Anti-Inflammatory Reliever Therapy for Asthma Using Inhaled Budesonide/Formoterol As-needed With or Without Maintenance in South African Children: A Pragmatic Open Label Phase 3 Randomised Controlled Trial
Phase: PHASE3
Conditions: Asthma
Sponsor: University of KwaZulu

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 1 of 151                        
 
 
Protocol Title: Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South African children: A 
Pragmatic Open Label Phase 3 Randomised Controlled Trial. 
 
 
Protocol Number: 
AIR-SA 001 
 
 
Short Title: 
AIR-South Africa 
Phase: 
3 
 
 
Sponsor Name: 
Dr Pinkie Mekgwe 
 
Chief Operations Officer  
Africa Health Research Institute (AHRI) 
 
 
Funder: 
National Institute for Health and Care Research (NIHR) UK 
 
 
Principal Investigator:       Professor Refiloe Masekela 
 
Department of Paediatrics and Child Health Africa Health 
Research Institute - Somkhele Via 618 to Hlabisa 
Somkhele Mtubatuba 3935 
 
 
 
 
 
 
 
Protocol Version and Approval Date: Version1.5; 14 Dec 2023 
 
  SAHPRA Reference No: 20231016

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 2 of 151                        
 
Clinical Sub-Investigators 
Institution 
Professor Willem Hanekom 
Africa Health Research Institute 
Dr Sbekezelo Thembelihle Hlophe 
University of KwaZulu-Natal 
Dr Limakatso Lebina 
Africa Health Research Institute 
Dr Ngundu Behuhuma 
Africa Health Research Institute 
Dr Ngcebo Mhlongo 
Africa Health Research Institute 
Dr Suné Liebetrau 
Africa Health Research Institute 
Dr Lucica Thaver 
Africa Health Research Institute 
Non-Clinical Trial Sub-Investigators  
Professor Kevin Mortimer 
University of KwaZulu-Natal and Cambridge 
University 
Prof Josue Mbonigaba 
University of KwaZulu-Natal 
Nqobile Ndimande  
University of KwaZulu-Natal  
Clinical Trial Coordinators  
Dr Anne Derache 
Africa Health Research Institute 
Nompumelelo Ngobese 
Africa Health Research Institute 
Clinical Trial Pharmacists  
Kristien Bird  
Africa Health Research Institute 
Mnqobi Khumalo 
Africa Health Research Institute 
Buhle Nhlapo 
Africa Health Research Institute 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 3 of 151                        
 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South African 
children: A Pragmatic Open Label Phase 3 Randomised Controlled Trial. 
 
 
I, the undersigned as National Principal Investigator agree that I have reviewed the 
application and protocol and will ensure that if the above-said clinical trial is approved, it will 
be conducted according to the submitted protocol and South African legal, ethical and I, the 
undersigned, am responsible for the conduct of the trial at this site and affirm that: 
1. I agree to personally conduct or supervise the study. 
2. I have read the protocol and agree that it contains all necessary details for carrying 
out the study as described. I will conduct this protocol as outlined therein, as per any 
approved protocol amendments, as per International Conference on Harmonisation - 
Guidelines for Good Clinical Practice (ICH-GCP) and all applicable Regulatory 
Authority requirements and national laws. 
3. I will not deviate from the protocol without prior written permission from the Sponsor 
and prior review and written approval from the Institutional Review Board or Ethics 
Committee, and Regulatory Authority, except where necessary to prevent immediate 
danger to the participant. 
4.  I have read and understand the information in the relevant Summary of Product 
Characteristics, and I am familiar with the Investigational Medicinal Product (IMP); I 
also understand the IMP use, including its potential risks and side effects. 
5. I agree to inform all participants that the IMPs are being used for investigational 
purposes and I will ensure that the requirements related to obtaining informed consent 
are in accordance with ICH-GCP Section and local requirements. 
6.  I agree to report adverse events that occur during the study to the Sponsor, to 
maintain adequate and accurate records and make those records available, in 
accordance with ICH-GCP, South African Good Clinical Practice and other local 
requirements. I agree to promptly report to the Biomedical Research Ethics 
Committee (BREC) all changes in the research activity and all unanticipated problems 
involving risk to the participants. 
7. I have sufficient time to properly conduct and complete the trial within the agreed trial 
period, and I will ensure that any qualified staff at my sites who are involved in the trial 
conduct are adequately trained regarding the IMP, the protocol, and their 
responsibilities for the foreseen duration of the trial to conduct the trial properly and 
safely. If I delegate any of my trial activities, I will provide the Sponsor with a 
Delegation of Activities Form. I agree to ensure that all associates, colleagues, and 
employees assisting in the conduct of the study are informed about their obligations in 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 4 of 151                        
 
meeting the above commitments. 
8. I understand that the study may be terminated, or enrolment suspended at any time 
by the Sponsor, with or without cause, or by me if it becomes necessary to protect the 
best interest of the participants. 
 
 
 
 
           
 
 14 Dec 2023 
 
 
 
 
(signature) 
(date of signature) 
 
 
Refiloe Masekela Principal Investigator 
University of KwaZulu Natal 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 5 of 151                        
 
 
 
 
SPONSOR APPROVAL SIGNATURE PAGE 
Anti-Inflammatory Reliever therapy for asthma using inhaled budesonide/formoterol as 
needed with or without maintenance in South African children: A Pragmatic Open Label 
Phase 3 Randomised Controlled Trial. 
 
 
I, the undersigned have read this protocol and I approve the design of this trial: 
 
 
 
Dr Pinkie Mekgwe 
                                           14 Dec 2023 
     
(name)                                                            (date of signature) 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 6 of 151                        
 
TABLE OF CONTENTS 
 
1 
ABBREVIATIONS AND DEFINITION OF TERMS ................................................................................................9 
2 
PROTOCOL SUMMARY ........................................................................................................................................ 12 
2.1 
SYNOPSIS .................................................................................................................................................. 12 
2.2 
SCHEDULE OF EVENTS ................................................................................................................................ 19 
3 
INTRODUCTION ..................................................................................................................................................... 21 
3.1 
BACKGROUND ............................................................................................................................................ 21 
3.2 
STUDY RATIONALE ...................................................................................................................................... 22 
3.3 
INVESTIGATIONAL MEDICINAL PRODUCT ....................................................................................................... 24 
3.3.1 Budesonide/ Formoterol ....................................................................................................................... 24 
3.3.2 Summary of Preclinical studies ............................................................................................................ 25 
3.4 
SUMMARY OF CLINICAL STUDIES .................................................................................................................. 27 
3.4.1 Pharmacokinetic properties .................................................................................................................. 27 
3.4.2 Safety ................................................................................................................................................... 29 
3.4.3 Special populations .............................................................................................................................. 31 
3.4.4 Drug to drug interactions ...................................................................................................................... 32 
3.4.5 Summary of potential risks and benefits .............................................................................................. 32 
4 
OBJECTIVES AND ENDPOINTS .......................................................................................................................... 34 
4.1 
PRIMARY OBJECTIVE ................................................................................................................................... 34 
4.2 
SECONDARY OBJECTIVES ............................................................................................................................ 34 
4.3 
PRIMARY ENDPOINT .................................................................................................................................... 34 
4.4 
SECONDARY ENDPOINTS ............................................................................................................................. 35 
4.5 
EXPLORATORY OBJECTIVES ......................................................................................................................... 35 
5 
STUDY DESIGN ...................................................................................................................................................... 35 
5.1 
OVERALL DESIGN ....................................................................................................................................... 36 
5.2 
INVESTIGATIONAL PRODUCT ........................................................................................................................ 36 
5.3 
COMPARATOR ............................................................................................................................................ 37 
5.4 
END OF STUDY AND STUDY DURATION ......................................................................................................... 39 
6 
STUDY POPULATION ........................................................................................................................................... 39 
6.1 
SITE AND PARTICIPANT RECRUITMENT ......................................................................................................... 39 
6.2 
INCLUSION CRITERIA ................................................................................................................................... 45 
6.3 
EXCLUSION CRITERIA .................................................................................................................................. 45 
6.4 
JUSTIFICATION OF INCLUSION AND EXCLUSION CRITERIA ............................................................................... 46 
6.5 
PARTICIPANT IDENTIFICATION ...................................................................................................................... 46 
6.6 
SCREEN FAILURES ...................................................................................................................................... 46 
6.7 
CO-ENROLMENT ......................................................................................................................................... 46 
6.8 
ENDPOINT CASE DEFINITIONS ..................................................................................................................... 46 
6.8.1 Clinical Endpoints ................................................................................................................................. 47 
6.8.2 Health economics Endpoints (N=200 participants). ............................................................................. 47 
7 
DISCONTINUATION/WITHDRAWAL ................................................................................................................... 47 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 7 of 151                        
 
