NeoSep1: a study to determine the ranking of existing and new antibiotics combinations to treat newborn babies who are in hospital with severe sepsis
| ISRCTN | ISRCTN48721236 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN48721236 |
| Secondary identifying numbers | v1.0 |
- Submission date
- 17/01/2022
- Registration date
- 24/02/2022
- Last edited
- 19/02/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
At present, babies who are admitted to hospital with sepsis are treated with medicines called “antibiotics”. In many countries, these antibiotics are those recommended by the World Health Organisation (WHO). Other countries use different antibiotics based on local policies but unfortunately, these are not always easily available. The use of different antibiotics also varies from baby to baby and between countries and hospitals.
More and more infections are being caused by bacteria that are “resistant” to commonly used antibiotics; this means these antibiotics will not kill the bacteria and therefore will not cure the infection. These bacteria are often called multidrug-resistant, as they are not killed by most antibiotics. We need to find new ways of treating these infections, and using combinations of existing antibiotics is one possibility. Fosfomycin, flomoxef, and amikacin are three antibiotics that could be combined into different two-drug regimens. Another option is to give stronger antibiotics at the start of treatment. The problem with doing this is that not all babies will need these stronger antibiotics, and the more we use them, the more resistance will develop to these antibiotics. So using them in lots of babies now, who don’t all need them, may mean that in the future we will not be able to use them in any babies who might need them.
The NeoSep1 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 sepsis. It will also test how well these new combinations work compared to other antibiotics or combinations of antibiotics that are currently used globally. We have worked out the right doses of fosfomycin, amikacin and flomoxef to use in an earlier part of this study by measuring levels of these drugs in babies’ blood.
Who can participate?
Over 3,000 babies aged 28 days old or younger who are in hospital with severe sepsis will be included in Part 1 and 2 of the NeoSep1 study. Participants will be recruited from all over the world, and in particular from low and middle-income countries such as South Africa, Kenya, and other countries in Africa and South East Asia.
What does the study involve?
The study will be divided into 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, 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 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 from dying.
Babies will generally get these antibiotics for about 7-10 days (their “first‑line” treatment). If a baby’s condition gets worse during this time, or doesn’t get better as would be expected, doctors will be able to give them different antibiotics (also known as “second-line” treatment) to see if they do better with different antibiotics. Which specific second-line antibiotics each baby gets will also be chosen at random from a set of combinations that doctors would use after each first-line treatment. Babies will get different second-line antibiotic treatments to those they already had as first-line. Babies will be followed up for 90 days, with a visit or telephone call 28 and 90 days after the baby entered the study to see if the baby is still doing well.
What are the possible benefits and risks of participating?
Participating in this study may not directly benefit the babies taking part, but the information we get from the study will help us work out the best available treatment combinations to treat babies with sepsis in the future. While in hospital, babies taking part in the study will be reviewed daily by the study clinicians and nurses, together with the regular hospital staff.
Where is the study run from?
Global Antibiotic Research & Development Partnership (Switzerland)
When is the study starting and how long is it expected to run for?
From August 2022 to December 2028
Who is funding the study?
Global Antibiotic Research & Development Partnership (Switzerland)
Who is the main contact?
