Using the CRP Test in Children Under 12 Years With Respiratory Symptoms in Kyrgyz Republic
Phase: NA
Conditions: Antibiotic Resistance, Respiratory Tract Infections, Pediatric Infectious Disease, CRP
Sponsor: Rigshospitalet, Denmark

 
                                     
 
                                         STUDY PROTOCOL 
 
 
COORDINAT
E 
BISHKEK - COPENHAGEN 2021 
     
CRP fOr respiratORy DIagnosis iN Kyrgyz pediATric practicE 

COORDINATE 
SOS COVID protocol V1.0 dd 2 APR 2020 
BRIEF PROTOCOL TITLE: CRP for respiratory diagnosis in Kyrgyz pediatric practice 
 
FULL PROTOCOL TITLE: Using the CRP test in children under 12 years with respiratory 
symptoms in Kyrgyz Republic 
 
EudraCT number  
N/A 
Version 
1.0 
Date 
18 NOV 2021 
Coordinating 
investigator/project leader 
Talant Soroonbaev, Jesper Kjærgaard 
Principal investigator 
Elvira Isaeva 
 
Other investigators 
Rune Munck Aabenhus, Anja Poulsen, Stine Lund, 
Susanne Reventlow, Jørgen Kurtzhals, Joakim 
Bloch 
Sponsor  
If relevant 
Project execution site(s) 
National Centre of Maternity and Childhood Care, 
Bishkek, Kyrgyzstan; 
National Centre of Cardiology and Internal 
Medicine 
named 
after 
academician 
M. 
Mirrakhimov, Bishkek, Kyrgyzstan; 
Kyrgyz Thoracic Society, Bishkek, Kyrgyzstan; 
Primary healthcare centres in Chui and Naryn 
regions of Kyrgyz Republic; 
Department of Public Health, section of general 
practice, Copenhagen University, Denmark; 
Department 
of 
Paediatrics, 
Copenhagen 
University, Denmark. 
 

COORDINATE 
SOS COVID protocol V1.0 dd 2 APR 2020 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE 
7 
2. 
OBJECTIVES 
9 
3. 
STUDY DESIGN 
9 
4. 
STUDY POPULATION 
11 
4.1 
Population (base) 
11 
4.2 
Inclusion criteria 
11 
4.3 
Exclusion criteria 
11 
4.4 
Sample size calculation 
11 
5. 
TREATMENT OF SUBJECTS 
12 
6. 
Intervention 
12 
7. 
METHODS 
13 
7.1 
Study parameters/endpoints 
13 
7.2 
Study setting 
13 
7.3 
Types of medical centres in Kyrgyzstan 
13 
7.4 
Randomisation, blinding and treatment allocation 
14 
7.5 
Study procedures 
14 
Screening and Eligibility Assessment 
15 
Informed Consent 
15 
Study Visit – Inclusion 
15 
Follow-up with Phone Calls 
16 
7.6 
Withdrawal of individual participants 
16 
7.7 
Follow-up of subjects withdrawn from study (?) 
16 
7.8 
Premature termination of the study 
16 
7.9 
Temporary halt for reasons of subject safety 
17 
7.10 AEs, SAEs and SUSARs 
17 
7.10.1 
Adverse events (AEs) 
17 
7.10.2 
Serious adverse events (SAEs) 
17 
7.11 Data Safety Monitoring Board (DSMB) / Safety Committee 
17 
7.12 Primary study parameter 
18 
7.13 Secondary study parameters 
18 
7.14 Other study parameters 
18 
7.15 Interim analysis (if applicable) 
18 
8. 
ETHICAL CONSIDERATIONS 
19 
8.1 
Regulation statement 
19 
8.2 
Recruitment and consent 
19 
Screening and Eligibility Assessment 
19 
Informed Consent 
19 
8.3 
Objection by minors or incapacitated subjects 
20 
8.4 
Benefits and risks assessment, group relatedness 
20 
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
21 

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SOS COVID protocol V1.0 dd 2 APR 2020 
9.1 
Handling and storage of data and documents 
21 
9.2 
Monitoring and Quality Assurance 
21 
9.3 
Annual progress report 
22 
9.4 
Temporary halt and (prematurely) end of study report 
22 
9.5 
Public disclosure and publication policy 
22 
10. 
STRUCTURED RISK ANALYSIS 
22 
11. 
REFERENCES 
22 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AI 
Assistant Investigator 
CA-ARTI 
Community Acquired Acute Respiratory Tract Infection 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CRP POCT 
C-reactive protein point-of-care testing 
COVID-19 
Coronavirus disease 2019 
FMC 
Family Medicine Centre 
FOP 
Feldsher-Obstetric Point 
FPG 
Family physicians groups 
GP 
General Practitioner 
HCW 
Healthcare Workers 
IC 
Informed Consent 
ICU 
Intensive care unit 
IMCI 
Integrated management of childhood Illness 
IRCT 
Individual Randomised Controlled Clinical Trial 
PI 
Principal Investigator 
RCT 
Randomised Controlled Clinical Trial 
RTI 
Respiratory Tract Infection 
SAE 
Serious Adverse Event 
SARS-CoV-
2 
Severe Acute Respiratory Syndrome Coronavirus-2 (virus causing COVID-19 
disease) 
SD 
Standard deviation 
SMG 
Study Management Group 
UCPH 
University of Copenhagen 
WHO 
World Health Organisation 

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SUMMARY 
 
Rationale: Respiratory tract infections are the most common cause to contact to the 
healthcare system worldwide and the most common cause of inappropriate use of antibiotics. 
And while lower respiratory tract infections are still the main cause of death for children under 
5 globally, only a small proportion of children with airway disease need antibiotics. 
Overuse of antibiotics globally is leading to increasing rates of antibiotic resistance and may 
lead to a ‘post-antibiotic’ era. Case fatality rates for pneumonia in children remain high in 
Central Asia and there is a lack of knowledge of which viruses and bacteria cause the disease. 
Antibiotic resistance patterns of common bacteria remain largely unknown in Central Asia 
which makes it challenging for clinicians to choose the right antibiotic to treat children with 
suspected bacterial pneumonia and sometimes healthcare workers overuse an antibacterial 
therapy even when the child does not need it. 
Randomised trials of using CRP point of care test (POCT) to guide antibiotic prescription for 
respiratory tract infections has been successful in lowering unnecessary antibiotic 
prescriptions in adults in high income countries but left a small concern for safety in the form 
of possibly slightly increased risk of hospitalisation in the CRP group. 
 
