Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202208856270989 Date of Approval: 22/08/2022
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title An open-label randomised controlled trial comparing novel combination and currently used antibiotic regimens for the empiric treatment of neonatal sepsis with a run-in confirmatory pharmacokinetic phase: NeoSep1
Official scientific title An open-label randomised controlled trial comparing novel combination and currently used antibiotic regimens for the empiric treatment of neonatal sepsis with a run-in confirmatory pharmacokinetic phase: NeoSep01
Brief summary describing the background and objectives of the trial The NeoSep01 study will test how well giving fosfomycin and amikacin, OR flomoxef and amikacin OR fosfomycin and flomoxef works to treat babies 28 days old or younger who are in hospital with severe infection of the blood. It will also test how well these new combinations work compared to other antibiotics or combinations of antibiotics that are currently used globally. The study will be divided in two parts: Part 1 and Part 2. Part 1 will measure the level of fosfomycin, amikacin and flomoxef in the baby’s blood; this is called a pharmacokinetic study or PK study. Each baby will get one of the three new combinations of antibiotics: fosfomycin and amikacin, OR flomoxef and amikacin OR fosfomycin and flomoxef. We will study 20 babies in each group, one after the other. We will use doses recommended in other studies. The information collected for Part 1 will will confirm how much fosfomycin and/or flomoxef we should use in the next part of the study. We will also collect data on any side-effects. Babies in Part 1 will be followed up for 28 days In Part 2 of the study we will check how well these three combinations, as well as other antibiotics that are used routinely to treat sepsis in newborn babies, treat bacterial infections and stop babies dying.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) NeoSep01
Disease(s) or condition(s) being studied Neonatal Diseases
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 03/10/2022
Actual trial start date 07/03/2023
Anticipated date of last follow up 31/07/2026
Actual Last follow-up date
Anticipated target sample size (number of participants) 3000
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
ISRCTN48721236 International Standard Randomised Controlled Trial Number
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Central randomisation by phone/fax Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Ampicillin and Gentamicin Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment Cohort 300 Active-Treatment of Control Group
Experimental Group Cefotaxime or Ceftraixone Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment Cohort 300
Experimental Group Fosfomycin and Amikacin Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment Cohort 300
Experimental Group Flomoxef and Amikacin Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment cohort 300
Experimental Group Fosfomycin and Flomoxef Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment Cohort 300
Experimental Group Ceftazidime Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment cohort 300
Experimental Group Ceftazidime and Amikacin Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment cohort 300
Experimental Group Piperacillin or Tazobactam Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment cohort 300
Experimental Group Piperacillin or Tazobactam and Amikacin Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment cohort 300
Experimental Group Meropenem Proposed doses based on dosing recommendations and other studies Proposed duration based on dosing recommendations and other studies Treatment cohort 300
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Currently admitted to hospital 2. Aged ≤28 days (post-natal age) 3. Weight ≥1000g 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), adapted from the WHO PSBI based scores for the hospital setting and developed using baseline clinical information and subsequent mortality from the NeoOBS study as described in Table 5:5; specifically, a baseline assessment NeoSep Severity Score of 5 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 more than 24 hours 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 administration of first-line antibiotics at no or minimal delay (see Section 4.5 for details) 1. A known 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 (see Section 6; these will vary according to the antibiotics on the specific randomisation list New born: 0 Day-1 Month 1 Day(s) 28 Day(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 27/07/2022 KEMRI SCIENTIFIC AND ETHICS REVIEW UNIT
Ethics Committee Address
Street address City Postal code Country
Off Raila Odinga Way, Nairobi Nairobi 00101 Kenya
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 02/08/2022 South African Health Products Regulatory Authority
Ethics Committee Address
Street address City Postal code Country
Loftus Park 402 Kirkness Street Arcadia Pretoria Pretoria 0001 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome For fosfomycin and flomoxef, the following primary pharmacokinetic (PK) parameters will be estimated from the population PK model: • clearance (CL), central volume of distribution (V) • postnatal maturation function parameters: fraction of size and scaled clearance at birth (Fm) and the rate of postnatal maturation of clearance (Km) 28 day mortality
