Effectiveness of C-reactive protein testing for optimising antibiotic treatment in neonates and children in Zanzibar

ISRCTN	ISRCTN25937092
DOI	https://doi.org/10.1186/ISRCTN25937092
ClinicalTrials.gov (NCT)	Nil Known
Clinical Trials Information System (CTIS)	Nil Known
Protocol serial number	Zan_CRP-POCT 001
Sponsor	International Centre for Antimicrobial Resistance Solutions (ICARS)
Funder	International Centre for Antimicrobial Resistance Solutions (ICARS)

Submission date: 15/01/2024
Registration date: 22/01/2024
Last edited: 13/05/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
The global increase in bacterial resistance to antibiotics is particularly impacting children due to the overuse and misuse of these medications. Insufficient diagnostic tools for timely identification of bacterial infections in children contribute to the problem by leading to the unnecessary prescription of antibiotics. C-reactive protein (CRP), a biomarker produced in response to inflammation, once measured, can aid clinicians in assessing the presence and severity of conditions like bacterial infections. Traditionally, diagnosing sepsis in this population involves time-consuming laboratory tests. The introduction of CRP Point-of-Care Testing (POCT) offers a potential solution for a quick and cost-effective diagnosis that can guide immediate treatment decisions. This trial aims to explore the effectiveness of CRP POCT in optimizing antibiotic treatment for neonates and children with suspected sepsis. By assessing CRP levels at the point of care, the trial aims to enhance diagnostic accuracy, tailor treatment strategies, and potentially improve children’s outcomes. The trial intends to recruit participants in Zanzibar and assess the impact of CRP POCT on diagnostic practices, contributing to the global understanding of antibiotic use practices in the pediatric population. Ultimately, the findings of this trial have the potential to improve healthcare practices, particularly in resource-limited settings like Tanzania, and optimize antibiotic usage in neonatal and pediatric care.

Who can participate?
Neonates at risk of/with early onset sepsis admitted neonates (0-28 days) with suspected sepsis and admitted children (6 months to 12 years) with febrile illness or diarrhea in selected hospitals in Zanzibar

What does the study involve:
Neonates between 0 and 28 days with the risk of early-onset sepsis according to the WHO criteria or admitted with suspected sepsis and children between 6 months and 12 years admitted with either febrile illness or/and diarrheal disease will be screened for eligibility at the participating hospitals by a research assistant (RA) before routine examination by a clinician. Parents/caregivers of eligible children will be requested for informed consent to participation, after having received oral and written information regarding the trial followed by subsequent randomization. Participants will be randomized to the intervention group (CRP POCT) or control group (usual care) by a responsible RA through the Sealed EnvelopTM programme. Case report forms (CRFs) will be filled out by RA for all participants at the first consultation. Participants assigned to the intervention group will have a CRP POCT during the consultation with their clinician where whereas children in the control group will not have the CRP POCT test taken. Participants will be randomized by a responsible RA through the Sealed Envelop™ programme. All participants will be contacted on the 7th and 28th day after randomization, by telephone calls from the RA who is blinded to the group allocation. If not reached by telephone the assistant will visit the child at the home address. Both interventional and control groups will receive standard care based on the Zanzibar/Hospital treatment guidelines.

What are the possible benefits and risks of participating?
Participants will benefit from a more accurate diagnosis of bacterial infection improved accuracy in diagnosing sepsis, better treatment decisions based on diagnostic information, and contributing to medical knowledge for potential future improvements in patient care. Potential risks include discomfort during blood sample collection and any inconvenience from additional testing (if it may be required).

Where is the study run from?
The Zan_CRP-POCT trial is being run by Zanzibar Health Research Institute and takes place at Mnazi Mmoja Hospital in Unguja and Chake Chake Hospital, Vitongoji Hospital and Adbullah Mzee (Mkoani) Hospital in Pemba.

When is the study starting and how long is it expected to run for:
February 2024 to May 2025

Who is funding the study?
International Centre for Antimicrobial Resistance Solutions (ICARS)

Who is the main contact:
Daniel Joshua, daniel.msesa@zahri.go.tz

Contact information

Prof Jeremiah Seni
Scientific

Weill-Bugando School of Medicine
Catholic University of Health and Allied Sciences (CUHAS)
Mwanza
33830
Tanzania

ORCID ID	0000-0003-2420-5329
Phone	+255784593000
Email	senijj80@bugando.ac.tz

Prof Stine Lund
Scientific

Global Health Unit
Rigshospitalet
Copenhagen
2200
Denmark

Phone	+4522440789
Email	stine.lund@regionh.dk

Prof Anja Poulsen
Scientific

Global Health Unit
Copenhagen
2200
Denmark

ORCID ID	0000-0002-9656-1552
Phone	+4535459871
Email	anja.poulsen.01@regionh.dk

Dr Mayassa Ally
Principal investigator

Zanzibar Health Research Institute
Zanzibar
71101
Tanzania

Phone	+255773319098
Email	mayassa.ally@zahri.go.tz

Mr Daniel Joshua
Scientific

Kilimani
Unguja
Zanzibar
71101
Tanzania

ORCID ID	0000-0002-1720-0506
Phone	+255714013008
Email	daniel.msesa@zahri.go.tz

Mr Daniel Joshua
Public

Kilimani
Unguja
Zanzibar
71101
Tanzania

ORCID ID	0000-0002-1720-0506
Phone	+255714013008
Email	daniel.msesa@zahri.go.tz

Mr Muhiddin Omar
Scientific

Mijini Magharibi
Unguja
Zanzibar
71101
Tanzania

Phone	+255777491223
Email	muhiddin.omar@yahoo.com

Prof Jeremia Seni
Public

Weill-Bugando School of Medicine
Catholic University of Health and Allied Sciences (CUHAS)
Mwanza
33830
Tanzania

Phone	+255784593000
Email	senijj80@gmail.com

Dr Mayassa Ally
Public

Zanzibar Health Research Institute
Zanzibar
71101
Tanzania

Phone	+255773319098
Email	doctormayassa@gmail.com

Dr Hanna Rahimi
Public

Global Health Unit, Rigshospitalet
Copenhagen
2200
Denmark

Phone	+45897956
Email	hanna.rahimi@regionh.dk

Study information

Primary study design	Interventional
Study design	Multicenter open-label individually randomized controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Effectiveness of the C-reactive protein point-of-care testing in optimizing antibiotic treatment in neonates and children: an open-label, individual randomized controlled trial
Study acronym	Zan_CRP-POCT
Study objectives	The hypothesis is that using CRP POCT to support the clinical decision-making on the antibiotic treatment of neonatal and pediatric patients in selected hospitals in Zanzibar will safely help to 1) reduce the use of prophylactic antibiotics in neonates with WHO risk factor of early-onset sepsis and 2) ensure adequate and appropriate antibiotic treatment for neonates with sepsis. Furthermore, for children 6 months to 12 years, the hypothesis is that 3) the use of CRP POCT will help to identify the majority of children who suffer from non-bacterial infections and assist in withholding or discontinuing antibiotic treatment when no benefit can be expected thus lowering unnecessary use of antibiotics or shortening the duration of use.
Ethics approval(s)	Approved 28/12/2023, Zanzibar Health Research Ethics Committee (ZAHREC) (Zanzibar Health Research Institute (ZAHRI), P.O. Box 236, Zanzibar, 72208, Tanzania; +255(0) 776 264 880; zahrec@zahri.go.tz), ref: ZAHREC/04/AMEND/DEC/2023/11
Health condition(s) or problem(s) studied	Neonates at risk of early onset sepsis, admitted neonates (0-28 days) with clinical signs of sepsis and admitted children (6 months to 12 years) with febrile illness or diarrhea
Intervention	In the proposed trial, CRP POCT equipment is scheduled to be supplied to the selected hospitals, accompanied by training sessions on its use and interpretation to support the clinical evaluation of neonates and children. The protocol outlines the procedures for CRP POCT measurement for neonates with risk factors for early onset sepsis, where levels below 30mg/L indicate no need for antibiotic treatment, 30-50mg/L warrant caution and clinical assessment, and levels above 50mg/L indicate the necessity for antibiotic treatment. For neonates admitted with suspected sepsis in the CRP group, regardless of CRP levels, antibiotic treatment will be initiated, and CRP reassessed after 18-24 hours. In the case of children aged 6 months to 12 years with fever, history of fever (in the last 72 hours), or diarrhea in the intervention group, CRP will be assessed at admission and after 18-24 hours. Communication will emphasize that CRP levels below 10mg/L suggest non-severe disease, between 10-50mg/L may require antibiotics based on trend, and levels above 50mg/L likely necessitate antibiotic continuation. Healthcare workers will be trained to consider both clinical symptoms and CRP values in diagnosis and treatment decisions, utilizing the Aidian QuickRead go CRP POCT machine for rapid results. The study will employ individual randomization through the Sealed Envelope™ program, with follow-up remaining blinded, and stratification by gender within the three study groups.
Intervention type	Device
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	QuikRead go CRP POCT
Primary outcome measure(s)	1. Duration of antibiotic treatment (number of 24-hour periods between the start and end of antibiotic treatment) measured using g patient medical records and clinical data registry filled by research assistants daily within 14 days of the admittance of included neonates and children in each study arm (superiority analysis) 2. Days to relapse of infection measured using patient medical records and follow-up forms within 72 hours after completion of the initial course of antibiotics and at the 7th and 28th day after randomization
Key secondary outcome measure(s)	1. Antibiotic consumption measured using records quantifying prescribed daily doses and daily defined dosage throughout the entire duration of antibiotic treatment at the end of the study 2. Antibiotics prescribed at birth or admittance measured using records of the type and dosage of antibiotics prescribed at the time of birth or admittance to the hospital at the end of the study 3. The number of days admitted in the hospital measured using records of the total days from admission to discharge until the patient was discharged at the end of the study 4. The number of days until the resolution of symptoms measured using records tracking the time from initial symptoms to complete resolution until symptoms are completely resolved at the end of the study 5. The number of days until discharge measured using records counting the days from admission to hospital discharge until the patient is discharged at the end of the study 6. Development of clinical signs of sepsis measured using records of the clinical assessment for the presence of sepsis indicators throughout the entire study duration 7. The number of days in antibiotic treatment (Drugs, Doses Administered) measured using records of the duration and dosage of antibiotic treatment throughout the entire duration of antibiotic therapy 8. The number of blood cultures before antibiotic treatment measured using records counting the instances of blood cultures taken before antibiotic initiation before the initiation of antibiotic treatment 9. Choice of antibiotic treatment according to local guidelines measured using records of the prescribed antibiotics in alignment with local guidelines at the time of antibiotic prescription at the end of the study 10. Re-admittance within 14 days measured using records tracking instances of re-admittance within 14 days following the initial discharge 11. Mortality measured using records documenting instances of patient mortality throughout the entire study duration
Completion date	31/05/2025

Eligibility

Participant type(s)	Patient
Age group	Child
Lower age limit	0 Days
Upper age limit	12 Years
Sex	All
Target sample size at registration	2261
Total final enrolment	1800
Key inclusion criteria	1. Between 0-28 days (inclusive) and fulfilling one of two inclusion criteria 1.1. Newborns at risk of early onset sepsis according to the WHO criteria and therefore eligible for prophylactic antibiotic treatment example: 1.1.1. Membranes ruptured over 18 hours before delivery or 1.1.2. Maternal fever (over 38 °C) during labour or 1.1.3. Amniotic fluid is foul smelling or purulent 1.2. All children from day 0 to day 28 admitted with suspected sepsis (clinical signs subjectively judged by the clinician) 2. Children between 6 months and 12 years with need of admission with either: 2.1. Febrile illness with a temperature above 38 degrees or below 36 degrees at admission, or a history of febrile illness within the last 72 hours 2.2. Diarrhea disease (defined as the passage of 3 or more loose or liquid stools per day) with or without fever 3. Parents/caregivers of admitted children are able and willing to comply with all study requirements 4. Parents/caregivers of admitted children are able and willing to give voluntary Informed consent
Key exclusion criteria	1. Age >28 days until 6 months 2. Severely ill where measurement of CRP POCT would delay the treatment process 3. Neonates who need surgery or have major congenital malformations that will require hospital admission 4. Children with known immunosuppression or severe chronic disease (HIV, hepatic disease, history of neoplastic disease, long-term systemic steroid use or similar conditions as assessed by the health care worker) 5. Parents/caregivers who are not able to participate in follow-up procedures 6. Positive rapid diagnostic test for malaria 7. Have taken antibiotics within 24 hours before admittance
Date of first enrolment	01/02/2024
Date of final enrolment	30/09/2024

Locations

Countries of recruitment

Tanzania

Study participating centres

Mnazi Mmoja Hospital

Stone Town-Vuga Street
P.O.BOX 672
Zanzibar
71101
Tanzania

Chake Chake Hospital

Kichungwani, Chake Chake
Pemba
74201
Tanzania

Vitongoji District Hospital

Vitongoji, Pemba, Zanzibar
Pemba
74212
Tanzania

Abdullah Mzee (Mkoani) Hospital

Mkoani, Pemba, Zanzibar, Tanzania
Pemba
74101
Tanzania

Kivunge District Hospital

North Unguja
Zanzibar
73103
Tanzania

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in non-publicly available repository
IPD sharing plan	The datasets generated and/or analysed during the current study are currently stored in a non-publicly available REDCap database. These data will become available in the foreseeable future after undergoing proper cleaning and anonymisation to remove any patient-identifiable information. As a research team, we have not yet finalized the duration for which the data will be stored or the criteria for access. These details will be shared once we have discussed and agreed on them internally.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

13/05/2025: Total final enrollment and individual participant data (IPD) sharing plan and summary added.
11/09/2024: The following changes were made to the trial record:
1. The overall end date was changed from 13/10/2024 to 31/05/2025.
2. The intention to publish date was changed from 01/02/2025 to 01/06/2025.
3. The plain English summary was updated to reflect these changes.
4. The study participating centre Kivunge District Hospital was added.
17/06/2024: The study contacts were amended.
14/06/2024: The following study participating centres were added: Vitongoji District Hospital and Abdullah Mzee (Mkoani) Hospital.
05/02/2024: Internal review.
22/01/2024: Study's existence confirmed by the Zanzibar Health Research Ethics Committee (ZAHREC).