Plain English Summary
Background and study aims
Current WHO guidelines recommend that infants from birth up to 59 days of age with signs of possible serious bacterial infections (PSBI) should be managed in the hospital with injectable antibiotics and supportive care. When a referral to hospital is not feasible or refused by the family, those with extremely severe signs (no movement at all, unable to feed at all or having convulsions) are categorized as critically ill, and those with less severe signs are classified under clinical severe infection (CSI). CSI can be managed at home on an outpatient/outreach basis with antibiotics.
The study is designed to rigorously assess treatment failure in infants in a uniform, standardized way. The ultimate goal is to evaluate the relative safety of outpatient treatment by comparing rates of treatment failure in hospital vs home care arms in low-risk infants with PSBI.
Who can participate?
Study-1: All young infants aged under 2 months old who have ONLY one of the signs of PSBI.
Study-2: All patients admitted to the study hospitals with higher risk signs of PSBI or two or more signs of CSI.
What does the study involve?
Patients in both studies will be assigned to one of 2 treatment groups i.e. hospital treatment or home treatment. Both the groups will receive the same treatment and will be followed up for 15 days.
What are the possible benefits and risks of participating?
There are no additional benefits or risks. The treatment regimens prescribed for both hospital and home care infants are standard antibiotics that are part of existing WHO guidelines and whose safety has already been established.
Where is the study run from?
Community Empowerment Lab, Lucknow (India)
When is the study starting and how long is it expected to run for?
January 2020 to December 2022
Who is funding the study?
World Health Organization (Switzerland)
Who is the main contact?
Dr Vishwajeet Kumar (scientific), vkumar@celworld.org
Dr Yaswant Kumar Rao (public), ykraoneo@yahoo.co.in
Trial website
Contact information
Type
Scientific
Primary contact
Dr Vishwajeet Kumar
ORCID ID
http://orcid.org/0000-0003-1084-7152
Contact details
26/11
Wazir Hasan Road
Lucknow
226001
India
+91 9935689777
vkumar@celworld.org
Type
Public
Additional contact
Dr Yaswant Kumar Rao
ORCID ID
Contact details
Head of Department Pediatrics
GSVM Medical College
Kanpur
208002
India
+91 9919080807
ykraoneo@yahoo.co.in
Additional identifiers
EudraCT number
Nil known
ClinicalTrials.gov number
Nil known
Protocol/serial number
Site Protocol for Uttar Pradesh, India, Version 1.3, 3 June 2020 (Based on WHO Generic Protocol, Version 2.3 - 2 June 2020, Universal Trial Number (UTN): U1111-1251-1576, ERC0003289)
Study information
Scientific title
Optimizing place of treatment and antibiotic regimens for young infants presenting with signs of possible serious bacterial infection
Acronym
PSBI
Study hypothesis
Young infants (YIs) with only one low-mortality risk sign (high body temperature ≥38°C or severe chest indrawing or fast breathing of ≥60 breaths per minute in <7 days old infants) of critical severe infection (CSI) presenting to the outpatient/emergency department of a hospital, who receive outpatient treatment, will experience a better, or at least non-inferior, clinical outcome than YIs that receive inpatient treatment. Similarly, among hospital-admitted YIs with a high-mortality risk sign (movement only when stimulated or not feeding well/stopped feeding well or low body temperature (<35.5°C)) or two or more signs of CSI who clinically improve 48 h after initiation of treatment and have a negative C-reactive protein (CRP) laboratory test (Population), does discharge from hospital on oral amoxicillin at home for the next five days (Intervention), compared with continued hospital management for next five days (Control).