Secondary Outcome For fosfomycin and flomoxef, the following secondary PK parameters will be derived from the population PK model: • Maximum plasma concentration (Cmax) • Time to Cmax (Tmax) • Apparent terminal elimination half-life (t1/2)Area under the plasma concentration-time curve from 0 to last observed time point (AUC0–last) • Area Under the Curve to infinity (AUC(0–∞)) • Volume of distribution at steady state (Vss) Potential PK/PD relationships: • Free drug AUC ratio to Minimum Inibitory Concentration (MIC) (fosfomycin) • Fraction of time for free concentration above MIC (flomoxef) Safety • Adverse events (AEs) based on the International Neonatal Consortium Neonatal Adverse Event Severity Scale (NAESS) through Day 28 • Modification (including discontinuation) of antibiotics for adverse reactions Days 3, 7, 14 and 28 after randomisation
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Kilifi County Hospital Hospital Road, Kilifi Kilifi 80108 Kenya
Chris Hani Baragwanath Academic Hospital 26 Chris Hani Road Johannesburg 1864 South Africa
Tygerberg Childrens Hospital Stellenbosch University 6 Jan Celliers Rd Stellenbosch Central Stellenbosch 7600 South Africa
Kawempe National Referral Hospital Plot 1035/3883, Kawempe Bombo Road Kampala Uganda
Mulago Specialised Women and Neonatal Hospital Owen Road, Mulago Kampala Uganda
Komfo Anokye Teaching Hospital Okomfo Anokye Road Kumasi Ghana
Mbagathi Hospital 1 Mbagathi Road, Off Raila Odinga Way - former Mbagathi Way Nairobi Kenya
Coast General Teaching and Referral Hospital Kisauni Road, Mombasa Mombasa Kenya
FUNDING SOURCES
Name of source Street address City Postal code Country
Global Antibiotic Research and Development Partnership 15 Chemin Camille-Vidart Geneva 1202 Switzerland
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Global Antibiotic Research and Development Partnership GARDP 15 Chemin Camille-Vidart Geneva 1202 Switzerland Charities/Societies/Foundation
COLLABORATORS
Name Street address City Postal code Country
MRC Clinical Trials Unit at UCL 90 High Holborn London WC1V 6LJ United Kingdom
St Georges University of London Cramner Terrace London SW17 0RE United Kingdom
University of Antwerp Universiteitsplein Antwerp B-2610 Belgium
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Christina Obiero CObiero@kemri-wellcome.org 254721889581 Hospital Road
City Postal code Country Position/Affiliation
Kilifi Kenya Principal Investigator KEMRI Wellcome Trust Research Programme
Role Name Email Phone Street address
Public Enquiries Sally Ellis sellis@gardp.org 41229077612 15 Chemin Camille-Vidart
City Postal code Country Position/Affiliation
Geneva 1202 Switzerland Childrens Antibiotics Project Leader GARDP
Role Name Email Phone Street address
Scientific Enquiries Sally Ellis sellis@gardp.org 41229077612 15 Chemin Camille-Vidart
City Postal code Country Position/Affiliation
Geneva 1202 Switzerland Childrens Antibiotics Project Leader
Role Name Email Phone Street address
Scientific Enquiries Sally Ellis sellis@gardp.org 41229077612 15 Chemin Camille-Vidart
City Postal code Country Position/Affiliation
Geneva 1202 Switzerland Childrens Antibiotics Project Leader
Role Name Email Phone Street address
Principal Investigator Maxensia Owor maxowor@mujhu.org 00256414541004 MU-JHU CARE Ltd/MU-JHU Research Collaboration, Upper Mulago Hill Road
City Postal code Country Position/Affiliation
Kampala Uganda Principal Investigator
Role Name Email Phone Street address
Principal Investigator John Amuasi amuasi@kccr.de 00233206300405 South-end Asuogya Road, KNUST
City Postal code Country Position/Affiliation
Kumasi Ghana Principal Investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Data will be shared according to a controlled access approach, based on the following principles: ▪ No data should be released that would compromise the ongoing trial ▪ There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose ▪ Investigators who have invested time and effort into developing the trial should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers; details on data sharing will be covered in a separate site agreement ▪ The resources required to process requests should not be under-estimated, particularly successful requests which lead to preparing data for release. Therefore adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources ▪ Data exchange complies with Information Governance and Data Security Policies in all of the relevant countries Researchers wishing to access NeoSep1 trial data should contact the Trial Management Group (TMG) in the first instance. Approval will be sought from the Sponsor and all requests will be reviewed and discussed by the TMG. Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol Researchers wishing to access NeoSep1 trial data should contact the Trial Management Group (TMG) in the first instance. Approval will be sought from the Sponsor and all requests will be reviewed and discussed by the TMG. Researchers wishing to access NeoSep1 trial data should contact the Trial Management Group (TMG) in the first instance. Approval will be sought from the Sponsor and all requests will be reviewed and discussed by the TMG.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Actual trial start date 19/10/2023 Updated date 07 Mar 2023
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 19/10/2023 Updated status Not yet recruiting Recruiting
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm updated Control Group, Ampicillin Gentamicin, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment Cohort, 300, Active-Treatment of Control Group
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm update Control Group, Ampicillin Gentamicin, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment Cohort, 300, Active-Treatment of Control Group Control Group, Ampicillin and Gentamicin, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment Cohort, 300, Active-Treatment of Control Group