Objective: This study seeks to gain evidence on whether use of C-reactive protein point-of-
care test can safely decrease prescription of antibiotics for children under 12 with acute 
respiratory symptoms in primary level healthcare centres in Kyrgyzstan. 
 
Study design: Multicentre, open-label, individual randomised controlled clinical trial with 14 
days blinded follow-up in rural Chui and Naryn regions of Kyrgyz Republic. Healthcare workers 
from ten selected healthcare centres will be trained in the CRP POCT and in interpreting the 
results in the field. 
 
Study population: Children aged from 6 month to 12 years attending the primary level 
healthcare centres during normal business hours with acute respiratory symptoms. 
 
Main study parameters: The proportion of patients in the two groups prescribed an antibiotic 
within 14 days of index consultation; length of disease, antibiotics given at index consultation, 
admissions and vital status. 
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Risks, inconvenience and burden associated with participating in this 
observational study are low. As part of the inclusion children in the CRP cluster group will have 
a finger-prick test performed. This may be unpleasant and course transient discomfort but 
poses no risks to the child. Follow-up will be three short phone calls day 3, 7 and 14 after 
inclusion. Risks includes possible undertreatment of serious disease, however previous 
studies have not found safety issues with CRP testing in children. There is no direct benefit to 
participants, but side effects and non-necessary medications are likely minimised.  

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1. INTRODUCTION AND RATIONALE 
 
Respiratory tract infections are the most common cause of contact to the health system and 
are the main reason for antibiotic overuse at the primary care level globally [1–3]. At the same 
time, acute lower respiratory infections (ALRI) are the most common cause of death among 
children under 5 globally [4], costing the lives of almost 1 million children annually [5]. 
Unfortunately, there is substantial overlap in the presentation of different causes of acute lower 
respiratory illness in young children, including bacterial pneumonia, viral infections and 
wheezing [6,7] and with increasing coverage of pneumococcal and Haemophilus influenza 
type b vaccination, only a smaller proportion of these need antibiotics [8,9]. At the same time, 
globally, most children are diagnosed and treated at a primary care clinic, primarily by mid-
level providers with only limited access to diagnostic equipment [3]. To assist healthcare 
providers in diagnosing under these conditions, various algorithms have been used, e.g. 
WHO’s Integrated Management of Childhood Illness, which bases diagnosis of respiratory 
diseases in children mainly on presence of cough and elevated respiratory rate [10]. This 
approach has been shown to severely over-diagnose pneumonia and thus result in 
unnecessary prescription of antibiotics [11]. Therefore, new approaches to diagnosing and 
treating respiratory infections in children are urgently needed. 
 
Concurrently, antimicrobial resistance is now what WHO calls a global health emergency and 
warns that ‘A post-antibiotic era—in which common infections and minor injuries can kill—far 
from being an apocalyptic fantasy, is instead a very real possibility for the 21st century [12] 
(Figure 1). Unnecessary prescription of antibiotics is extensive globally [2,12] and most 
healthcare providers are aware of the global threat of antimicrobial resistance but express the 
need for support for prescribing differently, such as knowledge of local resistance patterns of 
pathogens and better diagnostics to support a decision not to treat with an antibiotic [13]. 
 
 
Figure 1: Deaths attributable to antimicrobial resistance every year by 2050 (Source: BBC and 
Review on Antimicrobial Resistance – Tackling a Crisis for the Health and Wealth of Nations 
(2014)). 
 
 

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C-reactive protein (CRP) is an acute phase reactant produced by the liver which can be used 
as a marker of serious infection. Randomised trials of using CRP point of care test (POCT) to 
guide antibiotic prescription for respiratory tract infections has been successful in lowering 
unnecessary antibiotic prescriptions in adults in high income countries but left a small concern 
for safety in the form of possibly slightly increased risk of hospitalisation in the CRP group [14]. 
Trials of CRP POCT in children have been performed in Tanzania as part of an intervention 
package with a strict prescription limit of > 80 mg/L CRP with a reduction in antibiotic 
prescriptions from 40% to 2% [15]. In South-East Asia with a small but statistically significant 
effect (5% reduction) when used as either above or below a certain threshold (40 mg/L) in 
Thailand and Myanmar [16]. In a sub-group analysis from a trial in Vietnam with both children 
and adults where the numeric value of CRP was used after a short training in CRP 
interpretation along with clinical evaluation resulted in a 20% reduction from 64% to 44% [17]. 
A cross-cutting qualitative study of the above-mentioned studies in Thailand, Myanmar, and 
Vietnam showed that lack of non-antibiotic alternatives to prescribe led to lower adherence to 
the CRP POCT result [18].  
 
As the intervention of supplying CRP POCT to healthcare providers is more a behavioural than 
biomedical, previous trials have recommended that further trials are done in different contexts 
and that qualitative studies of reasons for success or failure [17].  
 
Central Asian countries have been underrepresented in health science, especially in primary 
care research. The clinical context of primary care in South-East Asian countries, like Vietnam, 
Thailand, and Myanmar, and Central-Asian countries, like Kyrgyzstan, are vastly different with 
different caseloads, different human resources, and varying time for consultations available 
[3]. At the same time, case fatality rates for pneumonia in children remain high in Central Asia 
(Figure 2) and there is a lack of knowledge of which viruses and bacteria cause the disease. 
Antibiotic resistance patterns of common bacteria remain largely unknown in Central Asia, 
which makes it challenging for clinicians to choose the right antibiotic to treat children with 
suspected bacterial pneumonia. 
Figure 2: Causes of Death in Children under 5 in Central Asia. 

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Figure 3 shows a graph of the distribution of morbidity in children aged 0 to 14 years in the 
Kyrgyz Republic (http://cez.med.kg/) with respiratory diseases being the most common 
(49,7%). Among all acute respiratory diseases in children, upper respiratory tract infections 
are the most common, as shown in Figure 4. The number of cases per 100,000 population 
seems to de-crease by 2020, but it is still quite high (http://cez.med.kg/).  
 