Ethics approval
1. Approved 12/06/2020, WHO ERC (20, Avenue Appia, 1211 Geneva 27, Switzerland; +41 22 7912111; nisary@who.int), ref: ERC.0003289
2. Approved 05/07/2020, CEL IEC (26/11, Wazir Hasan Road, Lucknow 226001 (UP) India; +91 (0)522-4932315; irb@cel.org.in), ref: CEL/RES/202007/001
3. Approved 21/07/2020, GSVM ethics committee (Room no. 125, 1st floor, GSVM medical College, Kanpur, India; +91-9454581649; ecgsvm@gmail.com), ref: EC104/July/2020
Study design
Open-label two-arm individually-randomized controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Home
Trial type
Treatment
Patient information sheet
See additional files
Condition
Critical severe infection (CSI) or critical illness of Possible Serious Bacterial Infection (PSBI) in sick young infants
Intervention
Young infants (YIs) <2 months old visiting outpatient clinics or emergency rooms of participating hospitals will be screened for one low-mortality risk sign of CSI (study-1) or one high-mortality risk sign/multiple low-mortality risk sign of CSI (Study-2).
For study-1, YIs will be consented and randomised through a sealed envelope for outpatient/home treatment (intervention group) or inpatient/hospital treatment (control group). The outpatient treatment with injectable gentamicin (once daily) for 2 days plus oral amoxicillin (twice daily) for 7 days. The inpatient antibiotic treatment for at least 7 days initiated with WHO recommended antibiotic regimen of injectable ampicillin (four time daily) plus injectable gentamicin (once daily) along with other supportive care. Outcome assessment will be carried by visiting all enrolled young infants on day 2, 4, 8 and 15 after enrolment. Outcome assessment will be conducted at the hospital or at home after discharge in the control arm and at home in the intervention arms. Outcomes will only be ascertained by the IOAs in accordance with the outcomes criteria
For study-2, YIs who were admitted at the study hospital with relatively higher-mortality risk signs of CSI at presentation/screening will be assessed for eligibility for this study 48 h after initiation of treatment and considered for inclusion in the study if: i) clinically well on day 3 defined as absence of all signs of critical illness or CSI, and ii) Laboratory test (CRP) negative. They will be randomised using sealed envelope and assigned to intervention or control treatment group. In the intervention group, they will be discharged from hospital and treated at home with oral antibiotics for 5 days. The control group will continue inpatient hospital injectable antibiotic treatment and supportive therapy for a total of 7 days. Outcome assessment will be carried out by visiting all enrolled young infants in the control arm at the hospital or at home after discharge and intervention arm enrolees at home on Day 8 and 15 of initiation of treatment.
In both the studies, all YIs will be followed up for 15 days after enrolment.
Drug dosages:
Gentamicin (strength 20 mg/ml) (Give once a day for 7 days)
Weight (kg) Dose (ml)
1.5 – 2.4 0.4
2.5 – 3.9 0.8
4.0 – 5.9 1.2
Ampicillin (strength 250 mg/1.5 ml) (Give 50 mg/kg body weight twice daily for 7 days)
Weight (kg) Dose (ml)
1.5 – 2.4 0.8
2.5 – 3.9 1.2
4.0 – 5.9 1.5
Gentamicin (I/M) (strength 20 mg/ml) (Give once a day for 2 days)
Weight (kg) Dose (ml)
1.5 – 2.4 0.4
2.5 – 3.9 0.8
4.0 – 5.9 1.2
Amoxicillin (250 mg per dose) (Give twice daily for 7 days)
Weight (kg) Dose (tablet)
1.5 – 2.4 0.5
2.5 – 3.9 0.5
4.0 – 5.9 1
Intervention type
Drug
Phase
Not Applicable
Drug names
Gentamicin, amoxicillin, ampicillin
Primary outcome measure
Measured using case report forms completed at follow up:
Study-1:
1. Death any time from randomization up to day 15 of initiation of therapy
2. Presence of any sign of critical illness (no movement at all, unable to feed at all, or convulsions) or any sign suggestive of another serious infection, e.g. meningitis, bone or joint infection, on day 2, 4 or day 8 of initiation of therapy
3. Presence of any new sign of CSI on day 4 or day 8 of initiation of therapy
4. Persistence of the presenting sign on day 8 of the initiation of therapy
Study-2:
1. Death between randomization (day 3 of initiation of therapy) and day 15 of initiation of therapy
2. Presence of any sign of critical illness (no movement at all, unable to feed at all, or convulsions) or any sign suggestive of another serious infection, e.g. meningitis, bone or joint infection, on day 8 of initiation of therapy
