Hospital and Research Institute, Servicio Madrileño de Salud, Madrid, Spain, Aristotle University Of Thessaloniki, Cardiff University, SYNAPSE Research Management Partners S.L, European Commission

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Late Onset Neonatal Sepsis
Keywords
sepsis, neonate, vancomycin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
242 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Vancomycin - Optimised Regimen
Arm Type
Experimental
Arm Description
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
Arm Title
Vancomycin - Standard Regimen
Arm Type
Active Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Vancomycin
Intervention Description
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.
Primary Outcome Measure Information:
Title
Successful outcome at Test of Cure visit
Description
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.
Time Frame
10±1 days after End of Actual Vancomycin Therapy
Secondary Outcome Measure Information:
Title
Clinically or microbiologically significant relapse or new infection requiring treatment with any other antibiotic for more than 24 hours
Time Frame
10±1 days after the End of Actual Vancomycin Treatment
Title
Successful outcome at Visit 4 or End of Actual Vancomycin Therapy including total duration of vancomycin therapy
Time Frame
Day 5±1 or Day 10±2
Title
Abnormal renal function tests at the Short-term Follow-Up Visit
Time Frame
30±5 days post-initiation of vancomycin therapy
Title
Abnormal hearing screening test
Time Frame
By Day 90 post-initiation of vancomycin therapy
Title
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
Time Frame
30±5 days post-initiation of vancomycin therapy
Title
Pharmacokinetic parameters of vancomycin using population PK modelling by allocation group
Description
Area under the plasma concentration time curve - AUC (mg*hour/L)
Time Frame
Up to 2 years (final data collection date for outcome measure)
Title
Probability of target attainment (PTA) with different study regimens
Description
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.
Time Frame
Up to 2 years (final data collection date for outcome measure)
Title
Relationship between CoNS species and duration of treatment and CRP response
Time Frame
Day 5±1 or Day 10±1
Title
Gut colonisation by vancomycin resistant organisms at baseline, Test of Cure Visit and Short-term Follow-Up Visit
Time Frame
Baseline, 10±1 days after end of vancomycin therapy, 30±5 days post-initiation of vancomycin therapy
Title
Skin colonisation and resistance patterns before and after vancomycin treatment
Time Frame
Baseline, 10±1 days after end of vancomycin therapy, 30±5 days post-initiation of vancomycin therapy
Title
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
Description
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
Time Frame
Day 3 and Day 5±1, Day 10±1 (standard arm only)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
72 Hours
Maximum Age & Unit of Time
90 Days
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mike Sharland, MD, FRCPCH
Organizational Affiliation
St George's, University of London
Official's Role
Study Chair
Facility Information:
Facility Name
Tallinn's Children's Hospital
City
Tallinn
Country
Estonia
Facility Name
Paediatric Intensive Care Unit, Clinicum of the University of Tartu
City
Tartu
Country
Estonia
Facility Name
Aghia Sophia Children's Hospital (A)
City
Athens
Country
Greece
Facility Name
Aghia Sophia Children's Hospital (B)
City
Athens
Country
Greece
Facility Name
Aghia Sophia Children's Hospital (C)
City
Athens
Country
Greece
Facility Name
Kyriakou Children's Hospital
City
Athens
Country
Greece
Facility Name
General University Hospital Attikon
City
Chaïdári
Country
Greece
Facility Name
Hippokration Hospital - Department of Neonatology
City
Thessaloniki
Country
Greece
Facility Name
Papageorgiou 2nd Department of Neonatology
City
Thessaloniki
Country
Greece
Facility Name
Ospedale "Di Venere" - Carbonara di Bari
City
Bari
Country
Italy
Facility Name
ASST Grande Ospedale Metropolitano Niguarda
City
Milan
Country
Italy
Facility Name
Azienda Ospedaliera di Padova
City
Padova
Country
Italy
Facility Name
Policlinico San Matteo
City
Pavia
Country
Italy
Facility Name
Ospedale Pediatrico Bambino Gesu'
City
Rome
Country
Italy
Facility Name
Hospital Sant Joan de Deu
City
Barcelona
Country
Spain
Facility Name
Hospital 12 de Octubre
City
Madrid
Country
Spain
Facility Name
Hospital Materno Infantil, La Paz
City
Madrid
Country
Spain
Facility Name
St Mary's Hospital
City
Manchester
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
32293527
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.
Results Reference
background
PubMed Identifier
34843669
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.
Results Reference
derived

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Neonatal Vancomycin Trial

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