 
Figure 3: The structure of morbidity in children from 0 to 14 years old in the Kyrgyz Republic 
(%) 2012-2020 
 
 
Figure 4: Dynamics of the prevalence of acute respiratory diseases in children under 14 years 
of age (per 100,000 child population) in the Kyrgyz Republic (2009-2020) 
 

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2. OBJECTIVES 
 
The aim of this project is to find out if the overuse of antibiotics in children with acute respiratory 
symptoms can be reduced by effectively identifying children at increased risk of infections who 
require antibiotic therapy and children who will not benefit from antibiotics. This is done by 
implementing CRP POCT at the primary healthcare level. 
 
Hypotheses: 
 
Supplying CRP POCT equipment to primary healthcare providers will help them identify the 
majority of children who suffer from viral infections and assist in withholding antibiotic treatment 
when no benefit can be expected and will help identify the severely sick children in need of 
urgent referral, thus lowering unnecessary use of antibiotics and improving primary care 
management by studying supplying supportive medication for those not in need of antibiotics. 
 
It will be an individually randomised clinical trial where CRP POCT is supplied to approximately 
14 healthcare centres. All children up to 12 years with respiratory symptoms have basic clinical 
data recorded as well as data needed to classify according to WHO IMCI pneumonia diagnostic 
criteria. CRP POCT is used at intervention sites and CRP results, diagnosis, and treatment is 
recorded. Follow-up phone calls will be made 3, 7 and 14 days after the health centre visit to 
record recovery, antibiotics use, hospitalisation and vital status of the participating children.  
 
3. STUDY DESIGN 
 
Multicentre, open-label, individual randomised controlled clinical trial with 14 days blinded 
follow-up will be conducted in low altitude Chui and high altitude Naryn regions of Kyrgyz 
Republic. Healthcare workers (HCW) from 14 randomly selected healthcare centres will be 
trained in the CRP POCT and in interpreting the results in the field. 
 
Children will be screened at 14 randomly selected primary healthcare centres using a 
screening form (see Appendix A). The 14 healthcare centres will consist of a combination of 
Family Medical Centres, Family Physician Groups and Feldsher-obstetric points. Screening 
will be performed by an assistant investigator (AI) prior to the children being examined by a 
local HCW. The screening form will include a list of symptoms from the eligibility criteria. If a 
child has at least one symptom from the inclusion criteria, the AI will receive a rapid diagnostic 
test for SARS-CoV-2 at the HCW's office. In case the test is negative, AI will ask the 
parent/caregiver about their child's participation in the study and offer to read and sign the 
informed consent (IC) form. Otherwise (the test is positive), the child will not be included in the 
study. If the parents agree to their child's participation in the study and have signed IC, the 
child is enrolled in the study and randomised to Group A or Group B. The randomisation will 
be carried out by a responsible person located in the Bishkek office through the Sealed 
Envelop™ programme (www.sealedenvelope.com). This person will be in touch with AIs by 
telephone and, upon the request of the AIs, will remotely randomise and report the result to 
AIs. The principal investigator will not to be aware of the results of the randomisation and 
follow-up will be blinded as well. 
 

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Group A: 
 
Participants assigned to Group A will take CRP POCT during a check-up with their HCW. The 
AI will attend the child's consultation with the local HCW and complete the case report form 
(CRF) (see Appendix C). Consequently, the CRP result will be recorded in the CRF, which will 
be the basis for choosing a treatment, depending on its result. 
 
Group B: 
 
HCWs will also consult children who have been randomised to Group B. The AI will complete 
the CRF for these children, but no CRP POCT test will be perform in this control group. They 
will receive the treatment prescribed by the HCW as usual care in an intention-to-treat model. 
 
Both groups will be assessed additionally on the 3rd, 7th and 14th day by phone calls from 
another AI who is blinded to the group allocation using Follow-up questionnaires (see Appendix 
E). 
 
The RCT study design is depicted in figure 5: 
 
 
 

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Figure 5: Multicentre, open-label, individual randomised controlled clinical trial with 14 days 
blinded follow-up. 
PILOT STUDY 
 
Prior to the start of the Main Study, a pilot study will be conducted to qualify and ensure 
practicality and acceptability of the main study. We aim to include 5-10 % of the original sample 
size calculation, approximately 60-75 (5%) children. The pilot study will access the number of 
eligible children and determine the number of caregivers willing to provide the informed 
consent form.  
In the pilot study we will see how the CRFs and follow-up interviews are executed in regard to 
time to complete, understanding the questions and ease of use, completeness and loss to 
follow-up. 
 
The pilot study will also involve qualitative interviews in the form of focus groups with 
healthcare workers and child caregivers. 
 
The pilot study will be carried out in the three different first level of healthcare system in Chui 
region of Kyrgyzstan, in three randomly selected villages. This will inform how the trial will 
work, whether or not the project will be acceptable and feasible and likely to provide the results 
within the designated time. 
 
 
4. STUDY POPULATION 
4.1 Population (base) 
 
All patients aged from 6 month to 12 years attending the primary care health clinics during 
normal business hours with symptoms as described in the inclusion criteria. 
 
Patients of both sexes and all ethnic background can be included. 
 
4.2 Inclusion criteria 
 
Inclusion criteria is:  
• 
Between 6 month and 12 years of age;  
• 
Parents/caregivers of a child are able and willing to comply with all study requirements; 
• 
Parents/caregivers of a child is able and willing to give Informed Consent; 
• 
Having at least one of the following focal symptoms lasting for less than 2 weeks: 
o Cough; 
o Fast/difficult breathing; 
o Sore throat; 
o Shortness of breath; 
o Wheezing 
 
4.3 Exclusion criteria 
 

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A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
• 
Severely ill and in need of urgent referral where measurement of CRP POCT would 
delay the process; 
• 
Terminally ill patients; 
• 
Patients with ear ache only; 
• 
Patients with known immunosuppression or severe chronic disease (HIV, liver disease, 
history of neoplastic disease, long term systemic steroid use or similar conditions as 
assessed by the health worker or AI); 
• 
Parents/caregivers who are not able to participate in follow-up procedures (lack of 
telephone etc); 
• 
Positive rapid diagnostic test for SARS-CoV-2; 
• 
Haven taken antibiotics within 24 hours before the index consultation 
 
4.4 Sample size calculation 
 
Provisional calculations show that a power of 90% to detect a 10% reduction in antibiotic use 
(from 55% to 45%) at a statistical significance level of 0.05 is achievable with the available 
resources resulting in recruitment of approximately 1046 children, 523 in each arm. With an 
expected dropout rate of 15% we aim to include 1204 children in total, 602 in each arm. 
 