7.1 
LOSS TO FOLLOW-UP .................................................................................................................................. 48 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................................................................... 48 
8.1 
SCREENING AND BASELINE ASSESSMENTS .................................................................................................. 48 
8.1.1 Demographics ...................................................................................................................................... 48 
8.1.2 Relevant medical and surgical history/current medical conditions including treatment ....................... 49 
8.2 
SAFETY ASSESSMENTS ............................................................................................................................... 49 
8.2.1 Physical examination ............................................................................................................................ 49 
8.2.2 Height and weight ................................................................................................................................. 49 
8.2.3 Vital signs ............................................................................................................................................. 49 
8.3 
EFFICACY ASSESSMENTS ............................................................................................................................ 49 
8.3.1 Patient Reported Outcomes ................................................................................................................. 49 
9 
STUDY TREATMENT/INVESTIGATIONAL PRODUCTS/DEVICES ................................................................. 50 
9.1 
BUDESONIDE-FORMOTEROL ........................................................................................................................ 50 
9.1.1 Packaging, labelling, storage and accountability ................................................................................. 50 
9.1.2 Overdose .............................................................................................................................................. 52 
9.1.3 Returns ................................................................................................................................................. 52 
9.1.4 Concomitant treatments ....................................................................................................................... 52 
9.1.5 Post-trial access ................................................................................................................................... 52 
9.2 
RESEARCH CAPACITY STRENGTHENING ....................................................................................................... 53 
10 
SAFETY CONSIDERATIONS ................................................................................................................................ 53 
10.1 
RESPONSIBILITIES FOR ENSURING THE SAFETY OF STUDY PARTICIPANTS...................................................... 53 
10.1.1 
Principal investigator ........................................................................................................................ 53 
10.1.2 
Study Sponsor .................................................................................................................................. 53 
10.1.3 
Study Funder .................................................................................................................................... 53 
10.1.4 
Safety Review Committee ................................................................................................................ 54 
10.1.5 
Data and Safety Monitoring Board ................................................................................................... 54 
10.2 
ADVERSE EVENTS ....................................................................................................................................... 56 
10.2.1 
Definitions ......................................................................................................................................... 56 
10.2.2 
Assessment and recording of adverse events ................................................................................. 57 
10.2.3 
Reporting of serious adverse events ................................................................................................ 60 
10.2.4 
Pregnancy ........................................................................................................................................ 60 
10.2.5 
Assessment and recording of adverse events ................................................................................. 61 
11 
STUDY LIMITATIONS ............................................................................................................................................ 61 
12 
STATISTICAL CONSIDERATIONS ...................................................................................................................... 62 
13 
ETHICAL CONSIDERATIONS .............................................................................................................................. 63 
13.1 
REGULATORY AND ETHICAL CONSIDERATIONS ............................................................................................. 63 
13.2 
INFORMED CONSENT PROCESS ................................................................................................................... 63 
13.3 
STUDY RECORDS AND CONFIDENTIALITY...................................................................................................... 64 
13.4 
COMPENSATION FOR INJURY ....................................................................................................................... 65 
13.5 
PARTICIPANT REMUNERATION ..................................................................................................................... 65 
13.6 
BUDGET ..................................................................................................................................................... 65 
13.7 
PROTOCOL AMENDMENTS ........................................................................................................................... 66 
13.8 
CLINICAL DATA RECORDS ........................................................................................................................... 66 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 8 of 151                        
 
13.9 
RECORD RETENTION .................................................................................................................................. 66 
13.10 
DISCONTINUATION OF THE STUDY ............................................................................................................ 67 
13.11 
PUBLICATION POLICY .............................................................................................................................. 67 
13.12 
STUDY AUDITS ....................................................................................................................................... 67 
14 
REFERENCES ........................................................................................................................................................ 68 
15 
APPENDICES .......................................................................................................................................................... 70 
15.1 
APPENDIX 1: STUDY SCREENING QUESTIONNAIRE FOR LESS THAN 18 YEARS ................................................. 70 
15.2 
APPENDIX 2: STUDY SCREENING QUESTIONNAIRE FOR 18 YEARS .................. ERROR! BOOKMARK NOT DEFINED. 
15.3 
APPENDIX 3: PATIENT INFORMATION AND CONSENT FORM ............................................................................. 73 
15.4 
APPENDIX 4: PATIENT INFORMATION AND PARENTS/GUARDIAN CONSENT ....................................................... 83 
15.5 
APPENDIX 5: PATIENT INFORMATION AND ASSENT ......................................................................................... 93 
15.6 
APPENDIX 6: ASTHMA SCREENING QUESTIONNAIRE ...................................................................................... 98 
15.7 
APPENDIX 7: BACKGROUND INFORMATION.................................................................................................. 100 
15.8 
APPENDIX 8: CHILDHOOD ASTHMA CONTROL TEST .................................................................................... 105 
15.9 
APPENDIX 9: ASTHMA CONTROL TEST ....................................................................................................... 109 
15.10 
APPENDIX 10: QUALITY OF LIFE QUESTIONNAIRE .................................................................................... 112 
15.11 
APPENDIX 11: SCHEDULED TELEPHONIC FOLLOW-UP .............................................................................. 117 
15.12 
APPENDIX 12: SCHEDULE FOLLOW-UP VISIT ........................................................................................... 120 
15.13 
APPENDIX 13: ASTHMA DIARY NATIONAL ASTHMA EDUCATION PROGRAMME (NAEP) .............................. 124 
15.14 
APPENDIX 14: THE ECONOMIC IMPACT OF ASTHMA TOOL ........................................................................ 127 
15.15 
APPENDIX 15: CHILD-FRIENDLY EQ-5D-Y ........................................................................................ 136 
15.16 
APPENDIX 16: HEALTH FACILITY COSTING TOOL FOR ASTHMA .................................................................. 140 
15.17 
APPENDIX 17: ASTHMA ADVERT ............................................................................................................ 146 
15.18 
APPENDIX: 18 SMART ACTION PLAN .................................................................................................. 147 
15.19 
APPENDIX 19: NAEP ASTHMA ACTION PLAN .......................................................................................... 149 
15.20 
APPENDIX 20: NAEP MEDICINE POSTER ................................................................................................ 151 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 9 of 151                        
 
