Neonatal SEPSISPhase 2NeoFosfoNCT03453177
Intravenous and Oral Fosfomycin in Hospitalised Neonates With Clinical Sepsis
A Phase 2 study testing PK and Analysis of Bacterial Isolates in people with Neonatal SEPSIS, run by Drugs for Neglected Diseases at 1 site in Kenya.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 28 days
- Conditions the study is for
- Neonatal SEPSIS
- What is being tested?
- PK and Analysis of Bacterial Isolates
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- 1 siteKenya
- Study dates
- 15 Mar 2018to 24 May 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 28 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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
Show all 13Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Intravenous and Oral Fosfomycin in Hospitalised Neonates With Clinical Sepsis: an Open-label Safety and Pharmacokinetics Study (neoFosfo)
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.
Read the detailed description
Antimicrobial resistance (AMR) has become a major issue in global health. Despite progress in the reduction of under 5 mortality rates in recent decades, the proportion of neonatal deaths occurring within this age group has increased, with almost one quarter of all neonatal deaths occurring due to serious bacterial infection. Common bacteria causing neonatal sepsis are now exhibiting widespread resistance to several classes of antibiotics. There is an urgent need to discover new, effective treatments and re-evaluate existing therapeutic agents to treat infections potentially caused by multi-drug resistant (MDR) pathogens. Gram-negative bacteria (GNB) predominate as the cause of neonatal sepsis, and are increasingly associated with high rates of resistance to the currently recommended WHO empirical therapy regimen of ampicillin/penicillin and gentamicin. There is therefore a need to develop an updated empiric regimen with improved efficacy in the context of increasing MDR sepsis in neonates. New antimicrobials under development will be expensive once licensed, and there are currently virtually no planned trials to assess their efficacy in neonates in low- and middle-income countries (LMICs).
One potential strategy is utilising an existing off-patent (and therefore affordable) antibiotic available in intravenous and oral formulations - fosfomycin. Fosfomycin has a wide spectrum of activity against Gram-positive and Gram-negative bacteria causing neonatal sepsis. It is mainly used for resistant urinary tract infections in adults, but has licenced neonatal and paediatric doses in Europe (though dosing regimens vary between countries). Both oral and IV formulations are available. A large clinical trial to assess the efficacy of a fosfomycin plus an aminoglycoside combination (compared to the current WHO recommended ampicillin and gentamicin) is anticipated, including sites in Kenya. The ultimate aim is for fosfomycin to be included in the WHO Essential Medicines List for children (EMLc) and be available for use in developing countries, where rates of resistance to ampicillin and gentamicin have been estimated at over 40%. The first steps before this trial are to clarify the pharmacokinetics (PK) and safety profile of fosfomycin in neonates, as well as generating further information regarding local patterns of bacterial susceptibility to fosfomycin. The aim of this study is to fulfil both these steps. Fosfomycin (IV and oral) PK will be investigated among 60 babies admitted to hospital and being treated for presumed sepsis; administered alongside the standard antibiotics. Another 60 babies receiving standard treatment only (without PK sampling) will be monitored in the same way to compare adverse events. In the laboratory at CGMR-C, previously archived bacterial isolates will be tested for their sensitivity to fosfomycin.
- Conditions
- Neonatal SEPSIS
- Being tested
- Standard of Care + Fosfomycin, PK, Analysis of Bacterial Isolates
- Medical subject headings
- Neonatal Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Standard of Care + FosfomycinDrug
Also called iv Fosfomycin, oral Fosfomycin
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).
PKProcedure or surgery
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.
Analysis of Bacterial IsolatesProcedure or surgery
For assessment of susceptibility patterns in bowel flora, we will systematically assess all admission and discharge nappy swabs.
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: Drug: Standard of Care + Fosfomycin; Procedure: PK; Procedure: Analysis of Bacterial Isolates |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetic disposition and absorption parameters of IV and oral fosfomycin in neonates with clinical sepsis
Fosfomycin Clearance (CL)
Measured: 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
Measured: 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)
Measured: 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
Biochemistry will be checked at 48 hours for participants in both groups
Measured: 48 hours
Difference between the groups in mean 7-day plasma sodium concentrations
Biochemistry will be checked at 7 days for participants in both groups
Measured: 7 days
Difference between groups in the rate of adverse events (any grade) to 28 days after enrolment in the study
Neonates will be reviewed every day by study clinicians, working together with the hospital team. All adverse events will be documented and reported in both arms.
Measured: from patient randomization to visit D28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Mar 2018
- Study start15 Mar 2018
- Primary completion14 Mar 2019
- Study completion24 May 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Neonatal SEPSISStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 120 participants (actual)
Sponsor and investigators
- Lead sponsor
- Drugs for Neglected Diseases
- Sponsor type
- University, hospital or other
- Collaborators
- KEMRI-Wellcome Trust Collaborative Research Program, University of Oxford
- Responsible party
- Sponsor
- Investigators
- James A Berkley, Prof, Principal investigator, KEMRI/Wellcome Trust Research Programme and University of Oxford - UK
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03453177
- Sponsor's protocol ID
- Neo-Fos-001
- Acronym
- NeoFosfo
- Status last verified
- Feb 2020
- First submitted
- 7 Feb 2018
- Last updated
- 17 Feb 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 35107141Obiero 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.
PubMed 35078765Kane 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.
