Neonatal Vancomycin Trial

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

Sponsors

Lead Sponsor: PENTA Foundation

Collaborator: St George's, University of London
Robert Debré Hospital
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

Source PENTA Foundation
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

Overall Status Terminated
Start Date February 27, 2017
Completion Date April 1, 2020
Primary Completion Date April 1, 2020
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Successful outcome at Test of Cure visit 10±1 days after End of Actual Vancomycin Therapy
Secondary Outcome
Measure 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 Up to 2 years (final data collection date for outcome measure)
Probability of target attainment (PTA) with different study regimens 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 Day 3 and Day 5±1, Day 10±1 (standard arm only)
Enrollment 242
Condition
Intervention

Intervention Type: Drug

Intervention Name: Vancomycin

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.

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

Gender: All

Minimum Age: N/A

Maximum Age: 90 Days

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Mike Sharland, MD, FRCPCH Study Chair St George's, University of London
Location
Facility:
Tallinn's Children's Hospital | Tallinn, Estonia
Paediatric Intensive Care Unit, Clinicum of the University of Tartu | Tartu, Estonia
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, Greece
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, Italy
Hospital Sant Joan de Deu | Barcelona, Spain
Hospital 12 de Octubre | Madrid, Spain
Hospital Materno Infantil, La Paz | Madrid, Spain
St Mary's Hospital | Manchester, United Kingdom
Location Countries

Estonia

Greece

Italy

Spain

United Kingdom

Verification Date

September 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Vancomycin - Optimised Regimen

Type: Experimental

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

Label: Vancomycin - Standard Regimen

Type: Active Comparator

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

Acronym NeoVanc
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov