Neonatal sepsis Infections and Infestations
Conditions
Interventions
3 divided doses per day
6. Ceftriaxone: 80-100 mg/kg total daily dose for sepsis
Randomisation:
Treatment allocation (Part 1 only): Run-in sequential treatment cohort:
1. Fosfomycin and amikacin
2. Flomoxef and amikacin
3. Flomoxef and fosfomycin
Randomisation (Part 2 only)
15 mg/kg total daily dose for suspected/confirmed meningitis
2. Ampicillin/amoxicillin: 100-150 mg/kg total daily dose for sepsis
200-400 mg/kg total daily dose for suspected/confirmed meningitis
2-3 divided doses per day
3. Benzylpenicillin: 100,000-200,000 IU/kg total daily dose for sepsis
100,000-200,000 IU/kg total daily dose for suspected/confirmed meningitis
2-4 divided doses per day
4. Cefotaxime: 100-150 mg/kg total daily dose for sepsis
150-200mg/kg total daily dose for suspected/confirmed meningitis
2-3 divided doses per day
5. Ceftazidime: 100-150 mg/kg total daily dose for sepsis
100-150 mg/kg total daily dose for suspected/confirmed meningitis
Sponsors
Global Antibiotic Research & Development Partnership
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 19/02/2025: 1. Currently admitted to hospital 2. Aged =28 days (post-natal age) 3. Weight =1000g 4. Clinical diagnosis of a new episode of sepsis with two or more of the following clinical signs together with planned treatment with IV antibiotics a. Abnormal temperature (180 bpm) i. Convulsions j. Irritability For making the diagnosis of significant sepsis, the neonate should have no alternative primary explanation for these criteria (such as Hypoxic Ischaemic Encephalopathy, hypothermia, hypoglycemia, prematurity etc) 5. At moderate to high risk of death from this episode of sepsis, based on a neonatal sepsis severity score (NeoSep Severity Score). This was adapted from the WHO pSBI based scores for the hospital setting and developed using baseline clinical information and subsequent mortality from the NeoOBS study; specifically, a NeoSep Severity Score of 5 or higher at presentation for this episode of sepsis (which may be before formal screening) 6. Can receive all potential treatment options on the relevant randomisation list for this neonate at their site, ensuring randomisation is possible (see country-specific appendices) 7. IV antibiotics about to be started OR not received more than 24 hours of IV antibiotics for this episode of neonatal sepsis at the point of randomisation Parent/guardian willing and able to provide consent (written or, if their neonate is severely ill, verbal consent which must be confirmed by written consent as soon as possible and wherever possible within 48 hours after the first trial specific procedure). Verbal consent allows for administration of first-line antibiotics at no or minimal delay _____ Previous inclusion criteria: 1. Currently admitted to hospital 2. Aged =28 days (post-natal age) 3. Weight >1000 g 4. Clinical diagnosis of a new episode of sepsis together with planned treatment with IV antibiotics 5. At moderate to high risk of death from this episode of sepsis, based on a neonatal sepsis severity score (NeoSep Severity Score) developed using baseline clinical information and subsequent mortality from the NeoOBS study; specifically, a baseline assessment NeoSep Severity Score of 4 or higher 6. Can receive at least 2 of the potential treatment options, ensuring randomisation is possible (Part 2 only) 7. IV antibiotics about to be started or not received >24 h of IV antibiotics for this episode of neonatal sepsis at the point of randomisation 8. Parent/guardian willing and able to provide consent (written or, if their baby is severely ill, verbal consent confirmed by written consent as soon as possible). Verbal consent allows for the administration of first-line antibiotics at no or minimal delay.
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 19/02/2025: 1. A known serious, non-infective co-morbidity anticipated to cause death within this admission (including major congenital abnormalities anticipated to cause death within this admission other than prematurity, e.g. known large ventricular septal defect) 2. Previously enrolled in this trial 3. Current participation in any other clinical study of an Investigational Medicinal Product (IMP) that is a systemic drug, unless it has received prior approval by the NeoSep1 Trial Management Group (TMG) 4. Known contraindication to any of the trial antibiotics on the randomisation list for the relevant neonatal sub-population in that site _____ Previous exclusion criteria as of 19/02/2025: 1. A serious, non-infective co-morbidity including major congenital abnormalities (other than prematurity), anticipated to cause death within this admission 2. Previously enrolled in this trial 3. Current participation in any other clinical study of an Investigational Medicinal Product (IMP) that is a systemic drug, unless it has received prior approval by the NeoSep1 Trial Management Group (TMG) 4. Known contraindication to any of the trial antibiotics on the randomisation list for the relevant neonatal sub-population in that site
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1: 1. PK parameters derived for fosfomycin and flomoxef using the population PK model using Day 1 PK samples taken at 5 min, 30 min, and 4 h post-treatment or 15 min, 1 h, and 6 h post-treatment from the population: 1.1. Clearance (CL) 1.2. Central volume of distribution (V) 1.3. Postnatal maturation function parameters: fraction of size and scaled clearance at birth (Fm) and the rate of postnatal maturation of clearance (Km) Part 2: 1. 28-day mortality measured from patient records at 28 days | — |
Secondary
| Measure | Time frame |
|---|---|
| Current secondary outcome measures as of 19/02/2025: Part 1: 1. PK parameters derived for fosfomycin and flomoxef using the population PK model using PK samples taken on Day 1 and Day 5: 1.1. Maximum plasma concentration (Cmax) 1.2. Time to Cmax (Tmax) 1.3. Apparent terminal elimination half-life (t1/2) 1.4. Area under the plasma concentration-time curve from 0 to last observed time point (AUC0–last) 1.5. Area Under the Curve to infinity (AUC(0–8)) 1.6. Volume of distribution at steady state (Vss) 2. Potential PK/PD relationships using PK and PD samples taken on Day 1 and Day 5: 2.1. Free drug AUC ratio to Minimum Inhibitory Concentration (MIC) (fosfomycin) 2.2. Fraction of time for free concentration above MIC (flomoxef) 3. Safety measured using the following: 3.1. Incidence of Grade 3/4 adverse events (AEs) based on the International Neonatal Consortium Neonatal Adverse Event Severity Scale (NAESS) measured from patient records between baseline and 28 days 3.2. Incidence of AEs of any grade related to antibiotics measured from patient records throughout the study 3.3. Modification of antibiotics for adverse reactions measured from patient records throughout the study Part 2: 1. Efficacy: 1.1. Clinical status, assessed daily after randomisation through to the earlier of discharge from a trial site or Day 28 using a clinical recovery score based on data from the NeoOBS observational study 1.2. Additional systemic antibiotics beyond the first randomised treatment through Day 28 1.3. Additional systemic antibiotics beyond the first randomised and second (for failure) treatment through Day 28 1.4. Length of stay during the index hospitalisation 1.5. Systemic antibiotic exposure (days on antibiotics) during the index hospitalisation 1.6. 90-day mortality 1.7. Change in C-reactive protein to Day 3 and 7 from baseline 1.8. Re-admission by Day 90 (all-cause) 2. Safety: 2.1. Grade 3/4 adverse events (AEs) graded using a combined low and middle income country (LMIC) | — |
Countries
Bangladesh, Ghana, India, Kenya, Pakistan, South Africa, Uganda, Viet Nam
Contacts
Public ContactNathalie Khavessian
Outcome results
None listed