PubMed 33855449
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Intravenous and Oral Fosfomycin in Hospitalised Neonates With Clinical Sepsis: an Open-label Safety and Pharmacokinetics Study (neoFosfo)
- ClinicalTrials.gov ID
- NCT03453177
- Acronym / sponsor ID
- NeoFosfo / Neo-Fos-001
- Conditions
- Neonatal SEPSIS
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 120 participants (actual)
- Lead sponsor
- Drugs for Neglected DiseasesUniversity, hospital or other
- Collaborators
- KEMRI-Wellcome Trust Collaborative Research Program, University of Oxford
- Study start
- 15 Mar 2018 (actual)
- Primary completion
- 14 Mar 2019 (actual)
- Study completion
- 24 May 2019 (actual)
- First posted
- 5 Mar 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Antimicrobial resistance (AMR) has become a major issue in global health. Despite progress in the reduction of under 5 mortality rates in recent decades, the proportion of neonatal deaths occurring within this age group has increased, with almost one quarter of all neonatal deaths occurring due to serious bacterial infection. Common bacteria causing neonatal sepsis are now exhibiting widespread resistance to several classes of antibiotics. There is an urgent need to discover new, effective treatments and re-evaluate existing therapeutic agents to treat infections potentially caused by multi-drug resistant (MDR) pathogens. Gram-negative bacteria (GNB) predominate as the cause of neonatal sepsis, and are increasingly associated with high rates of resistance to the currently recommended WHO empirical therapy regimen of ampicillin/penicillin and gentamicin. There is therefore a need to develop an updated empiric regimen with improved efficacy in the context of increasing MDR sepsis in neonates. New antimicrobials under development will be expensive once licensed, and there are currently virtually no planned trials to assess their efficacy in neonates in low- and middle-income countries (LMICs).
One potential strategy is utilising an existing off-patent (and therefore affordable) antibiotic available in intravenous and oral formulations - fosfomycin. Fosfomycin has a wide spectrum of activity against Gram-positive and Gram-negative bacteria causing neonatal sepsis. It is mainly used for resistant urinary tract infections in adults, but has licenced neonatal and paediatric doses in Europe (though dosing regimens vary between countries). Both oral and IV formulations are available. A large clinical trial to assess the efficacy of a fosfomycin plus an aminoglycoside combination (compared to the current WHO recommended ampicillin and gentamicin) is anticipated, including sites in Kenya. The ultimate aim is for fosfomycin to be included in the WHO Essential Medicines List for children (EMLc) and be available for use in developing countries, where rates of resistance to ampicillin and gentamicin have been estimated at over 40%. The first steps before this trial are to clarify the pharmacokinetics (PK) and safety profile of fosfomycin in neonates, as well as generating further information regarding local patterns of bacterial susceptibility to fosfomycin. The aim of this study is to fulfil both these steps. Fosfomycin (IV and oral) PK will be investigated among 60 babies admitted to hospital and being treated for presumed sepsis; administered alongside the standard antibiotics. Another 60 babies receiving standard treatment only (without PK sampling) will be monitored in the same way to compare adverse events. In the laboratory at CGMR-C, previously archived bacterial isolates will be tested for their sensitivity to fosfomycin.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 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 | Drug: Standard of Care + Fosfomycin, Procedure: PK, Procedure: Analysis of Bacterial IsolatesFosfomycin 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). |
Who may qualify
- Ages
- Up to 28 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Standard of Care + FosfomycinAlso: iv Fosfomycin, oral FosfomycinFosfomycin 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 plus Fosfomycin |
| PKTwo 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. | Procedure or surgery | Standard of Care plus Fosfomycin |
| Analysis of Bacterial IsolatesFor assessment of susceptibility patterns in bowel flora, we will systematically assess all admission and discharge nappy swabs. | Procedure or surgery | Standard of Care plus Fosfomycin |
Primary outcome
Pharmacokinetic disposition and absorption parameters of IV and oral fosfomycin in neonates with clinical sepsis
Time frame: Participants will be followed for the duration of enrolment, an expected average of 7 days
Fosfomycin Clearance (CL)
Pharmacokinetic disposition and absorption parameters of IV and oral
Time frame: Participants will be followed for the duration of enrolment, an expected average of 7 days
Fosfomycin Volume of Distribution
Pharmacokinetic disposition and absorption parameters of IV and oral
Time frame: Participants will be followed for the duration of enrolment, an expected average of 7 days
Fosfomycin Oral Bioavailability (F)
3 secondary outcomes
Difference between the groups in mean 48-hour plasma sodium concentrations
Time frame: 48 hours
Difference between the groups in mean 7-day plasma sodium concentrations
Time frame: 7 days
Difference between groups in the rate of adverse events (any grade) to 28 days after enrolment in the study
Time frame: from patient randomization to visit D28
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2020.
- Derived from this study: PubMed 35107141Gastine 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.
- Derived from this study: PubMed 35078765Obiero 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.
- Derived from this study: PubMed 33855449Kane 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James A Berkley, Prof principal investigator
KEMRI/Wellcome Trust Research Programme and University of Oxford - UK
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing PK and Analysis of Bacterial Isolates in people with Neonatal SEPSIS, run by Drugs for Neglected Diseases at 1 site in Kenya.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Kenya. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacokinetic disposition and absorption parameters of IV and oral fosfomycin in neonates with clinical sepsis (time frame: Participants will be followed for the duration of enrolment, an expected average of 7 days). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03453177, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2020.