3. Presence of any sign of CSI on day 8 of initiation of therapy
Secondary outcome measures
There are no secondary outcome measures
Overall trial start date
01/01/2020
Overall trial end date
31/12/2022
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Study-1:
1. Aged <2 months
2. Living in a geographic area where follow-up for 14 days can be accomplished presenting to outpatient clinics or emergency rooms of participating hospitals
3. ONLY one of the following low-risk signs of PSBI:
3.1. Body temperature ≥38°C
3.2. Severe chest indrawing
3.3. Fast breathing (infants aged <7 days)
Study-2:
1. Aged <2 months
2. Admitted to the study hospitals with relatively higher-mortality risk signs of CSI at presentation (not feeding well, movement only on stimulation, low body temperature <35.5°C, two or more of the six signs of CSI)
3. Clinically well on day 3 defined as absence of all signs of critical illness (not feeding at all, no movement at all, convulsions) or CSI (not feeding well, movement only when stimulated, low body temperature (<35.5°C, high body temperature (≥38°C), severe chest indrawing, fast breathing in <7 days old)
4. Laboratory test negative
5. Family lives within a catchment area where a follow-up of up to day 15 can be accomplished
Participant type
Patient
Age group
Neonate
Gender
Both
Target number of participants
Study-1: 7,000 infants. Study-2: 5,250 infants
Participant exclusion criteria
Study-1:
1. Weight <2 kg at the time of presentation (if age at screening is less than 10 days) or weight for age <-3z
2. Appearance of low-mortality risk signs in first 24 h of life
3. Signs of critical illness (no movement at all, unable to feed at all, convulsions)
4. Signs of CSI associated with a high risk of mortality (stopped feeding well, movement only on stimulation, low body temperature < 35.5°C or two or more of the six signs of CSI)
5. Any sign suggestive of another serious illness/condition, such as major congenital malformations, severe jaundice, conditions requiring major surgery, meningitis, bone or joint infection, severe dehydration, etc.
6. Hospitalized for any illness in the previous 2 weeks
7. Prior use of injectable antibiotics for the same illness
8. Previously included in this study or currently included in any other study
Study-2:
1. Weight <2 kg at the time of presentation (if age at screening is less than 10 days) or weight-for-age <-3z
2. Signs of critical illness on admission (no movement at all, unable to feed at all, or convulsions)
3. Appearance of any high-mortality risk sign or multiple low-mortality risk signs in first 24 h of life
4. Hospitalized for any illness in the previous 2 weeks
5. Prior use of injectable antibiotics for the same illness
6. Previously included in this study or currently included in any other study
7. Any other reason to stay in hospital, as decided by the treating physician
Recruitment start date
01/01/2021
Recruitment end date
31/10/2022
Locations
Countries of recruitment
India
Trial participating centre
Community Empowerment Lab
26/11, Wazir Hasan Road
Uttar Pradesh
Lucknow
226001
India
Trial participating centre
Hallet District hospital
Uttar Pradesh
Kanpur
208002
India
Sponsor information
Organisation
World Health Organization
Sponsor details
Department of Maternal
Newborn
Child and Adolescent Health
World Health Organization
20 Avenue Appia
Geneva
27
Switzerland
+41 22 7912111
nisary@who.int
Sponsor type
Other
Website
Funders
Funder type
Research organisation
Funder name
World Health Organization
Alternative name(s)
WHO
Funding Body Type
private sector organisation
Funding Body Subtype
International organizations
Location
Switzerland
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer-reviewed journal.
IPD sharing statement:
All data generated or analysed during this study will be included in the subsequent results publication.
Intention to publish date
01/01/2023
Participant level data
Other
Basic results (scientific)
Publication list
Publication citations
Additional files
- ISRCTN11693277_PIS_Study1_V.1_06Apr20.pdf Uploaded 13/10/2020
- ISRCTN11693277_PIS_Infants_V.1_06Apr20.pdf Uploaded 13/10/2020
- ISRCTN11693277_PIS_Study2_V.1_06Apr20.pdf Uploaded 13/10/2020
- ISRCTN11693277_PROTOCOL_v1.3_3June2020.pdf Uploaded 13/10/2020