 
1 
Abbreviations and Definition of terms 
 
Abbreviation 
Definition 
ABPI 
Association of British Pharmaceutical Industry 
ACDIS 
Africa Centre Demographic Information System 
ACT 
Asthma Control Test 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AHRI 
Africa Health Research Institute 
AHRI Link 
Africa Health Research Institute Link 
ATP 
Adenosine Triphosphate 
ATS 
American Thoracic Society 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BREC 
Biomedical Research Ethics Committee 
cACT 
Childhood Asthma Control Test 
cAMP 
Cyclic Adenosine Monophosphate 
CDMS 
Clinical Data Management System 
COPD 
Chronic Obstructive Pulmonary Disease 
CTU 
Clinical Trials Unit 
CYP3A4 
Cytochrome P450 3A4 
DAIDS 
Division of Allergy and Infectious Diseases 
DMP 
Data Management Plan 
DPI 
Dry Powder Inhaler 
DSA 
Demographic Surveillance Area 
DSID 
Directory Services Identifier 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EOS 
End Of Study 
ERS 
European Respiratory Society 
EQ-5D-Y 
Euro Quality of Life Youth version 
FEV1 
Forced Expiratory Volume in one second 
GINA 
Global Initiative for Asthma 
HDSS 
Health Demographic Surveillance System 
HIV 
Human Immunodeficiency Virus 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 10 of 151                        
 
HPA 
Hypothalamus Pituitary Adrenal Axis 
ICF 
Informed Consent Form 
ICH GCP 
International Conference on Harmonization Good Clinical Practice 
ICS 
Inhaled Corticosteroids 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
Kg 
Kilogram 
LABA 
Long-Acting Beta -2- Agonist 
LMIC 
Low to Middle Income Countries 
MART 
Maintenance and Reliever Therapy 
MoH 
Minister of Health 
MRHDID 
Maximum Recommended Human Daily Inhalation Dose 
NCD 
Non-Communicable Disease 
NIHR 
National Institute of Health and Care Research 
PAQLQ 
Paediatric Asthma Quality of Life Questionnaire 
PEFR 
Peak Expiratory Flow Rate 
PIP 
Population Intervention Platform 
PIPSA 
Population Intervention Program Surveillance Area 
pMDI 
Pressurised Metered Dose Inhaler 
PRN 
Pro Re Nata (As needed) 
QALY 
Quality Adjusted Life Year 
QOL 
Quality of Life 
QTc 
Corrected QT interval 
SAE 
Serious Adverse Events 
SAGCP 
South African Good Clinical Practice 
SAHPRA 
South African Health Products Regulatory Authority 
SAP 
Statistical Analysis Plan 
SAPRIN 
South African Population Research Infrastructure Network 
SDG 
Sustainable Development Goals 
SOE 
Schedule of Events 
SPO2 
Saturated Partial Pressure of Oxygen  
SRC 
Scientific Review Committee 
SRT 
SubRip Text 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
TEAE 
Treatment Emergent Adverse Event 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 11 of 151                        
 
TIE 
Time, Inconvenience and Expense 
TMC 
Trial Management Committee 
TMF 
Trial Master File 
TSC 
Trial Steering Committee 
SABA 
Short Acting Beta-2- Agonist 
SMART 
Symbicort Maintenance and Reliever Therapy 
UKZN 
University of KwaZulu-Natal 
US 
United States 
WHO 
World Health Organisation 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 12 of 151                        
 
2 
Protocol Summary 
2.1 
Synopsis 
 
Protocol Title 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Phase 3 Randomised Open-Label 
Controlled Trial. 
Short Title 
AIR-SA 001 
Rationale 
Over the last two decades non-communicable diseases (NCDs) have 
been rising in sub-Saharan Africa, and NCDs are set to overtake 
communicable, maternal, neonatal, and nutritional diseases combined 
as the leading cause of mortality in sub-Saharan Africa by 2030.1 Many 
NCDs have their roots in childhood with lifestyle changes in 
combination with an increasing median population age in Africa making 
a further dramatic rise in NCDs in Africa’s near future highly likely.2 The 
World Health Organization (WHO) now considers the prevention and 
control of NCDs as an urgent development issue and essential to the 
achievement of the Sustainable Development Goals (SDG) and this 
can only be achieved with childhood interventions.3, 4 The 2018 WHO 
report on NCDs, reported 3.8 million deaths annually from non-
communicable respiratory diseases (asthma and chronic obstructive 
pulmonary disease), with 78% of deaths in low-income and middle-
income countries (LMICs). Asthma morbidity and mortality are 
preventable with inhaled therapies-however, there is lack of evidence 
on how to deliver these in an affordable and effective way 
The WHO highlights asthma as an under-appreciated cause of poverty 
in LMICs that retards economic and social development, erodes the 
health and well-being of those affected and has a negative impact on 
families and societies. Asthma aggravates poverty and poverty 
aggravates asthma.5 Children miss out on education, adults lose days 
at work and the costs of drugs, emergency visits, and hospitalisation 
are major financial burdens, not only for individuals/families but also for 
struggling health systems. 
In South Africa, asthma is the most common NCD in childhood affecting 
1 in 5 children with a prevalence of asthma symptoms at 21% in 
adolescence.6 Despite the availability of asthma medicines in the 
Essential Medicines List, asthmatic children report having severe 
asthma symptoms in over 50% of those with asthma. South Africa still 
reports the fourth highest mortality rate globally. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 13 of 151                        
 
The core to asthma management includes use of chronic use of anti-
inflammatory inhaled corticosteroids to address the inflammatory 
process in the airways (maintenance) and bronchodilators (relievers) 
for relief of the bronchospasm. Many studies have shown that asthma 
mortality is linked to poor use of anti-inflammatory inhaler treatment and 
over-reliance on short- acting β2 bronchodilator reliever therapy to treat 
asthma exacerbations. In many LMICs including South Africa, the use 
of controller treatment use of anti-inflammatory inhalers is limited, with 
only 40% of people with severe asthma symptoms using regular ICS for 
chronic asthma treatment, but with over 89% using their short-acting β2 
agonists. There is a large body of evidence showing that overuse of 
SABAs is linked with asthma mortality and poorer outcomes. 
The combination treatment with budesonide/formoterol for the 
management of asthma has transformed asthma treatment in high-
income countries (HIC), where it is recommended in the very first step 
of asthma treatment as both an anti-inflammatory and reliever therapy. 
With the “as needed” use of budesonide/formoterol, asthmatics benefit 
from the additional dose of a maintenance anti-inflammatory dose, 
which improves symptom control and reduces exacerbations. This 
approach has not been adopted in many LMICs related to access to 
budesonide/formoterol and its cost and therefore, people in LMICs are 
relegated to use of Track 2 of Global Initiative of Asthma (GINA) 
treatment which still suggests the use of separate anti-inflammatory 
and reliever inhalers. 
To address this gap, a large body of randomised controlled clinical trial 
evidence (SYGMA7, 8, Novel START9, PRACTICAL7, and several trials 
of SMART9, 10, 11, 12), have shown that use of budesonide/formoterol as 
needed (for exacerbations) and for long-term controller treatment 
compared to separate inhaled corticosteroid and short-acting 
bronchodilators, reduces the number of asthma exacerbations and 
improves quality of life. The trials have though been limited in that there 
is no data on the cost-effectiveness of this approach in lower resourced 
settings and limited data from small studies participant numbers (<100) 
of this approach in children 6-11 years of age. Based on this, the 
approach of using budesonide/formoterol has not been recommended 
by the Global Initiative of Asthma (GINA) strategy for global asthma 
management in Step 1 and 2 of treatment in children 6-11 years of age 
both in HIC and LMICs, but rather on the higher steps of asthma 
treatment where symptoms are more severe. 
We therefore propose in a randomised controlled trial to assess the 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 14 of 151                        
 