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm updated Experimental Group, Flomoxef, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment Cohort, 300, Experimental Group, Cefotaxime or Ceftraixone, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment Cohort, 300,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm updated Experimental Group, Fosfomycin and Amikacin, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment Cohort, 300,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm update Experimental Group, Flomoxef and Amikacin, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment cohort, 300,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm update Experimental Group, Fosfomycin and Flomoxef, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment Cohort, 300,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm update Experimental Group, Ceftazidime, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment cohort, 300,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm update Experimental Group, Ceftazidime and Amikacin, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment cohort, 300,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm update Experimental Group, Piperacillin or Tazobactam, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment cohort, 300,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm update Experimental Group, Piperacillin or Tazobactam and Amikacin, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment cohort, 300,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 19/08/2022 Treatment arm update Experimental Group, Meropenem, Proposed doses based on dosing recommendations and other studies, Proposed duration based on dosing recommendations and other studies, Treatment cohort, 300,
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 19/08/2022 Site update Kilifi County Hospital, Hospital Road, Kilifi, Kilifi, , Kenya Kilifi County Hospital, Hospital Road, Kilifi, Kilifi, 80108, Kenya
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 19/08/2022 South Africa sites updated Chris Hani Baragwanath Academic Hospital , 26 Chris Hani Road, Johannesburg, 1864, South Africa
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 19/08/2022 South Africa site updated Tygerberg Childrens Hospital Stellenbosch University, 6 Jan Celliers Rd Stellenbosch Central, Stellenbosch, 7600, South Africa
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 10/01/2025 Additional site under part II of the study Kawempe National Referral Hospital, Plot 1035/3883, Kawempe Bombo Road, Kampala, 0000, Uganda
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 10/01/2025 Additional site under part II of the study Kawempe National Referral Hospital, Plot 1035/3883, Kawempe Bombo Road, Kampala, 0000, Uganda Kawempe National Referral Hospital, Plot 1035/3883, Kawempe Bombo Road, Kampala, , Uganda
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 10/01/2025 Additional site under part II of the study Mulago Specialised Women and Neonatal Hospital, Owen Road, Mulago, Kampala, 0000, Uganda
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 10/01/2025 Additional site under part II of the study Mulago Specialised Women and Neonatal Hospital, Owen Road, Mulago, Kampala, 0000, Uganda Mulago Specialised Women and Neonatal Hospital, Owen Road, Mulago, Kampala, , Uganda
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 10/01/2025 Additional site under part II of the study Komfo Anokye Teaching Hospital, Okomfo Anokye Road, Kumasi, , Ghana
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 10/01/2025 Additional site under part II of the study Komfo Anokye Teaching Hospital, Okomfo Anokye Road, Kumasi, , Ghana Komfo Anokye Teaching Hospital, Okomfo Anokye Road, Kumasi, 0000, Ghana
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 10/01/2025 Additional site under part II of the study Komfo Anokye Teaching Hospital, Okomfo Anokye Road, Kumasi, 0000, Ghana Komfo Anokye Teaching Hospital, Okomfo Anokye Road, Kumasi, , Ghana
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 10/01/2025 Additional site under part II of the study Mbagathi Hospital, 1 Mbagathi Road, Off Raila Odinga Way - former Mbagathi Way , Nairobi, , Kenya
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 10/01/2025 Additional site under part II of the study Coast General Teaching and Referral Hospital, Kisauni Road, Mombasa, Mombasa, , Kenya
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 29/01/2025 PACTR Admin
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 29/01/2025 PACTR Admin
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 29/01/2025 PACTR Admin
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 29/01/2025 PACTR Admin
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 29/01/2025 PACTR Admin TRUE, KENYA MEDICAL RESEARCH INSTITUTE, Kenya, Kenya, 0000, Kenya, , 16 Dec 2022, 2540202722541, ddrt@kemri.go.ke, 23898_30195_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Contact People Contacs List 17/01/2025 Previous personnel left the organisation. Scientific Enquiries, Subasree, Srinivasan, Dr., ssrinivasan@gardpna.org, , 41225551990, 15 Chemin Camille-Vidart, Geneva, 1202, Switzerland, Medical Director GARDP Scientific Enquiries, Sally, Ellis, Ms., sellis@gardp.org, , 41229077612, 15 Chemin Camille-Vidart, Geneva, 1202, Switzerland, Childrens Antibiotics Project Leader
Section Name Field Name Date Reason Old Value Updated Value
Contact People Contacs List 17/01/2025 Uganda PI details Principal Investigator, Maxensia, Owor, Dr., maxowor@mujhu.org, , 00256414541004, MU-JHU CARE Ltd/MU-JHU Research Collaboration, Upper Mulago Hill Road, Kampala, , Uganda, Principal Investigator
Section Name Field Name Date Reason Old Value Updated Value
Contact People Contacs List 17/01/2025 Ghana PI details Principal Investigator, John, Amuasi, Dr., amuasi@kccr.de, , 00233206300405, South-end Asuogya Road, KNUST, Kumasi, , Ghana, Principal Investigator