Sally Ellis
sellis@gardp.org
Contact information
Public
Global Antibiotic Research and Development Partnership (GARDP)
15 Chemin Camille-Vidart
Geneva
1202
Switzerland
| Phone | +41 22 555 1912 |
|---|---|
| mrcctu.neosep@ucl.ac.uk |
Principal Investigator
St George’s, University of London (SGUL)
Paediatric Infectious Diseases Research Group
Institute for Infection and Immunity
2nd Floor, Jenner Wing
Cramner Terrace
London
SW17 0RE
United Kingdom
 ORCID ID |
0000-0001-8626-8291 |
|---|---|
| Phone | +44 (0)208 725 5382 |
| msharland@sgul.ac.uk |
Study information
| Study design | Phase III/IV/pragmatic public health multicentre Personalized Randomized Controlled Trial (PRACTical) incorporating a Sequential Multiple Assignment Randomised Trial (SMART) design |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | An open-label randomised controlled trial comparing novel combination and existing antibiotic regimens for the empiric treatment of neonatal sepsis with a run-in confirmatory pharmacokinetic phase (NeoSep1) |
| Study acronym | NeoSep1 |
| Study hypothesis | Part 1: Recommended doses of fosfomycin and floxomef, in combinations to be studied in Part 2, will provide adequate drug levels in neonates with sepsis. Part 2: Mortality in hospitalised neonates with sepsis can be reduced by choosing a top-ranked antibiotic regimen compared with the WHO recommended empiric antibiotic regimens for neonatal sepsis and other currently used regimens. |
| Ethics approval(s) | 1. Approved 31/08/2022, Stellenbosch University Health Research Ethics Committee (Stellenbosch University, Private Bag X1, Matieland, 7602, Stellenbosch, South Africa; +27 021 938 9075; blanchep@sun.ac.za), ref: M22/05/007 2. Approved 15/08/2022, University of the Witwatersrand Human Research Ethics Committee (Medical) (Suite 189, Private Bag x2600, Houghton 2041, South Africa; +27 11 274 9200; HREC-Medical.ResearchOffice@wits.ac.za), ref: 220509B 3. Approved 27/07/2022, Research Ethics Committee of Kenya Medical Research Institute (Scientific and Ethics Review Unit, P.O Box 54840 00200 off Mbagathi Road, Nairobi, Kenya; +254 0717 719 477; seru@kemri.org), ref: KEMRI/RES/7/3/1 4. Approved 02/08/2022, South African Health Products Regulatory Authority (SAHPRA) (Building A, Loftus Park, 2nd Floor, Kirkness Rd, Arcadia 0083, South Africa; +27 012 501 0413; enquiries@sahpra.org.za), ref: 20220614 5. Approved 21/12/2022, Pharmacy and Poisons Board (PPB) (Lenana Road, P.O. Box 27663-00506, Nairobi, Kenya; +254 709 770 100; info@pharmacyboardkenya.org), ref: PPB/ECCT/22/08/03/2022(335) |
| Condition | Neonatal sepsis |
| Intervention | 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): The main empiric treatment trial (Part 2) will use a novel tailored randomised controlled trial (PRACTical) design, in which each neonate is randomised to pre-defined first-line regimens that are considered clinically acceptable for that specific site and neonatal sub-population. The design will also incorporate a Sequential Multiple Assignment Randomised Trial (SMART) design to allow randomisation to second-line treatment where indicated. For the second randomisation, personalised randomisation lists will be determined by the neonate’s first randomised regimen and what is clinically appropriate for that specific site. Dosing: Dosing will depend on the treatment regimen given at enrolment (part 1) or randomisation (part 2). The following provides a summary on the proposed dosing 1. Amikacin: 15 mg/kg total daily dose for sepsis; 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; 3 divided doses per day 6. Ceftriaxone: 80-100 mg/kg total daily dose for sepsis; 80-100 mg/kg total daily dose for suspected/confirmed meningitis; 1-2 divided doses per day 7. Cloxacillin: 100-150 mg/kg total daily dose for sepsis; 100-150 mg/kg total daily dose for suspected/confirmed meningitis; 2-3 divided doses per day 8. Flomoxef: 120-150 mg/kg total daily dose for sepsis; 120-150 mg/kg total daily dose for suspected/confirmed meningitis; 2-3 divided doses per day 9. Fosfomycin: 200-300 mg/kg total daily dose for sepsis; 200-300 mg/kg total daily dose for suspected/confirmed meningitis; 2 divided doses per day 10. Gentamicin: 5-7 mg/kg total daily dose for sepsis; 5-7 mg/kg total daily dose for suspected/confirmed meningitis; 1 divided doses per day 11. Meropenem: 60 mg/kg total daily dose for sepsis; 