efficacy of budesonide/formoterol compared to the standard of care 
(separate inhaled corticosteroid and bronchodilator) inhaler approach to 
prevent asthma exacerbations, improve asthma control and quality of 
life and to also assess the cost-effectiveness of budesonide/formoterol 
compared to standard of care in children and adolescents in South 
Africa. The data will be novel as we will for the first time include a large 
number of children in a clinical trial comparing the two approaches, to 
provide definitive evidence of the efficacy and cost-effectiveness of this 
approach in children and adolescents. 
Overall Design 
This is a Phase 3 single-centre open label randomised controlled trial 
with two equal sized groups to assess the efficacy of 
budesonide/formoterol 80/4.5 (6-11 years) and 160/4.5 (12-18 years) 
compared to the standard of care in reducing asthma exacerbations 
over 52 weeks 
Children and adolescents with a diagnosis of asthma or newly 
diagnosed with asthma will be screened for eligibility for enrolment. 
Those who had an asthma exacerbation in the previous year will be 
randomised 1:1, to either receive budesonide/formoterol inhaler for both 
symptom relief and for chronic anti- inflammatory maintenance therapy 
or the standard of care which is separate inhalers for symptom relief 
(short acting bronchodilator salbutamol) and chronic maintenance 
therapy with inhaled corticosteroids (beclomethasone or budesonide) 
and/or long-acting beta agonists or montelukast as determined by 
treating physicians. All asthma exacerbations and clinic/hospital 
admissions will be recorded for the duration of the 52-week follow-up. 
Participants will be followed up at 13, 26, 39 and 52 weeks. The 13- 
and 39-week visit will be telephonic visits to capture the primary end-
point i.e. asthma exacerbations. Adverse events and medication 
changes data will also be collected. 
An independent Data and Safety Monitoring Board (DSMB) will be 
convened for this study with expertise in asthma and asthma clinical 
trials. The purpose of the DSMB will be to monitor the study for safety 
and operational futility with pre-defined stopping criteria. In addition, a 
Trial Steering Committee (TSC) will also provide overall supervision of 
the trial and ensure the trial is delivered in accordance with ICH-GCP. 
The TSC has been established with an independent Chair and include 
additional independent members including an observer early career 
researcher. Representatives of the Trial Funder (NIHR) and Sponsor 
(AHRI) will be invited to all TSC meetings. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 15 of 151                        
 
Sample 
population 
Children and adolescents age 6-18 years with a diagnosis of asthma 
and at least one asthma exacerbation in the previous 12 months. 
Sample size 
1038 participants will be enrolled into the study (519 per treatment 
arm). 
Recruitment 
Participants will be recruited from the network of AHRI Somkhele CTU 
and its primary health care clinics (n=6). 
Participants who meet the eligibility criteria will be referred to the  study 
staff for eligibility screening and enrolment in the trial. 
Study Duration 
52 weeks per participant 
Inclusion criteria 
• 
Age for inclusion children and adolescents 6-18 years at the 
time of consent 
• 
Known asthmatic on treatment. 
• 
Newly diagnosed asthma based on investigator review and/or 
medical report. 
• 
All patients will have their asthma diagnosis confirmed (both 
new or known asthmatic patients) by either spirometry with 
reversibility or excessive diurnal variability by PEFR twice daily 
over 2 weeks. 
• 
Ability to perform Peak Expiratory Flow rate and/or 
bronchodilator reversibility testing. 
• 
Only participants with mild, or moderate asthma , based on 
medical history 
• 
At least one exacerbation of asthma in the past year as defined 
by an event requiring treatment with systemic corticosteroids for 
≥3 days and/or a hospitalisation/emergency room visit for 
asthma requiring treatment with systemic corticosteroids. 
• 
Written consent from the participant or parent/guardian and 
assent from study participants where applicable. 
• 
Participant and/or parent/guardian agrees to comply with the 
study procedures, including the completion of the visits and be 
available for contact for telephonically for the non-contact visits. 
Exclusion criteria 
• 
Tuberculosis (TB): active TB disease and contact with people 
with active TB disease in the last 6 months. 
• 
Chronic sputum expectoration, chest pain, shortness of breath, 
dizziness, or light-headedness in the last 2 months. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 16 of 151                        
 
• 
Cardiac arrythmia. 
• 
Chronic conditions: thyrotoxicosis, phaeochromocytoma, 
cardiovascular disease, severe hypertension. 
• 
Uncontrolled diabetes mellitus 
• 
Patients with Peak Expiratory Flow Rate < 50% of 
predicted , as these would be classified as severe 
asthmatics. 
• 
Patients with any history of life-threatening asthma, 
defined as any history of significant asthma episode(s) 
requiring intubation associated with hypercapnia, 
respiratory arrest, hypoxic seizures, or asthma related 
syncopal episode(s). 
• 
Any use of biological therapy or immunomodulatory therapy 
such as methotrexate or regular oral prednisolone for the 
asthma management (STEP 5 GINA therapy). 
• 
Any surgical or medical condition that would significantly alter 
the absorption, distribution, metabolism or excretion of the IMP 
which may jeopardise the safety of the participants. The 
investigator should make this determination in consideration of 
the volunteer’s medical history. 
• 
Any physical, mental or social condition, laboratory abnormality 
of history of illness that in the investigator’s judgement might 
jeopardise the safety of the participant in the context of the 
study or might interfere with study procedures or the ability of 
the participant to adhere to and complete the study. The 
investigator should make this determination consideration of the 
volunteer’s medical history. 
• 
Inability to present for follow-up or leaving the study area within 
12 months of enrolment. 
Investigational 
Product 
Budesonide-formoterol fumarate dihydrate at two dose strengths 80/4.5 
and 160/4.5 administered via a pressurized metered dose inhaler 
(pMDI) or dry powder inhaler (DPI), respectively. The dosing will be 
dependent on asthma symptom severity ranging from 1 dose as 
needed and titrated up or down depending on asthma control.  
• 
step 1-2: 1-dose as required. 
• 
step 3: 1 dose twice a day and 1 dose as required  
• 
step 4: 2 doses twice a day and 1 dose as required 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 17 of 151                        
 
Objectives 
The primary objective is to assess the efficacy of a combination 
corticosteroid/rapid-onset long-acting ß2 agonist (ICS/LABA) 
budesonide/formoterol inhaler ‘as required’ or, if clinically indicated, 
‘both as required, and regularly’ to reduce asthma exacerbations 
compared to the standard of care for asthma. 
Secondary 
objectives 
The secondary objectives are to assess the cost-effectiveness of 
budesonide/formoterol compared to the standard of care from the 
individual, household, health system level and quality of life and to 
assess the impact of budesonide/formoterol compared to standard of 
care on quality of life. 
Primary Endpoint The primary endpoint will be the number of severe asthma 
exacerbations in the treatment year, defined as “events requiring 
systemic corticosteroids for three or more days and/or a 
hospitalisation/emergency room visit for asthma requiring systemic 
corticosteroids.” 
Secondary 
Endpoints 
Clinical Endpoints 
• 
Asthma Control Test (ACT) for ≥ 12 years or Childhood ACT 
(cACT) for children 6-11 years. 
• 
Paediatric Asthma Quality of Life Questionnaire (PAQLQ) 
• 
Peak Expiratory Flow Rate  
• 
School or work absence for carers/guardians 
• 
Adverse events (AE) 
• 
Serious Adverse Events (SAEs). 
Health economics Endpoints (N=200 participants) 
• 
Quality of survival estimates: time to first exacerbation, health-
related quality of life using validated generic preference-based 
measures of health (EQ-5D-Y), adverse effects, school, work, 
household labour absences. 
• 
Household-level economic impact by socio-economic stratum 
(World Bank approach): out-of-pocket expenditures, loss of 
household productivity time and income (productivity losses), 
borrowing, and education losses. 
• 
Health system: health care costs related to in/out patient 
treatment of both the usual care and the intervention, including 
overhead costs, as well as cost savings from reduced 
exacerbations due to intervention and cost per quality-adjusted 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 18 of 151                        
 
life year (QALY) gained. 
• 
Utility preferences as derived from the EQ-5D-Y questionnaire. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 19 of 151                                
 