We expect to be able to include a sufficient number of patients in approximately three months. 
Each clinic has a patient flow of approximately 10 – 25 children per week. With 14 clinics, the 
weekly flow of potential participants is 100 – 250 even if only less than 1 in 2 patients are 
enrolled; we will still keep our schedule. 
There has not been a diminished flow of patients at the healthcare centres curing the COVID-
19 pandemic, so the study should be able to move ahead on schedule even in the face of the 
pandemic. 
 
5. TREATMENT OF SUBJECTS 
 
Children with the relevant age and symptoms will be consulted by a researcher, and with the 
consent of the parent / caregivers the child will be included in the study. In this case, the child 
in the control group will receive treatment according to the usual recommendations of the 
health workers. A child in the intervention group will receive an antibiotic only in accordance 
with the results of the CRP and the assessment of the health worker. If the child does not need 
antibiotic therapy, treatment will be prescribed in accordance with the recommendations for 
the management of acute respiratory viral infections without prescribing antibiotics, prescribing 
e.g. acetaminophen or other supportive treatment. 
 
 
6. Intervention 
 
CRP POCT equipment will be supplied at healthcare centres, along with a short training in use 
and interpretation supporting the clinical evaluation of the child. It will be communicated that 
CRP levels less than 10 indicate that the disease is not severe, and antibiotics is most likely 
not needed, if between 10 and 50, that antibiotics might be needed, and if more than 50 that it 

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is likely that they are needed. With CRP between 10-50 the HCW are instructed to take the 
clinical picture into account together with the value of the test. With obvious symptoms of 
bacterial infection such as high fever, very affected general condition, purulent sputum, signs 
of acute otitis media, persisting rhinosinusitis over 10 days etc. The training will also include 
knowledge of CRP pharmacodynamics and cases where a low CRP might need to be 
interpreted cautiously, e.g. a history of fever lasting less than 24 hrs. HCWs will be instructed 
to use CRP POCT for all patients in the intervention group and use the information to guide 
diagnosis and treatment choice. We will use Aidian (Copenhagen, Denmark) QuickRead go 
CRP POCT set-up (Figure 3). 
 
 
 
Figure 3: Aidian CRP POCT. 
 
7. METHODS 
7.1 Study parameters/endpoints 
 
The primary outcome of the randomised trial is antibiotic prescription within 14 days from the 
index consultation, measured as proportion of children in each study group who receive an 
antibiotic (superiority analysis). 
However, any reduction in antibiotic use must be balanced without any compromise to patient 
safety and the study will therefore include two primary outcomes. The second primary study 
outcome is patient safety measured as the number of days until recovery (non-inferiority 
analysis). 
 
Secondary outcomes include other treatment, antibiotics given at index consultation, re-
consultations, admissions and vital status. 
 
7.2 Study setting 
 
The study will be conducted in primary care in the rural areas in Chui region of Kyrgyz Republic, 
a Central Asian mountainous lower middle-income country with 6.2 million inhabitants (Figure 

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3). The study will be conducted in 14 randomly selected healthcare centres and consist of 
villages with between 590 and 10764 inhabitants. From previous research in the areas, we 
know that during winter-time on average, approximately 25 children visit a health centre with 
respiratory symptoms per week [3]. 
 
7.3 Types of medical centres in Kyrgyzstan 
 
The Family Medicine Centre (FMC) is a unified complex, which employs doctors of all 
specialties and provides outpatient treatment for patients belonging to the area. The FMC also 
provides basic diagnostic services (general and biochemical blood tests, urine tests, stool 
analysis, electrocardiography, echocardiography, X-ray and ultrasound). 
 
Family physician groups (FPG) is a medical institution that brings together family doctors, 
therapists, pediatricians, obstetrician-gynecologists, nurses and paramedics (depending on 
the population in the area and staffing), providing primary health care for patients related to 
the area. If it is necessary to take clinical tests, blood, urine or stool are taken from the patient 
and sent to the FMC. Results come in a few days. If it is necessary to pass biochemical tests 
or to undergo an instrumental examination, the patient is sent for this to the FMC or, if 
necessary, for a consultation with a narrow specialist. 
 
A feldsher-obstetric point (FOP) is a structural unit of a medical and preventive institution 
that provides pre-hospital primary health care in rural areas, where feldshers and nurses act 
as medical personnel. In FOPs, pre-medical examination of patients belonging to this village 
is carried out. If it is necessary to consult a family doctor, the patient is referred to the FPG. 
There is no diagnostic equipment in FOPs. 
 
A feldsher is a medical specialist who occupies an intermediate position between a doctor 
and a nurse. He can work both under the guidance of a doctor and independently. 
 
7.4 Randomisation, blinding and treatment allocation 
 
Randomisation 
will 
occur 
through 
a 
web 
based 
service 
Sealed 
Envelope™ 
https://www.sealedenvelope.com/ and conducted in a designated room by a dedicated 
member of the research team. Participants will be randomised (1:1) to either standard care or 
care according to CRP POCT. A dedicated member of the research team will inform the 
assessors of group allocations via telephone. 
 
7.5 Study procedures 
 
Recruitment: 
 
The recruitment of participants will be carried out at 14 selected health centres among the 
children in attendance. AI screening will be used to select patients with the symptoms 
described in the STUDY POPULATION section. Further, in case the child is eligible for the 

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study, the AI will ask the parent / guardian about their child's participation in the study and offer 
to read and sign the IC form. 
 
Special requirements during the COVID-19 Pandemic: 
 
Given the COVID-19 pandemic, a Safety Concept for the COORDINATE Project has been 
developed. Due to the current situation with COVID-19, the following requirements must be 
observed for the study: 
 
1. Participants and HCWs must wear disposable masks; 
2. The consultation room and corridors should be equipped with alcohol-based wall sanitisers; 
3. Cleaning in the room and in the corridors should be carried out strictly using chlorine 
solution; 
4. Participants (children and caregivers), hospital stuff and research group must maintain 
social distance and refrain from close contact; 
5. All children included in the study will receive a rapid diagnostic test for SARS-CoV-2 
 
Screening and Eligibility Assessment 
 
Children aged 6 month to 12 years will be assessed against the inclusion criteria by an AI and 
if eligible, be included upon signing of an IC by their parents/caregivers and have their CRF 
completed on paper.  The AI will have a screening form. (See Appendix A) The selected 
children will then be randomised via a web programme (www.sealedenvelope.com) into two 
groups: Group A, who will receive antibiotics prescribed according to CRP POCT and provision 
of alternative non-antibiotic supportive treatment (e.g. paracetamol and/or salbutamol as 
relevant) for children with respiratory diseases that do not need antibiotics and Group B, who 
will receive the usual care. 
 
