Intravenous and Oral Fosfomycin in Hospitalised Neonates With Clinical Sepsis

NCT03453177 | Completed Phase 2 DMC

• 1 other identifier: Neo-Fos-001
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

Neonatal sepsis has a high risk of morbidity and mortality. The current WHO and national guidelines recommend antibiotics to which resistance is reported in neonatal populations, although the available data is limited. Research on alternative empirical regimens for neonatal sepsis which are affordable, safe and cost-effective, with a step-down oral option, is needed. AMR is an issue of global public health concern and is one of the WHO's global health priority areas. Understanding the benefits, risks, MIC capacity and PK of fosfomycin will influence global policy on the case management of neonates with sepsis in Kenya and international settings.

Conditions

Neonatal SEPSIS

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetic disposition and absorption parameters of IV and oral fosfomycin in neonates with clinical sepsis

  Fosfomycin Clearance (CL)

  Participants will be followed for the duration of enrolment, an expected average of 7 days

• Pharmacokinetic disposition and absorption parameters of IV and oral

  Fosfomycin Volume of Distribution

  Participants will be followed for the duration of enrolment, an expected average of 7 days

• Pharmacokinetic disposition and absorption parameters of IV and oral

  Fosfomycin Oral Bioavailability (F)

  Participants will be followed for the duration of enrolment, an expected average of 7 days

Secondary Outcomes (3)

• Difference between the groups in mean 48-hour plasma sodium concentrations

  48 hours

• Difference between the groups in mean 7-day plasma sodium concentrations

  7 days

• Difference between groups in the rate of adverse events (any grade) to 28 days after enrolment in the study

  from patient randomization to visit D28

Study Arms (2)

Standard of Care

NO INTERVENTION

ampicillin 50mg/kg twice daily and gentamicin \[3mg/kg for babies \<2kg or 5mg/kg for babies \>2kg\] once daily for 7 days, as per Kenyan guidelines).

Standard of Care plus Fosfomycin

EXPERIMENTAL

Fosfomycin will initially be administered IV for at least 48 hours together with standard care (ampicillin + gentamicin). Then, once babies are tolerating oral feeds and clinically improved, fosfomycin will be changed to oral administration to complete a total of 7 days of fosfomycin (or until the baby is discharged).

Drug: Standard of Care + Fosfomycin; Procedure: PK; Procedure: Analysis of Bacterial Isolates

Interventions

Standard of Care + Fosfomycin DRUG

Fosfomycin will initially be administered IV for at least 48 hours together with standard care (ampicillin + gentamicin). Then, once babies are tolerating oral feeds and clinically improved, fosfomycin will be changed to oral administration to complete a total of 7 days of fosfomycin (or until the baby is discharged).

Also known as: iv Fosfomycin, oral Fosfomycin

Standard of Care plus Fosfomycin

PK PROCEDURE

Two PK samples will be taken after each of the first IV and oral doses, with sampling times allocated within possible early (5, 10 or 60 minutes) and late (2, 4 or 8 hours) time-points after starting the IV and PO formulations; then again together with biochemistry after 7 days for those babies whom remain as inpatients.

Standard of Care plus Fosfomycin

Analysis of Bacterial Isolates PROCEDURE

For assessment of susceptibility patterns in bowel flora, we will systematically assess all admission and discharge nappy swabs.

Standard of Care plus Fosfomycin

Eligibility Criteria

• Age: Up to 28 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age 0 to 28 days inclusive
• Weight \>1500g
• Born (an estimated) \>34 weeks gestation (calculated as per the Ballard Maturational Assessment)
• Admitted to hospital and eligible to receive IV antibiotics, according to national guidelines

You may not qualify if:

• Baseline sodium level \>= 150mmol/L
• Baseline creatinine \>= 150 micromol/L
• Presenting with severe (grade 3) Hypoxic Ischaemic Encephalopathy (HIE), defined as per Sarnat and Sarnat as a stuporous, flaccid infant (with or without seizure activity) with suppressed brainstem and autonomic functions and absent reflexes
• Requiring cardiopulmonary resuscitation on admission
• Jaundice requiring exchange transfusion
• Admitted as a transfer after an overnight inpatient stay at another hospital
• Known allergy or contraindication to fosfomycin
• A specific clinical indication for another class of antibiotic (other than the nationally recommended standard-of-care)
• More than 4 hours after initiating ampicillin plus gentamicin (one dose), which allows for administration of these first-line antibiotics not to be delayed by study procedures
• Concurrent participation in another clinical trial
• Attending clinician's judgement that the child is so severely ill that adequate communication about the study with the parent or legal guardian is not possible.
• Not planning to remain resident in the County for the next 28 days.
• Lack of consent

Sponsors & Collaborators

• Drugs for Neglected Diseases: lead
• KEMRI-Wellcome Trust Collaborative Research Program: collaborator
• University of Oxford: collaborator

Study Sites (1)

KEMRI / Wellcome Trust Research Programme

Kilifi, 80108, Kenya

Location

Related Publications (3)

• Gastine S, Obiero C, Kane Z, Williams P, Readman J, Murunga S, Thitiri J, Ellis S, Correia E, Nyaoke B, Kipper K, van den Anker J, Sharland M, Berkley JA, Standing JF. Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis. J Antimicrob Chemother. 2022 Feb 2;77(2):448-456. doi: 10.1093/jac/dkab413.

  PMID: 35107141 DERIVED

• Obiero CW, Williams P, Murunga S, Thitiri J, Omollo R, Walker AS, Egondi T, Nyaoke B, Correia E, Kane Z, Gastine S, Kipper K, Standing JF, Ellis S, Sharland M, Berkley JA; NeoFosfo Study Group. Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload. Arch Dis Child. 2022 Sep;107(9):802-810. doi: 10.1136/archdischild-2021-322483. Epub 2022 Jan 25.

  PMID: 35078765 DERIVED

• Kane Z, Gastine S, Obiero C, Williams P, Murunga S, Thitiri J, Ellis S, Correia E, Nyaoke B, Kipper K, van den Anker J, Sharland M, Berkley JA, Standing JF. IV and oral fosfomycin pharmacokinetics in neonates with suspected clinical sepsis. J Antimicrob Chemother. 2021 Jun 18;76(7):1855-1864. doi: 10.1093/jac/dkab083.

  PMID: 33855449 DERIVED

MeSH Terms

Conditions

Neonatal Sepsis

Interventions

Standard of Care; Fosfomycin

Condition Hierarchy (Ancestors)

Sepsis; Infections; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; Organophosphonates; Organophosphorus Compounds; Organic Chemicals

Study Officials

• James A Berkley, Prof

  KEMRI/Wellcome Trust Research Programme and University of Oxford - UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 7, 2018
• First Posted: March 5, 2018
• Study Start: March 15, 2018
• Primary Completion: March 14, 2019
• Study Completion: May 24, 2019
• Last Updated: February 17, 2020

Record last verified: 2020-02

Locations

KE (1)