2.2 
Schedule of Events 
Table 1. Schedule of events 
 
Visit 1 
Screening and 
enrolment 
Visit 2 
First follow up 
(Telephonic)1 
Visit 3 
Second follow up 
(Clinic visit) 
Visit 4 
Third follow up 
visit 
(Telephonic)1 
Visit 5 
End of study 
(Clinic visit) 
Visit week and study window 
1 
13 ± 2 weeks 
26 ± 2 weeks 
39 ± 2 weeks 
52 ± 2 weeks 
Informed consent 
x 
 
 
 
 
Medical history and demographics 
x 
 
x 
 
x 
Vitals, weight and height 
x 
 
x 
 
x 
Physical examination 
x 
 
x 
 
x 
Inclusion/exclusion criteria check 
x 
 
 
 
 
Randomisation 
x 
 
 
 
 
Asthma review 
i) 
Asthma exacerbation (attacks) 
ii) 
Medication changes (including use of additional 
medications) 
iii) 
Days lost at school 
iv) 
Days lost from work for asthma parent(s)/guardian 
v) 
Serious adverse events 
vi) 
Adverse events 
x 
x 
x 
x 
x 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 20 of 151                                
 
 
 
ACT/ cACT score1 
x 
 
x 
 
x 
PAQLQ 
x 
 
x 
 
x 
EQ-5D-Y ¶ 
x 
 
 
 
x 
Health economics questionnaires2 
x 
 
x 
 
x 
Spirometry and bronchodilator reversibility testing 
x 
 
 
 
 
Spirometry 
x 
 
x 
 
x 
Peak Expiratory Flow rate (PEFR)3 
x 
 
 
 
 
Written asthma action plan and diary assessments4 
x 
 
x 
 
x 
Inhaler technique assessment and demonstration 
x 
 
x 
 
x 
Dispense trial medication 
x 
 
x 
 
x 
Participant reimbursement 
x 
 
x 
 
x 
1 This is based on feasibility and the pragmatic design of the study. AHRI has an excellent telephonic system with experienced research nurses who are well equipment to 
conduct telephonic consultations with study participants and all participants who require assessment by the study team and the research doctors will be required to present to the 
research facility.  
2 EQ-5D-Y questionnaire only to sub-set of participants for follow-up (n=200), with health economics outcome data 
3 Peak expiratory flow rate (Measured with MicroLife AG Asthma Analyser electronic peak flow meter version 3.2.6) 
4 All participants will be provided and Asthma Action Plan (adapted from the Modified from Australian action plan with permission from National Asthma Council Australia and 
AstraZeneca Australia) the SMART Action Plan specifically for Budesonide/Formoterol and the National Asthma Education Program Action Plan (standard of Care). 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 21 of 151                        
 
3 
INTRODUCTION 
3.1 
Background 
Africa comprises 15% of the world’s population but bears 25% of the global disease burden and 
produces only 2% of the world’s research output.13 There is therefore, urgency to develop local 
research capacity to inform context-specific policy decisions. Asthma is the commonest chronic 
disease in children globally affecting 1 in 10 children and adolescents. South Africa has the 
highest asthma prevalence in Africa with 1 in 5 (21%) adolescents exhibiting asthma symptoms.6 
The core to asthma management includes use of chronic anti-inflammatory inhaled 
corticosteroids to address the inflammatory process in the airways (maintenance) and 
bronchodilators (relievers) for relief of the bronchospasm. Many studies have shown that asthma 
mortality is linked to poor use of anti-inflammatory inhaler treatment and over-reliance on short-
acting β2 bronchodilator reliever therapy to treat asthma exacerbations. In many LMICs, 
including South Africa, the use of controller anti-inflammatory inhalers is limited, with only 40% 
of people with severe asthma symptoms using regular inhaled corticosteroids (ICS) for chronic 
asthma treatment, but with over 89% using their short-acting β2 agonists. There is a large body 
of evidence showing that overuse of Short acting beta-2- agonist (SABA) is linked with asthma 
mortality and poorer outcomes. 
 
The combination treatment with budesonide/formoterol for the management of asthma has 
transformed asthma treatment in high-income countries (HIC), where it is recommended in the 
very first step of asthma treatment as both an anti-inflammatory and reliever therapy. With the 
“as needed” use of budesonide/formoterol, asthmatics benefit from the additional dose of a 
maintenance anti-inflammatory dose, which improves symptom control and reduces 
exacerbations. This approach has not been adopted in many LMICs related to issues of access 
and affordability of budesonide/formoterol. Therefore, people in LMICs are relegated to use of 
Track 2 of Global Initiative of Asthma (GINA) treatment, which still suggests the use of separate 
anti-inflammatory and reliever inhalers. 
 
There is a fundamental lack of clinical trial evidence to inform clinical care or policy for people 
with asthma in sub-Saharan Africa and South Africa. The proposed trial will provide important 
new clinical trial evidence about the clinical- and cost-effectiveness of a simple, pragmatic and 
intuitive approach with budesonide/formoterol compared to the standard of care in South Africa, 
and importantly assess the cost-effectiveness of this approach in a paediatric population where 
there is limited data and no recommendation for this approach in children 6-11 years of age.14 
The experimental group participants will use a single inhaled corticosteroid/fast-acting long 
acting β2 agonists (budesonide/formoterol) inhaler initially just ‘as required’ and then titrated up 
to ‘both as required, and regularly’ if they remain symptomatic or have asthma exacerbations. 
This single ICS/LABA inhaler approach has the potential to transform asthma care by becoming 
the standard of care in South Africa, the wider sub-Saharan African region and other areas of 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 22 of 151                        
 
the world where asthma management is inadequate because of the multi-faceted consequences 
of resource limitations.14 
3.2 
Study Rationale 
Over the last two decades non-communicable diseases (NCDs) have been rising in sub- 
Saharan Africa, and NCDs are set to overtake communicable, maternal, neonatal, and 
nutritional diseases combined as the leading cause of mortality in sub-Saharan Africa by 2030.1 
Many NCDs have their roots in childhood with lifestyle changes in combination with an 
increasing median population age in Africa making a further dramatic rise in NCDs in Africa’s 
near future highly likely.2 The World Health Organization (WHO) now considers the prevention 
and control of NCDs as an urgent development issue and essential to the achievement of the 
Sustainable Development Goals (SDG) and this can only be achieved with childhood 
interventions.3, 4 The 2018 WHO report on NCDs, reported 3.8 million deaths annually from non-
communicable respiratory diseases (asthma and chronic obstructive pulmonary diseases), with 
78% of deaths in low-income and middle-income countries (LMICs). Asthma morbidity and 
mortality are preventable with inhaled therapies-however, there is lack of evidence on how to 
deliver these in an affordable and effective way. 
 