80-120 mg/kg total daily dose for suspected/confirmed meningitis; 3 divided doses per day 12. Piperacillin/tazobactam: 240-300 mg/kg (piperacillin) total daily dose for sepsis total daily dose for suspected/confirmed meningitis; 3-4 divided doses per day Treatment: Part 1: Planned duration of treatment at enrolment for culture-negative is to Day 7±2 days, for culture-positive is to Day 10 [-3,+4 days] if there is no switch. If antibiotics are switched, the total planned duration of antibiotic treatment including first and second-line treatment is 14 ±7 days depending on the baby’s condition. Part 2: Planned duration of treatment at enrolment for culture-negative is Day 7±2 days, for culture-positive is Day 10 [-3,+4] days if there is no switch. If antibiotics are switched the total duration of antibiotic treatment including first and second-line treatment is 14 ±7 days depending on the baby's condition. Assessments: Assessments (Part 1): PK assessment on Day 1 and Day 5; Clinical assessment on Day 1, Day 5, Day 7, Day 14, and Day 28 Assessments (Part 2): Clinical assessments on Day 3, Day 7, Day 14, Day 28, and Day 90 |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III/IV |
| Drug / device / biological / vaccine name(s) | Ampicillin* and gentamicin, cefotaxime or ceftriaxone, fosfomycin and amikacin, fosfomycin and flomoxef, flomoxef and amikacin, ceftazidime and amikacin, piperacillin/tazobactam and amikacin, meropenem *or benzylpenicillin or cloxacillin or flucloxacillin or amoxicillin |
| Primary outcome measure | 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 outcome measures | 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–∞)) 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) relevant adapted Division of AIDS (DAIDS) and International Neonatal Consortium Neonatal Adverse Event Severity Scale (NAESS) through Day 28 2.2. Adverse events of any grade related to antibiotics through Day 28 2.3. Modification (including discontinuation) of antibiotics for adverse reactions through Day 28 2.4. Neurodevelopment as assessed by the WHO Global Scale for Early Development (GSED) package at Day 28 and Day 90 Note: Serious Adverse Events will be collected for pharmacovigilance and analysed descriptively but they are not trial outcome measures because the severity of illness of the population means that they will likely commonly be related to the underlying condition. _____ Previous secondary outcome measures: 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–∞)) 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 measured using the following: 1.1. Clinical status measured using a clinical recovery score based on data from the NeoOBS observational study (NeoSep Recovery Score) at 3, 7, 14, and 28 days after randomisation 1.2. Clinically appropriate need for additional antibiotics beyond the first randomised treatment measured from patient records between the first randomised treatment and the end of the study 1.3. Clinically appropriate need for additional antibiotics beyond the first randomised and second (for failure) treatment measured from patient records between the second randomised treatment and the end of the study 1.4. Cure, defined as clinical improvement and no need for further antibiotic treatment for the original sepsis episode, measured using clinical assessment at the test of cure (TOC) visit (Day 14 ±3 days after randomisation) 1.5. Length of stay during the index hospitalisation measured from patient records between hospital admission and discharge 1.6. Systemic antibiotic exposure (days on antibiotics) during the index hospitalisation measured from patient records between hospital admission and discharge 1.7. 90-day mortality measured from patient records at 90 days 1.8. Change in C-reactive protein at baseline, 3, and 7 days (selected sites based on availability) 2. Safety measured using the following: 2.1. 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 2.2. Incidence of AEs of any grade related to antibiotics measured from patient records throughout the study 2.3. Modification of antibiotics for adverse reactions measured from patient records throughout the study |
| Overall study start date | 29/04/2021 |
| Overall study end date | 31/12/2028 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Neonate |
| Upper age limit | 28 Days |
| Sex | Both |
| Target number of participants | 3,060 |