Informed Consent 
 
When the patient consults at the healthcare centres, explanation of the study, provision of 
study-related information, patient information sheet and IC will be performed at the practice. 
All study personnel will be trained by the national network facilitator or Principal Investigator 
(PI), detailing no less than: the exact nature of the study, implications and constraints of the 
study, and risks and benefits of participation. The study will provide a patient information sheet 
(appendix D) that includes all necessary information available in the official national language. 
10 minutes will be given to the parents/caregivers to consider the information given to them 
and to ask any questions they may have about the study to decide whether their child will 
participate in the study. As participants are not of legal age of consent in their jurisdiction, 
consent will be provided by their parent/caregiver. It will be clearly stated in the patient 
information sheet and verbally explained to the participant that they are free to withdraw from 
the study at any time for any reason without impacting their future care, and with no obligation 
to provide the reason for withdrawal. 
 
 
 
 
 

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Study Visit – Inclusion 
 
Patients will be included when they attend the health clinic upon fulfilment of the above-
mentioned criteria. During the consultation and upon IC the baseline CRF data will be gathered 
(see appendix A, for the exact information that will be recorded). The CRF will be completed 
by the AI; the examination will be carried out by the clinic's HCW. 
• 
Demographic details including: sex, age, co-morbidities, BMI category; 
• 
Duration of CA-ARTI symptoms prior to consulting; 
• 
Presence of specific RTI and general symptoms; 
• 
Overall severity rating (HCW perception); 
• 
Clinical assessments and results of clinical examination (oxygen saturation, respiratory 
rate, blood pressure, heart rate, body temperature); 
• 
All diagnostic tests performed or ordered; 
• 
Management: antibiotic, antiviral prescription, other (symptomatic) medication prescribed 
and advised; 
• 
Additional advices: preventive measures for themselves and their family members, time-
off, home isolation, hygienic measures; 
• 
Referral to hospital or public health authority; 
• 
During this visit a swab will be taken see below; 
• 
COVID-19-specific questions; 
• Participants randomised to a control group will receive routine care. Participants 
randomised to the CRP group will take the CRP test 
 
Follow-up with Phone Calls 
 
There will be no scheduled follow-up visit at the health clinic required by the study. 
Parents/caregivers will be phoned 3, 7 and 14 days after the index consultation to record 
outcomes. Phone calls will be blinded and performed by another AI (see appendix D): 
• 
Number of symptomatic days after the consultation; 
• 
Duration of specific symptoms; 
• 
Return to school/work and usual activities; 
• 
Additional contacts with HCWs; 
• 
Any medicine bought over-the-counter or prescribed by other HCWs including the name of 
the drug(s); 
• 
Additional diagnostic testing, including SARS-CoV-2 and outcomes; 
• 
Complications (hospitalisation -days in hospital, ICU, medication/oxygen/ventilation 
received there-, pneumonia, death); 
• 
Infections in their households; 
• 
General well-being; 
• Diarrhea 
 
7.6 Withdrawal of individual participants 
Participants can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. If any subjects are withdrawn, the reason(s) will be recorded in the CRF. 
 

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7.7 Follow-up of subjects withdrawn from study 
The phone numbers of the parents/caregivers of the withdrawn or abandoned participants, if 
they wish, will be recorded and later called to find out the child's condition. The reasons for the 
refusal will also be recorded in a special section in the CRF. 
 
7.8  Premature termination of the study and interim analysis 
Since we are planning to include all subjects within two to three months, we do not plan to 
make an interim analysis. If the inclusion period will be longer than 3 months we will do an 
interim analysis or when 500 participants are included which ever comes first. The interim 
analysis will assess our primary outcome, safety outcome and adverse events. The PI will 
present the results of interim analysis to the Data Safety Monitoring Board (DSMB) / Safety 
Committee (see section 7.11). 
 
SAFETY REPORTING 
7.9 Temporary halt for reasons of subject safety 
 
The study maybe halted for various reasons such as an urgent safety measures, further to a 
serious breach, serious sickness of researcher.  A temporary halt applies when the suspension 
is imposed on all sites; suspension of the study at a single site due to logistical reasons is not 
considered a temporary halt. 
 
The decision on whether a temporary halt should be imposed on a study will ultimately be a 
steering committee decision (and the decision-making process should be evidenced on file). 
 
7.10 AEs, SAEs and SUSARs 
7.10.1 
Adverse events (AEs) 
Adverse events may include the following: 
• 
Allergic reaction to an antibiotic or any other drug during treatment (skin rash, 
lacrimation, flushing) 
• 
Individual intolerance to an antibiotic or any other drug. 
• 
Positive a rapid diagnostic test for SARS-CoV-2 
7.10.2 
Serious adverse events (SAEs) 
As part of the study, we will collect the following outcomes at day 3, 7 and 14: 
• Death 
• Inpatient hospitalisation 
SAE data will also be recorded in the CRF. 
 
7.11 Data Safety Monitoring Board (DSMB) / Safety Committee 
If need be a Data Safety Monitoring Board or Steering/Safety Committee will be activated and 
interim analysis including SAE will be presented and discussed. The primary responsibilities 
of the DSMB are to 1) periodically review and evaluate the accumulated study data for 
participant safety, study conduct and progress, and, when appropriate, efficacy, and 2) make 
recommendations to Principal Investigator concerning the continuation, modification, or 

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termination of the trial. The DSMB considers study-specific data as well as relevant 
background knowledge about the disease, test agent, or patient population under study. 
Items reviewed by the DSMB include: Interim/cumulative data for evidence of study-related 
adverse events; Interim/cumulative data for evidence of efficacy according to pre-established 
statistical guidelines, if appropriate; Data quality, completeness, and timeliness; Performance 
of individual centres; Adequacy of compliance with goals for recruitment and retention, 
including those related to the participation of women and minorities; Adherence to the protocol; 
Factors that might affect the study outcome or compromise the confidentiality of the trial data 
(such as protocol violations, unmasking, etc.);  
The Data Safety Monitoring Board (DSMB) will consist of PI, coordinators from Denmark and 
Kyrgyz Republic and Professor Muhtar Asheraliev (paediatrician).  
 