The WHO highlights asthma as an under-appreciated cause of poverty in LMICs that retards 
economic and social development, erodes the health and well-being of those affected and has a 
negative impact on families and societies. Asthma aggravates poverty and poverty aggravates 
asthma.5 Children miss out on education, adults lose days at work and the costs of drugs, 
emergency visits, and hospitalisation are major financial burdens, not only for 
individuals/families but also for struggling health systems. Of particular concern, is that asthma 
prevalence and burden is increasing across Africa as a consequence of urbanisation and 
westernisation. In Africa in 1990, about 11.7% (74 million including 34.1 million children) of the 
population had asthma; by 2010 this had increased to 12.8% (119 million including 49.7 million 
children).1 
 
The WHO recognises that in Africa, asthma is underdiagnosed and undertreated and 
consequently the burden of severe asthma symptoms and mortality rates are disproportionately 
high.11 In South Africa, half of all children with asthma symptoms have severe asthma symptoms 
with less than half of these using anti-inflammatory inhalers i.e. ICS for asthma management. 
Safe, effective inhaled asthma treatments were developed over half a century ago but a large 
proportion of children and adolescents with asthma in LMICs have yet to benefit, leading to 
ongoing avoidable morbidity and mortality. An important principle of asthma treatment is the 
step-wise approach whereby treatment is stepped up and down in response to asthma control 
and exacerbation risk. Current South African national asthma treatment approaches start with 
reliever medication (e.g. inhaled salbutamol) used ‘as required’ at the lowest step with the 
addition of regular preventer medication (e.g. ICS) and other therapies including long-acting β2 
agonists (LABA) at higher steps or leukotriene receptor antagonists in children.14 However, 
treatment can become complex especially when several inhalers are used which can affect 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 23 of 151                        
 
adherence, with over-use of SABAs being identified as a key barrier to achieving asthma control. 
15 
 
Over the last decade a considerable body of clinical trial and clinical practice evidence has 
emerged supporting the efficacy and safety of combination inhalers containing an ICS and a 
rapid-onset LABA for maintenance and reliever therapy known as single maintenance and 
reliever therapy (SMART).9, 10, 11, 12 In addition, the SYGMA 1 trial demonstrated that the use of 
‘as required’ budesonide/formoterol compared with regular budesonide in patients aged ≥12 
years, was non-inferior for asthma exacerbation prevention in patients with mild asthma.9 The 
SYGMA 2 trial10 and the more real-life pragmatic Novel START and PRACTICAL15, 16 trials have 
provided further compelling evidence for the anti-inflammatory reliever approach and 
consequently, single ICS/LABA therapy from the outset of treatment initiation is now being used 
in HICs from the first step in asthma treatment. Although GINA recommends the use of this 
approach in adolescents, this is based on very small contributions of adolescents to the overall 
study populations.14  
 
The proposed trial will evaluate, for the first time, a highly pragmatic approach to asthma 
treatment in a South African setting and in younger children 6-11 years, building on the findings 
of SYGMA9, 10, Novel START15, PRACTICAL16, and several trials of SMART.9, 10, 15, 16 Use of a 
single ICS/LABA inhaler in the way we propose, has the potential to improve compliance, reduce 
exacerbations, reduce the cost of long-term treatment and improve the quality of life for children 
and adolescents with asthma in South Africa, that can potentially be generalised to other low-
resourced settings at a primary care level. 
 
Relevant systematic reviews and the need for this trial in light of these 
 
The fundamental lack of clinical trials of asthma treatments in the paediatric age group, mean 
there is also a lack of relevant systematic reviews of clinical trials evidence. Although also 
limited, we have a better understanding of the epidemiology of asthma in sub-Saharan Africa 
and this has been subject to systematic review: a 2013 systematic review of the prevalence of 
asthma in Africa concluded there were few studies and indications that asthma was both under-
reported and increasing in prevalence.1 In marked contrast, there is a substantial body of clinical 
trials evidence relating to asthma treatments in high-resource settings including multiple trials of 
maintenance and reliever therapy (MART) as summarised above. The most recent systematic 
review and meta-analysis of MART identified 16 randomised clinical trials involving 22,748 
participants and found that MART, compared with the same dose of ICS and LABA as 
maintenance treatment, was associated with a reduced risk of asthma exacerbations (RR 0.68; 
95% CI, 0.58 to 0.80).8 Whilst it seems likely that such clinical benefits would be seen if MART 
was available in South Africa at the primary care level, the lack of clinical trial evidence relating 
to the clinical- and cost-effectiveness of MART is a major road block to informing clinical care 
and policy- and decision-making in South Africa and this means that adolescents with asthma do 
not benefit from this approach and it’s not included in the South African Paediatric and 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 24 of 151                        
 
Adolescent guidelines.17 Secondly, the lack of data of the use of this approach means that 
budesonide/formoterol is only recommended for children with moderate-severe asthma only 
from GINA Step 3, based on the lack of evidence of this approach in children 6-11 years of age.  
 
The proposed AIR-South Africa-001 trial, offers the opportunity to change this situation and 
evaluate the MART approach in a highly pragmatic way with clear pathways to delivering a step-
change in access to quality assured asthma treatments for the poorest in the South African 
population who may have the least access to regular asthma care. The setting where the study 
is conducted lends itself to the practicality of this approach to individuals in a primary care 
setting in a rural population. 
 
High-quality clinical trial evidence of the health and economic impacts seen when children and 
adolescents with asthma adopt the proposed single inhaler-based approach to asthma 
management is needed to inform policy- and decision-making across health, commercial, 
development and community sectors at international, regional and local levels. The results of 
this trial will benefit international (e.g. WHO) policy- and decision-makers by contributing new 
evidence about the health and economic impacts of this approach to asthma management of 
broadly generalizable relevance. It will be relevant to Ministers of Health (MoH) in South Africa 
and other LMICs, and will have new effectiveness, economic data to guide decisions about 
funding asthma management programmes for improving lung health. 
 
3.3 
Investigational Medicinal Product 
3.3.1 Budesonide/ Formoterol 
The Investigational Medicinal Product (IMP) consists of a combination of Budesonide 
(corticosteroid) and Formoterol Furamate (fast-acting β2 agonist) dihydrate. The IMP is 
currently available and registered in dry powder form turbuhaler (Symbicort ) and a 
pressurised metered dose inhaler (Vannair). 
 
The recommended doses are pMDI/DPI 80/4.5 1-2 puffs twice daily OR 1 puff as needed (a 
maximum daily dose of 8 puffs) for children 6-11 years of age and 160/4.5 1-2 inhalations 
twice daily or 1 puff as needed (a maximum daily dose of 12 puffs) for adolescents 12-18 years 
 
Budesonide is a mixture of two isomers: Pregna-1,4-diene-3,20-dione,16,17- 
butylidenebis(oxy)-11,21-dihydroxy-,[11β,16α(R)] and Pregna-1,4-diene-3,20-dione,16,17- 
butylidenebis(oxy)-11,21-dihydroxy-,[11β,16α(S)]. Budesonide is a glucocorticosteroid and 
consists of a 1:1 mixture of two epimers, 22R and 22S. It is a white to off-white crystalline 
powder and is freely soluble in chloroform, sparingly soluble in ethanol, practically insoluble in 
water and in heptane. Budesonide melts at 224°C to 231.5°C, with decomposition. 
Budesonide is an agonist of glucocorticoid receptors. Among its effects are, it controls a) the 
rate of protein synthesis, b) depresses the migration of polymorphonuclear leukocytes and 
fibroblasts, c) reverses capillary permeability and d) stabilizes the lysosomes at the cellular 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 25 of 151                        
 
level to prevent or control inflammation. It has a potent glucocorticoid activity and weak 
mineralocorticoid activity. 
 
Formoterol is a relatively selective long-acting agonist of beta2-adrenergic receptors, although 
it does carry some degree of activity at beta1 and beta3 receptors. Beta2 receptors are found 
predominantly in bronchial smooth muscle (with a relatively minor amount found in cardiac 
tissue) whereas beta1 receptors are the predominant adrenergic receptors found in the heart - 
for this reason, selectivity for beta2 receptors is desirable in the treatment of pulmonary 
diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Formoterol has 
demonstrated an approximately 200-fold greater activity at beta2 receptors over beta1 
receptors. On a molecular level, activation of beta receptors by agonists like formoterol 
stimulates intracellular adenylyl cyclase, an enzyme responsible for the conversion of ATP to 
cyclic AMP (cAMP). The increased levels of cAMP in bronchial smooth muscle tissue result in 
the relaxation of these muscles and subsequent dilation of the airways, as well as inhibition of 
the release of hypersensitivity mediators (e.g. histamine, leukotrienes) from culprit cells, 
especially mast cells. 
 
