Neonatal Vancomycin Trial

Late Onset Neonatal Sepsis Clinical Trial

— 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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02790996
• Other study ID #: NeoVanc
• Status: Terminated
• Phase: Phase 2
• Start date: February 27, 2017
• Est. completion date: April 1, 2020

Study information

• Verified date: September 2020
• Source: PENTA Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 242
• Est. completion date: April 1, 2020
• Est. primary completion date: April 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 90 Days

Eligibility

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

Related Conditions & MeSH terms

• Late Onset Neonatal Sepsis
• Neonatal Sepsis
• Sepsis

Intervention

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.

Locations

Country	Name	City	State
Estonia	Tallinn's Children's Hospital	Tallinn
Estonia	Paediatric Intensive Care Unit, Clinicum of the University of Tartu	Tartu
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	Athens
Greece	General University Hospital Attikon	Chaïdári
Greece	Hippokration Hospital - Department of Neonatology	Thessaloniki
Greece	Papageorgiou 2nd Department of Neonatology	Thessaloniki
Italy	Ospedale "Di Venere" - Carbonara di Bari	Bari
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milan
Italy	Azienda Ospedaliera di Padova	Padova
Italy	Policlinico San Matteo	Pavia
Italy	Ospedale Pediatrico Bambino Gesu'	Rome
Spain	Hospital Sant Joan de Deu	Barcelona
Spain	Hospital 12 de Octubre	Madrid
Spain	Hospital Materno Infantil, La Paz	Madrid
United Kingdom	St Mary's Hospital	Manchester

Sponsors (13)

Lead Sponsor	Collaborator
PENTA Foundation	Aristotle University Of Thessaloniki, Bambino Gesù Hospital and Research Institute, Cardiff University, Consorzio per Valutazioni Biologiche e Farmacologiche, European Commission, Robert Debré Hospital, Servicio Madrileño de Salud, Madrid, Spain, St George's, University of London, SYNAPSE Research Management Partners S.L, Therakind limited, University of Liverpool, University of Tartu

Countries where clinical trial is conducted

Estonia,  Greece,  Italy,  Spain,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Successful outcome at Visit 4 or End of Actual Vancomycin Therapy including total duration of vancomycin therapy		Day 5±1 or Day 10±2
Secondary	Abnormal renal function tests at the Short-term Follow-Up Visit		30±5 days post-initiation of vancomycin therapy
Secondary	Abnormal hearing screening test		By Day 90 post-initiation of vancomycin therapy
Secondary	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
Secondary	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)
Secondary	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)
Secondary	Relationship between CoNS species and duration of treatment and CRP response		Day 5±1 or Day 10±1
Secondary	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
Secondary	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
Secondary	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)