STATISTICAL ANALYSIS PLAN 
7.12 General principles 
This study is designed as an RCT to test effectiveness of CRP POCT in lowering prescription 
of antibiotics to children from 6 month to 12 years of age in 14 primary health clinics in 
Kyrgyzstan presenting with acute respiratory tract infection (see protocol for inclusion criteria) 
without compromising patient safety. The children will be randomised into two groups: in the 
intervention group CRP POCT will be measured and used to guide clinical decision-making 
regarding antibiotic use, in the control group standard care will be performed without CRP 
measurement. The primary outcome is the proportion of children receiving antibiotics within 14 
days from the index consultation in each study arm. The main statistical analysis will follow an 
intention to treat (ITT) principle, in which all enrolled children will be analysed in the groups 
they are randomised to. Safety outcomes as well as other secondary outcomes will be 
assessed as described in 1.2. 
 
The statistical analysis will be performed after data from the last follow up has been entered. 
Analysis will be performed by the investigators of the study using SAS statistical software. Data 
will be stored in REDcap.  
7.13 Randomisation 
The children will be randomised into two groups using the online randomisation tool ‘Sealed 
Envelope’ (www.sealedenvelope.com). Randomisation will be stratified by male/female as well 
as age<5 years and age>5 years. 
7.14 Primary study outcomes 
The primary study outcome is the proportion of included children in each study arm that are 
prescribed an antibiotic within 14 days from the index consultation (superiority analysis).  
 
However, any reduction in antibiotic use must be balanced without any compromise to patient 
safety and the study will therefore include two primary outcomes. The second primary study 
outcome is patient safety measured as the number of days until recovery (non-inferiority 
analysis). 
7.15 Secondary study parameters/outcomes 
- 
Antibiotics prescribed at the index consultation 

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- 
Antiviral treatment at follow up 
- 
Reconsultation within 14 days from index consultation 
- 
Hospital referral at index consultation 
- 
Hospital admission at follow up 
- 
Mortality 
7.16 Power calculation 
As the study employs a combined superiority and non-inferiority approach based on the two 
related primary study outcomes; we provide two power calculations and opt for the 
conservative number of participants to ensure the adequate sample size for answering both 
primary outcomes. Power calculations are performed using sample size calculators provided 
by Sealed Envelope™. 
Superiority power calculations show that for a power of 90% to detect a 10% reduction in 
antibiotic use (from 55% to 45% based on previous pilot registrations in the area) at a statistical 
significance level of 0.05 a total of 1046 children, 523 in each arm are necessary.  
In our non-inferiority power calculation, we apply a margin of non-inferiority of one day (24 
hours), i.e. the intervention arm is allowed to have a mean time to recovery that is one day 
longer than the mean recovery time in the control arm without being deemed inferior. The 
duration of acute respiratory tract infection in children is approximately 7 days with a standard 
deviation of 5 days. Hence, for a power of 90% and a statistical significance level of 0.05 a 
total of 858 children are needed.  
To be able to assess both outcomes we will opt for the conservative measure, e.g. the 
superiority measure.  
With an expected dropout rate of 15% we aim to include 1204 children in total, 602 in each 
arm. This is deemed achievable with the available resources. We expect to be able to include 
a sufficient number of patients in approximately three months. Each clinic has a patient flow of 
approximately 10 – 25 children per week. With 10 clinics, the weekly flow of potential 
participants is 100 – 250 even if only less than 1 in 2 patients are enrolled; we will still keep 
this schedule. 
7.17 Data cleaning and data checking 
Before unblinding and analysis the data will be checked for outlying, missing and/or otherwise 
faulty values. Faulty input and/or extreme outliers will be corrected, and it will be attempted to 
trace missing values. 
7.18 Analysis of baseline variables 
An unadjusted comparison will be done between baseline variables of the intervention and 
non-intervention group. Baseline variables to be compared include age, sex, comorbidities, 
number of siblings, smoking in household, study site and speciality of health worker. 
7.19 Analysis of main outcomes 
The main superiority outcome of antibiotic reductions at day 14 will be assessed by a 
multivariate logistic regression model and results presented both as odds ratio and as the 
absolute risk difference of antibiotic exposure in the two study arms. This analysis will be done 
as intention to treat (ITT). 
The main non-inferiority outcome of patient safety will be assessed by a multivariate, 
generalised, linear model to calculate an adjusted 95% confidence interval (CI) for the 

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difference between CRP-guided and standard therapy in the number of days until recovery. 
This analysis will both be done as ITT and per-protocol (PP). 
7.20 Missing data and lost to follow up 
To correct for potential differences in between the groups with regard to missing data and 
patients that are lost to follow up the main analysis will be done with inverse probability 
weighing (IPW). 
 
7.21 Analysis of secondary outcomes 
Antibiotic treatment at follow up 
Using linear regression we will compare how many in the intervention and non-intervention 
group are prescribed antibiotics at the index consultation.  
 
Antiviral treatment at follow up 
Using linear regression we will compare how many in the intervention and non-intervention 
group start antiviral treatment (prescribed or bought over-the-counter) within 14 days after the 
index consultation.  
 
Reconsultations 
Using linear regression we will compare how many in the intervention and non-intervention 
group come for reconsultations (planned and unplanned) within 14 days after the index 
consultation. 
 
Hospital referral at index consultation 
Using linear regression we will compare how many in the intervention and non-intervention 
group are referred to hospital at the index consultation. 
 
Hospital admission at follow up 
Using linear regression we will compare how many in the intervention and non-intervention 
group are or have been admitted into hospital until day 14 after the index consultation. 
 
Mortality 
Using linear regression we will compare mortality status in the intervention and non-
intervention group. 
Secondary outcomes will be expressed with 95% two-sided confidence intervals.  
 
7.22 Adjustment for baseline variables 
The analyses of the outcomes will be adjusted for the stratification variables – age and sex – 
so as to boost the power of the analyses. Additionally, clinical relevant variables such as 
respiratory frequency, fever and other severity markers will be included.  
 

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7.23 Presentation of data 
Descriptive data will be presented either by means and standard deviations, or medians and 
interquartile ranges -as appropriate- for continuous data, or by numbers and percentages for 
categorical data. Data may also be investigated using visual tools (e.g. histogram, box-plot, 
scatter plot, Kaplan-Meier curves). 
 
7.24 Interim analysis 
Since we are planning to include all subjects within two to three months, we do not plan to 
make an interim analysis. If the inclusion period will be longer than 3 months we will do an 
interim analysis or when 500 participants are included which ever comes first. The interim 
analysis will assess our primary outcome, safety outcome and adverse events. The PI will 
present the results of interim analysis to the Data Safety Monitoring Board (DSMB) / Safety 
Committee (see section 7.11). 
 
8. ETHICAL CONSIDERATIONS 
8.1 Regulation statement 
The study will be conducted in accordance with the latest version of the principles of the 
Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013), in 
accordance with the Medical Research Involving Human Subjects Act (WMO) and other 
applicable privacy laws, local guidelines, regulations and Acts. 
 
The team will ensure the correct regulatory approvals are gained prior to initiation of study. 
The protocol, and attached documents (ICFs, patient information sheets, CRF and phone 
questionnaire) will be submitted to an appropriate Research Ethics Committee (REC), and, if 
needed, additional regulatory authority. If necessary, approvals for all substantial amendments 
to the original approved documents will be obtained. Any substantial amendment to the 
protocol must be approved by all collaborating parties before they are submitted for national 
REC and regulatory approvals. 
 
No patients will be enrolled in a country until all approvals have been obtained for that country’s 
primary care network and sites. 
 
Medical management of participants in this study must never be compromised by study 
procedures. At all times, priority will be given to samples required for medical management. 
 
8.2 Recruitment and consent 
Recruitment 
All children presenting or consulting the primary care health clinic for their CA-ARTI symptoms 
described above can be included in the study. Therefore, the HCWs from primary care health 
clinics (doctors, nurses, practice assistants and medical students) may be involved in the 
inclusion procedures.  
 
Screening and Eligibility Assessment 
Any child aged from 6 month to 12 years contacting the participating health clinics and who 
meets the eligibility criteria will potentially be included. Patients will be assessed against the 

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inclusion criteria by the HCWs and if eligible, be included upon signing of an IC by their 
parents/caregivers and have their CRF completed on paper or online. 
 
Informed Consent 
When the patient consults at the health clinic, explanation of the study, provision of study-
related information, patient information sheet and IC will be performed at the practice. Al study 
personal will be trained by the national network facilitator or PI, detailing no less than: the exact 
nature, implications and constraints of the study, and risks and benefits of participation. The 
study will provide a patient information sheet (appendix B) that includes all necessary 
information available in the official national language. Half a day will be given to the 
parents/caregivers to consider the information given to them and to ask any questions they 
may have about the study to decide whether their child will participate in the study. As 
participants are not of legal age of consent in their jurisdiction, consent will be provided by their 
parent/legal guardian. It will be clearly stated in the patient information sheet and verbally 
explained to the participant that they are free to withdraw from the study at any time for any 
reason without impacting their future care, and with no obligation to provide the reason for 
withdrawal. 
 
8.3 Objection by minors or incapacitated subjects 
Not applicable 
 
8.4 Benefits and risks assessment, group relatedness 
For the children being managed at participating health centres during the intervention period, 
the study adds a finger prick and, for some, a tracheal swab, which does give some discomfort 
for the child. On the other hand, it is the intention that the improved diagnosis will lead to better 
treatment for the child’s condition. There is a slight risk that a child has a severe infection with 
eg. a short prodrome before presenting to the clinician leading to a CRP that is not yet elevated, 
and if the CRP levels are followed strictly that such a child is not treated with antibiotics. To 
counter this, part of the training given with the CRP POCT intervention will address such issues 
and highlight that if the clinician is worried for the child despite a low CRP count, antibiotic 
therapy should be started. It will also be emphasized that if in doubt, the clinician should re-
evaluate the child eg. the next day or what is clinically meaningful. Previous studies very similar 
to this have shown to be safe for participants. 
 
Sample analyses will become available weeks after the samples were taken, and thereby don’t 
and can’t influence patient care or management. Upon request, the national coordinator can 
supply the sample results to the health clinics after full data analysis, if participants wants to 
inquire their results. 

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9. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
9.1 Handling and storage of data and documents 
All study-specific documents and laboratory outcomes will be coded with the participant ID, a 
unique number incorporating the country (one letter K), healthcare centre (two letters) and 
sequential numbers, so not by name or personal identifiers of the patient. The CRF, swab, 
contact form and information from phone calls will be identified with this ID. All study 
documents will be stored securely and only accessible by study staff: PI and designated 
members of the research team, recruiters in the practices and personnel specifically dedicated 
for patient follow-up. After completion of follow-up the contact form will be destroyed. The 
participant code-list (name, birthdate and study ID) will be stored at the healthcare centre. 
 
All paper patient-related documents (ICF, CRF, registration of phone calls) will be stored safely 
in a locked cabinet in the practice, or office of the PI. The eCRF and electronic entries stored 
securely at the REDCap online system maintained by the Rigshospitalet and Danske 
Regioner, Denmark. The REDCap system meets all International Conference on 
Harmonisation on Good Clinical Practice requirements safeguarding data integrity and 
electronic data security regulations. Data traffic within REDCap over the internet is encrypted 
using secured data communication protocols. The central databases and web servers are 
hosted in a secure data centre. The database (PostgreSQL) is backed up every day. Users 
will have a role-based access to RO after they log-in using their own personal username and 
password. This role-based access to the system will avoid unauthorised data access and 
prevents users from performing actions that they do not have authorisation for. The system 
logs all data entry steps with timestamps and user information, thereby creating an audit trail. 
Electronic data will be stored for at least 5 years. See Data Management Plan for further 
details. 
 
Direct access to source, patient and REDCap data and will be granted to authorised 
representatives from the Colaborating parties, host institution and the regulatory authorities to 
permit study-related monitoring, audits and inspections to ensure compliance with regulations. 
Coded data can be made available for research purposes after permission from the study 
responsibles. 
 
With the procedures described the the personnel dedicated for participant follow-up will ensure 
that the patients’ privacy is maintained.  
All documents will be stored securely and are only accessible by the national network 
coordinator and dedicated study personnel. At the healthcare centres, all staff will safeguard 
the privacy of patients’ personal data. 
 
9.2 Monitoring and Quality Assurance 
Monitoring 
Monitoring will be implemented as soon as the study starts, checking study procedures, swab 
taking and storage, patient inclusion and data entry. Central monitoring will be performed by a 
responsible delegate from Copenhagen University. This procedure will be reviewed as 
necessary over the course of the study to reflect significant changes to the protocol or 
outcomes of any monitoring activities. 

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No on-site monitoring visits are planned during the study due to the short inclusion period, vast 
number of clinics and travel constraints. If required health clinics may be monitored at the end 
of the study, or afterwards by the PI or a responsible delegate.  
 
Quality Assurance Procedures 
The study will be conducted and executed in accordance with the approved protocol, and 
relevant regulations. Prior to starting the study, all study-related staff will be trained in study 
procedures by the PI and core team. This will include training, delegation of responsibilities, 
and set-up to the local recruiting health clinics including procedures related to CRP testing.  
 
9.3 Annual progress report 
The PI will submit a summary of the progress of the study to the collaborating parties once a 
year. Information will be provided on the date of inclusion of the first subject, numbers of 
subjects included and numbers of subjects that have completed the trial, serious adverse 
events, other problems, and amendments. 
 
9.4 Temporary halt and (prematurely) end of study report 
The collaborating parties must immediately be informed in case of a temporary halt of the study 
or prematurely end of study including the reason(s) of such an action. 
 
The PI will notify the collaborating parties of the end of the study within a period of 8 weeks. 
The end of the study is defined as the last patient’s follow-up phone call. 
Within one year after the end of the study, the investigator will submit a final study report with 
the results of the study, including any publications/abstracts of the study, to the collaborating 
parties and relevant sponsors. 
 
9.5 Public disclosure and publication policy 
The investigators will be involved in reviewing drafts of manuscripts, abstracts and press 
releases. Authors will acknowledge how the study was funded. Authorship will be determined 
in accordance with the ICMJE guidelines and other contributors will be acknowledged. 
 
 
10. STRUCTURED RISK ANALYSIS 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 

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11. REFERENCES 
 
1. Risk R, Naismith H, Burnett A, Moore SE, Cham M, Unger S. Rational prescribing in 
paediatrics in a resource-limited setting. Arch Dis Child 2013; 98: 503–9. 
2. Havers FP, Hicks LA, Chung JR, et al. Outpatient Antibiotic Prescribing for Acute 
Respiratory Infections During Influenza Seasons. JAMA Netw Open 2018; 1: e180243. 
3. Kjærgaard J, Anastasaki M, Stubbe Østergaard M, et al. Diagnosis and treatment of acute 
respiratory illness in children under five in primary care in low-, middle-, and high-income 
countries: A descriptive FRESH AIR study. PLoS One 2019; 14: e0221389. 
4. Hug L, Sharrow D, You D. Levels & Trends in Child Mortality. New York, 2017 
http://www.childmortality.org/files_v21/download/IGME report 2017 child mortality final.pdf. 
5. Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of child mortality in 2000 
– 13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet 
2015; 385: 430–40. 
6. Zar HJ, Ferkol TW. The global burden of respiratory disease-Impact on child health. Pediatr 
Pulmonol 2014; 434: 430–4. 
7. Lai CKW, Beasley R, Crane J, Foliaki S, Shah J, Weiland S. Global variation in the 
prevalence and severity of asthma symptoms: Phase Three of the International Study of 
Asthma and Allergies in Childhood (ISAAC). Thorax 2009; 64: 476–83. 
8. Hazir T, Nisar Y Bin, Abbasi S, et al. Comparison of oral amoxicillin with placebo for the 
treatment of world health organization-defined nonsevere pneumonia in children aged 2-59 
months: a multicentre, double-blind, randomised, placebo-controlled trial in pakistan. Clin 
Infect Dis 2011; 52: 293–300. 
9. Shao AF, Rambaud-Althaus C, Samaka J, et al. New Algorithm for Managing Childhood 
Illness Using Mobile Technology (ALMANACH): A Controlled Non-Inferiority Study on Clinical 
Outcome and Antibiotic Use in Tanzania. PLoS One 2015; 10: e0132316. 
10. WHO. Integrated Management of Childhood Illness Chart Booklet. 2014. 
11. Nantanda R, Tumwine JK, Ndeezi G, Ostergaard MS. Asthma and pneumonia among 
children less than five years with acute respiratory symptoms in Mulago Hospital, Uganda: 
Evidence of under-diagnosis of asthma. PLoS One 2013; 8: 1–9. 
12. WHO. ANTIMICROBIAL RESISTANCE Global Report on Surveillance. Geneva, 2014 
http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1. 
13. O’Neill J. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. 
2016 https://amr-review.org/sites/default/files/160525_Final paper_with cover.pdf. 
14. Aabenhus R, Jensen J-US, Jørgensen KJ, Hróbjartsson A, Bjerrum L. Biomarkers as point-
of-care tests to guide prescription of antibiotics in patients with acute respiratory infections in 
primary care. Cochrane database Syst Rev 2014; : CD010130. 
15. Keitel K, Samaka J, Masimba J, et al. Safety and Efficacy of C-reactive Protein–guided 
Antibiotic Use to Treat Acute Respiratory Infections in Tanzanian Children: A Planned 
Subgroup Analysis of a Randomised Controlled Noninferiority Trial Evaluating a Novel 
Electronic Clinical Decision Algori. Clin Infect Dis 2019; : 1–9. 

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12 of 22 
16. Althaus T, Greer RC, Swe MMM, et al. Effect of point-of-care C-reactive protein testing on 
antibiotic prescription in febrile patients attending primary care in Thailand and Myanmar: an 
open-label, randomised, controlled trial. Lancet Glob Heal 2019; 7: e119–31. 
17. Do NTT, Ta NTD, Tran NTH, and Et al. Point-of-care C - reactive protein testing to reduce 
inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese 
primary health care: a randomised controlled trial. Lancet Glob Heal 2016; 4: e633–41. 
18. Haenssgen MJ, Charoenboon N, Do NTT, et al. How context can impact clinical trials: a 
multi-country qualitative case study comparison of diagnostic biomarker test interventions. 
Trials 2019; 20: 111. 
 
 
Appendix A: Screening form 
 
Appendix B: Patient Information Sheets and Informed Consent Forms 
 
Appendix C: CRF  
 
Appendix D: Phone questionnaire for follow-up