| Participant 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 (<35.5°C Or ≥38°C) b. Chest indrawing or increase in oxygen requirement or increase of respiratory support c. Abdominal distension d. Difficulty in feeding or feeding intolerance e. Evidence of shock including cold peripheries f. Lethargy, or reduced or no spontaneous movement g. Cyanosis h. Abnormal heart rate (bradycardia <80 bpm; tachycardia >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. |
| Participant 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 |
| Recruitment start date | 07/03/2023 |
| Recruitment end date | 03/06/2027 |
Locations
Countries of recruitment
- Bangladesh
- Ghana
- India
- Kenya
- Pakistan
- South Africa
- Uganda
- Viet Nam
Study participating centres
Francie Van Zijl Avenue
Parow
Western Cape
Cape Town
7505
South Africa
Diepkloof
319-Iq
Johannesburg
1860
South Africa
Kilifi
-
Kenya
-
Ghana
-
Kenya
-
Kenya
-
Uganda
-
Uganda
-
Bangladesh
Bangladesh
-
India
-
India
-
India
-
Malaysia
-
Pakistan
-
Viet Nam
Sponsor information
Charity
15 Chemin Camille-Vidart (formerly Chemin Louis-Dunant)
Geneva
1202
Switzerland
| Phone | +41 22 555 19 90 |
|---|---|
| contact@gardp.org | |
| Website | https://gardp.org/ |
"ROR" |
https://ror.org/0284j4180 |
Funders
Funder type
Charity
No information available
Results and Publications
| Intention to publish date | 31/12/2029 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | A clinical trial report will be prepared by the Sponsor with input from investigators as appropriate. One copy of the final trial report must be dated and signed by the Sponsor’s medical monitor, principal investigators, trial statistician and the clinical trial manager before being transmitted to the regulatory authorities and local ethics committees if required. A publication policy will be drafted reflecting the following principles: 1. All parties including GARDP, MRC CTU, SGUL, Penta, and participating sites will contribute to the preparation of publication 2. Upon trial completion and finalisation of the trial report, the results of the trial will be submitted for publication to a peer-reviewed journal and posted in a publicly accessible database of clinical trial results 3. Authorship of any publication will be based on the uniform requirements for manuscripts submitted to biomedical journals as defined by the International Committee of Medical Journal Editors (ICMJE) 4. The PK and safety data from Part 1 will be published separately from Part 2, both in a peer-reviewed journal. |
| IPD sharing plan | The contact details for data release requests are Sally Ellis, Childrens Antibiotics Project Leader (+41 22 9077612, sellis@gardp.org). The data sharing policy will be summarised in the study protocol. We intend to make the protocol available via the registry in due course, providing clarification on the details of individual participant data (IPD) sharing. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 1.0 | 04/04/2022 | 12/04/2023 | No | No |
| Statistical Analysis Plan | Part 1 version 1.0 |
08/06/2023 | 29/05/2024 | No | No |
| Poster results | Part 1 results | 30/04/2024 | 10/06/2024 | No | No |
| Other files | Protocol Appendix 1 version 1.0 |
20/06/2024 | 19/02/2025 | No | No |
| Other files | Protocol Appendix 2 version 1.0 |
20/06/2024 | 19/02/2025 | No | No |
| Other files | Protocol Appendix 3 version 1.0 |
20/06/2024 | 19/02/2025 | No | No |
| Protocol file | version 3.0 | 03/10/2024 | 19/02/2025 | No | No |
| Statistical Analysis Plan | Part 2 version 1.0 |
30/01/2025 | 19/02/2025 | No | No |
Additional files
- ISRCTN48721236_Protocol_v1.0_04April2022.pdf
- ISRCTN48721236 NeoSep1_PART_1_Statistical Analysis Plan_v1.0 08Jun2023.pdf
- Part 1
- ISRCTN48721236 NeoSEP Part1 results ESPID poster_30Apr24.pdf
- Part 1 results
- ISRCTN48721236 NeoSep1_PART_2_Statistical Analysis Plan_v1.0_2025_01_30_signed.pdf
- Part 2
- ISRCTN48721236 NeoSep1_protocol_v3.0_2024_10_03_signed.pdf
- ISRCTN48721236 NeoSep1_Appendix_1_Master_Country_Specific_Appendix_1.0_2024_06_20.pdf
- Protocol Appendix 1
- ISRCTN48721236 NeoSep1_Appendix_2_Adverse Event Report_Adapted DAIDS_NAESS_v1.0_2024_06_20.pdf
- Protocol Appendix 2
- ISRCTN48721236 NeoSep1_Appendix_3_SAEs_exempted_from_expedited_reporting_v1.0_2024_06_20.pdf
- Protocol Appendix 3
Editorial Notes
19/02/2025: The following changes were made to the trial record:
1. The statistical analysis plan (part 2) was uploaded as an additional file.
2. The study design was changed from "Phase II/III multicentre personalized randomized controlled trial (PRACTical) incorporating a Sequential Multiple Assignment Randomised Trial (SMART) design" to "Phase III/IV/pragmatic public health multicentre Personalized Randomized Controlled Trial (PRACTical) incorporating a Sequential Multiple Assignment Randomised Trial (SMART) design".
3. The phase was changed from II/III to III/IV.
4. The drug name was changed from "Ampicillin and gentamicin, cefotaxime or ceftriaxone, fosfomycin and amikacin, flomoxef and amikacin , ceftazidime, piperacillin/tazobactam, piperacillin/tazobactam and amikacin, meropenem" to "Ampicillin* and gentamicin, cefotaxime or ceftriaxone, fosfomycin and amikacin, fosfomycin and flomoxef, flomoxef and amikacin, ceftazidime and amikacin, piperacillin/tazobactam and amikacin, meropenem *or benzylpenicillin or cloxacillin or flucloxacillin or amoxicillin".
5. The secondary outcome measures were changed.
6. The inclusion criteria were changed.
7. The exclusion criteria were changed.
8. The Countries of recruitment Brazil, Congo, Democratic Republic, Switzerland were removed and Bangladesh, Ghana, Malaysia, Viet Nam were added.
9. The study participating centres Kumasi Centre for Collaborative Research in Tropical Medicine, Mbagathi Hospital, Coast General Teaching and Referral Hospital, Kawempe National Referral Hospital, Mulago Specialised Women and Neonatal Hospital, Child Health Research Foundation, Sir Salimullah Medical College Hospital, Lokmanya Tilak Municipal College and General Hospital, Pt B D Sharma PGIMS, The Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Tunku Azizah Kuala Lumpur Hospital, The Aga Khan University Hospital (AKUH), Vietnam National Children's Hospital were added.
10. The plain English summary was updated to reflect these changes.
11. Uploaded protocol v3.0 (not peer-reviewed) as an additional file.
12. Protocol appendices x3 were uploaded an additional files.
10/06/2024: Part1_Final_Statistical_Report replaced with poster.
30/05/2024: The following changes were made to the study record:
1. The overall study end date was changed from 31/12/2027 to 31/12/2028.
2. The intention to publish date was changed from 30/06/2028 to 31/12/2029.
29/05/2024: The following changes were made to the trial record:
1. The statistical analysis plan was uploaded as an additional file.
2. The Part1_Final_Statistical_Report was uploaded as an additional file.
3. The overall end date was changed from 30/10/2026 to 31/12/2027.
4. The recruitment end date was changed from 01/08/2026 to 03/06/2027.
5. The plain English summary was updated to reflect these changes.
12/04/2023: Protocol uploaded (non peer reviewed).
11/04/2023: Ethics approval updated.
04/04/2023: The following changes have been made:
1. Ethics approval updated.
2. Participant information sheet updated.
28/03/2023: The following changes have been made:
1. Ethics approval updated.
2. Phase has been changed from phase III to phase II/III.
3. Study design has been changed from "Phase III, multicentre, personalized randomized controlled trial (PRACTical) incorporating a Sequential Multiple Assignment Randomised Trial (SMART) design" to "Phase II/III, multicentre, personalized randomized controlled trial (PRACTical) incorporating a Sequential Multiple Assignment Randomised Trial (SMART) design".
4. The recruitment start date has been changed from 01/08/2022 to 07/03/2023.
11/02/2022: Trial’s existence confirmed by Global Antibiotic Research & Development Partnership.