3.3.2 Summary of Preclinical studies 
3.3.2.1 General toxicity 
In animal reproduction studies, budesonide/formoterol (Symbicort), administered by the 
inhalation route, was teratogenic, embryocidal, and reduced fetal weights in rats at less than 
the maximum recommended human daily inhalation dose (MRHDID) on a mcg/m2 basis.18  
 
Budesonide alone, administered by the subcutaneous route, was teratogenic, embryocidal, 
and reduced fetal weights in rats and rabbits at less than the MRHDID, but these effects were 
not seen in rats that received inhaled doses up to 4 times the MRHDID. Studies of pregnant 
women have not shown that inhaled budesonide alone increases the risk of abnormalities 
when administered during pregnancy. Experience with oral corticosteroids suggests that 
rodents are more prone to teratogenic effects from corticosteroid exposure than humans.18 
 
Formoterol fumarate alone, administered by the oral route, was teratogenic in rats and rabbits 
at 1600 and 65,000 times the MRHDID, respectively. Formoterol fumarate was also 
embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in 
rats at 110 times the MRHDID. These adverse effects generally occurred at large multiples of 
the MRHDID when formoterol fumarate was administered by the oral route to achieve high 
systemic exposures. No teratogenic, embryocidal, or developmental effects were seen in rats 
that received inhalation doses up to 375 times the MRHDID.18, 19 
 
3.3.2.2 Carcinogenesis 
No reported carcinogenesis has been found with exposure to budesonide/formoterol.19, 20 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 26 of 151                        
 
3.3.2.3 Mutagenesis 
Formoterol 
In an embryo-fetal development study in pregnant rabbits dosed during the period of 
organogenesis from gestation days 6-18, subcapsular cysts on the liver were observed in the 
fetuses at a dose 65,000 times the MRHDID (on a mcg/m2 basis with a maternal oral dose of 
60,000 mcg/kg/day). No teratogenic effects were observed at doses up to 3800 times the 
MRHDID (on a mcg/m2 basis at maternal oral doses up to 3500 mcg/kg/day).18, 19 
 
3.3.2.4 Fertility 
Budesonide 
In a fertility and reproduction study, male rats were subcutaneously dosed for 9 weeks and 
females for 2 weeks prior to pairing and throughout the mating period. Females were dosed 
up until weaning of their offspring. Budesonide caused a decrease in prenatal viability and 
viability in the pups at birth and during lactation, along with a decrease in maternal body- 
weight gain, at doses less than the MRHDID (on a mcg/m2 basis at maternal subcutaneous 
doses of 20 mcg/kg/day and above). No such effects were noted at a dose less than the 
MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 5 mcg/kg/day).19 
 
Formoterol 
In a fertility and reproduction study, male rats were orally dosed for 9 weeks and females for 2 
weeks prior to pairing and throughout the mating period. Females were either dosed up to 
gestation day 19 or up until weaning of their offspring. Males were dosed up to 25 weeks. 
Umbilical hernia was observed in rat fetuses at oral doses 1600 times and greater than the 
MRHDID (on a mcg/m2 basis at maternal oral doses of 3000 mcg/kg/day and higher).19 
Brachygnathia was observed in rat fetuses at a dose 8000 times the MRHDID (on a mcg/m2 
basis at a maternal oral dose of 15,000 mcg/kg/day). Pregnancy was prolonged at a dose 
8000 times the MRHDID (on a mcg/m2 basis at a maternal oral dose of 15,000 mcg/kg/day). 
Fetal and pup deaths occurred at doses approximately 1600 times the MRHDID and higher 
(on a mcg/m2 basis at oral doses of 3000 mcg/kg/day and higher) during gestation.19 
 
3.3.2.5 Development 
In an embryo-fetal development study in pregnant rats dosed during the period of 
organogenesis from gestation days 6-16, budesonide/formoterol produced umbilical hernia in 
fetuses at doses less than the MRHDID (on a mcg/m2 basis at maternal inhaled doses of 
12/0.66 mcg/kg/day and above). Fetal weights were reduced at approximately 5 and 3 times 
the MRHDID, respectively (on an AUC basis at a maternal inhaled dose of 80/4.4 mcg/kg 
(budesonide/formoterol)). No teratogenic or embryocidal effects were detected at doses less 
than the MRHDID (on a mcg/m2 basis at a maternal inhaled dose of 2.5/0.14 mcg/kg/day).19 
 
Budesonide 
In an embryo-fetal development study in pregnant rabbits dosed during the period of 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 27 of 151                        
 
organogenesis from gestation days 6-18, budesonide produced fetal loss, decreased fetal 
weight, and skeletal abnormalities at doses less than the MRHDID (on a mcg/m2 basis at a 
maternal subcutaneous dose of 25 mcg/kg/day). In an embryo-fetal development study in 
pregnant rats dosed during the period of organogenesis from gestation days 6-15, 
budesonide produced similar adverse fetal effects at doses approximately 8 times the 
MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 500 mcg/kg/day).18, 19 In 
another embryo-fetal development study in pregnant rats, no teratogenic or embryocidal 
effects were seen at doses up to 4 times the MRHDID (on a mcg/m2 basis at maternal 
inhalation doses up to 250 mcg/kg/day). In a peri-and post-natal development study, rats 
dosed from gestation day 15 to postpartum day 21, budesonide had no effects on delivery, 
but did influence growth and development of offspring. Offspring survival was reduced, and 
surviving offspring had decreased mean body weights at birth and during lactation at doses 
less than the MRHDID and higher (on a mcg/m2 basis at maternal subcutaneous doses of 20 
mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.18, 19 
 
Formoterol 
In an embryo-fetal development study in pregnant rats dosed during the period of 
organogenesis from gestation days 6-15, no teratogenic, embryocidal or developmental 
effects were seen at doses up to 375 times the MRHDID (on a mcg/m² basis with maternal 
inhalation doses up to 690 mcg/kg/day). In an embryo-fetal development study in pregnant 
rabbits dosed during the period of organogenesis from gestation days 6-18, subcapsular 
cysts on the liver were observed in the fetuses at a dose 65,000 times the MRHDID (on a 
mcg/m2 basis with a maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were 
observed at doses up to 3800 times the MRHDID (on a mcg/m² basis at maternal oral doses 
up to 3500 mcg/kg/day).18, 19  
 
In a pre- and post-natal development study, pregnant female rats received formoterol at oral 
doses of 0, 210, 840, and 3400 mcg/kg/day from gestation day 6 through the lactation period. 
Pup survival was decreased from birth to postpartum day 26 at doses 110 times the MRHDID 
and higher (on a mcg/m2 basis at maternal oral doses of 210 mcg/kg/day and higher), 
although there was no evidence of a dose- response relationship. There were no treatment-
related effects on the physical, functional, and behavioral development of rat pups.19 
 
3.4 
Summary of clinical studies 
3.4.1 Pharmacokinetic properties 
Absorption 
The fixed-dose combination of budesonide and formoterol and the corresponding 
monoproducts have been shown to be bioequivalent with regard to systemic exposure of 
budesonide and formoterol, respectively. In spite of this, a small increase in cortisol 
suppression was seen after administration of the fixed-dose combination compared with the 
monoproducts. The difference is considered not to have an impact on clinical safety. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 28 of 151                        
 
There was no evidence of pharmacokinetic interactions between budesonide and formoterol.20 
 
Pharmacokinetic parameters for the respective substances were comparable after the 
administration of budesonide and formoterol as monoproducts or as the fixed-dose 
combination. For budesonide, AUC was slightly higher, rate of absorption more rapid and 
maximal plasma concentration higher after administration of the fixed combination. For 
formoterol, maximal plasma concentration was similar after administration of the fixed 
combination.20  
 
Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached 
within 30 minutes after inhalation. In studies, mean lung deposition of budesonide after 
inhalation via the powder inhaler ranged from 32% to 44% of the delivered dose. The systemic 
bioavailability is approximately 49% of the delivered dose. In children 6-16 years of age the 
lung deposition falls in the same range as in adults for the same given dose. The resulting 
plasma concentrations were not determined.20 
 
Inhaled formoterol is rapidly absorbed and the maximum plasma concentration is reached 
within 10 minutes after inhalation. In studies the mean lung deposition of formoterol after 
inhalation via the powder inhaler ranged from 28% to 49% of the delivered dose. The systemic 
bioavailability is about 61% of the delivered dose.20 
 
Distribution and biotransformation 
Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume 
of distribution is about 4 l/kg for formoterol and 3 l/kg for budesonide. Formoterol is inactivated 
via conjugation reactions (active O-demethylated and deformylated metabolites are formed, 
but they are seen mainly as inactivated conjugates). Budesonide undergoes an extensive 
degree (approximately 90%) of biotransformation on first passage through the liver to 
metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major 
metabolites, 6-beta-hydroxy-budesonide and 16-alfa-hydroxy-prednisolone, is less than 1% of 
that of budesonide. There are no indications of any metabolic interactions or any displacement 
reactions between formoterol and budesonide.20 
 
Elimination 
The major part of a dose of formoterol is transformed by liver metabolism followed by renal 
elimination. After inhalation, 8% to 13% of the delivered dose of formoterol is excreted 
unmetabolised in the urine. Formoterol has a high systemic clearance (approximately 1.4 
l/min) and the terminal elimination half-life averages 17 hours.20 
 
Budesonide is eliminated via metabolism mainly catalysed by the enzyme Cytochrome P450 
3A5 (CYP3A4). The metabolites of budesonide are eliminated in urine as such or in 
conjugated form. Only negligible amounts of unchanged budesonide have been detected in 
the urine. Budesonide has a high systemic clearance (approximately 1.2 l/min) and the plasma 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 29 of 151                        
 
elimination half-life after intravenous dosing averages 4 hours.20 
 
The pharmacokinetics of budesonide or formoterol in children and patients with renal failure 
are unknown. The exposure of budesonide and formoterol may be increased in patients with 
liver disease.20 
 
Linearity/Non-linearity 
Systemic exposure for both budesonide and formoterol correlates in a linear fashion to 
administered dose.20 
 
3.4.2 Safety 
As the study drug contains both budesonide and formoterol, the same pattern of undesirable 
effects as reported for these substances may occur. No increased incidence of adverse 
reactions has been seen following concurrent administration of the two compounds. The most 
common drug related adverse reactions are pharmacologically predictable side effects of β2 
agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear 
within a few days of treatment.20      
 
Adverse reactions, which have been associated with budesonide or formoterol, are given 
below, listed by system organ class and frequency. Frequencies are defined as: very common 
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10 000 to 
<1/1000) and very rare (<1/10 000). The most common side effects include oral candidiasis, 
headache and tremor, palpitations, mild irritation in the throat, coughing, dysphonia including 
hoarseness. Rinsing of the mouth after use minimises risk of candidiasis and dysphonia.20 
 
Table 2: Side effects of budesonide-formoterol(20) 
 
System 
Frequency 
Adverse Drug Reaction 
Infections and 
infestations 
Common 
Candida infections in the oropharynx, Pneumonia in COPD 
patients) 
Immune system 
disorders 
Rare 
Immediate and delayed hypersensitivity reactions, 
e.g. exanthema, urticaria, pruritus, dermatitis, angioedema 
and anaphylactic reaction 
Endocrine 
disorders 
Very rare 
Cushing's syndrome, adrenal suppression, growth 
retardation, decrease in bone mineral density 
Metabolism and 
nutrition disorders 
Rare 
Hypokalaemia 
Very rare 
Hyperglycaemia 
Psychiatric 
disorders 
Uncommon 
Aggression, psychomotor hyperactivity, anxiety, sleep 
disorders 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 30 of 151                        
 
Very rare 
Depression, behavioural changes (predominantly in 
children) 
Nervous system 
disorders 
Common 
Headache, tremor 
Uncommon 
Dizziness 
Very rare 
Taste disturbances 
Eye disorders 
Uncommon 
Vision blurred 
Very rare 
Cataract and glaucoma 
Cardiac disorders 
Common 
Palpitations 
Uncommon 
Tachycardia 
Rare 
Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular 
tachycardia, extrasystoles 
Very rare 
Angina pectoris. Prolongation of corrected QT (QTc) 
interval 
Vascular disorders Very rare 
Variations in blood pressure 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Common 
Mild irritation in the throat, coughing, dysphonia including 
hoarseness 
Rare 
Bronchospasm 
Gastrointestinal 
disorders 
Uncommon 
Nausea 
Skin and 
subcutaneous 
tissue disorders 
Uncommon 
Bruises 
Musculoskeletal 
and connective 
tissue disorders 
Uncommon 
Muscle cramps 
 
Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for 
prolonged periods. These effects are much less likely to occur than with oral corticosteroids. 
Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal 
suppression, growth retardation in children and adolescents, decrease in bone mineral density, 
cataract and glaucoma. Increased susceptibility to infections and impairment of the ability to 
adapt to stress may also occur. Effects are probably dependent on dose, exposure time, 
concomitant and previous steroid exposure, and individual sensitivity.20 
 
Treatment with β2 agonists may result in an increase in blood levels of insulin, free fatty acids, 
glycerol and ketone bodies.20 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 31 of 151                        
 
In paediatric participants budesonide-formoterol can affect growth and this will be monitored 
throughout the study. 
 
3.4.3 Special populations 
Budesonide-formoterol should be administered with caution in patients with thyrotoxicosis, 
phaeochromocytoma, diabetes mellitus, untreated hypokalaemia, hypertrophic obstructive 
cardiomyopathy, idiopathic sub valvular aortic stenosis, severe hypertension, aneurysm or 
other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or 
severe heart failure. Caution should be observed when treating patients with prolongation of 
the QTc-interval. Formoterol itself may induce prolongation of the QTc-interval.20 
 
Potentially serious hypokalaemia may result from high doses of β2 adrenoceptor agonists. 
Concomitant treatment of β2 adrenoceptor agonists with drugs which can induce 
hypokalaemia or potentiate a hypokalaemic effect, e.g., xanthine derivatives, steroids and 
diuretics, may add to a possible hypokalaemic effect of the β2 adrenoceptor agonist. 
Particular caution is recommended in unstable asthma with variable use of rescue 
bronchodilators, in acute severe asthma as the associated risk may be augmented by hypoxia 
and in other conditions when the likelihood for hypokalaemia is increased. It is recommended 
that serum potassium levels are monitored during these circumstances. 
As for all β2 adrenoceptor agonists, additional blood glucose controls should be considered in 
diabetic patients.20 
 
The need for, and dose of inhaled corticosteroids should be re-evaluated in patients with active 
or quiescent pulmonary tuberculosis, fungal and viral infections in the airways. 
 
Pregnancy 
For budesonide-formoterol or the concomitant treatment with formoterol and budesonide, no 
clinical data on exposed pregnancies are available. Data from an embryo-fetal development 
study in the rat, showed no evidence of any additional effect from the combination. There are 
no adequate data from use of formoterol in pregnant women. In animal studies formoterol has 
caused adverse effects in reproduction studies at very high systemic exposure levels. Data on 
approximately 2000 exposed pregnancies indicate no increased teratogenic risk associated 
with the use of inhaled budesonide.20 In animal studies glucocorticosteroids have been shown 
to induce malformations. This is not likely to be relevant for humans given recommended 
doses. Animal studies have also identified an involvement of excess prenatal glucocorticoids in 
increased risks for intrauterine growth retardation, adult cardiovascular disease and permanent 
changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at 
exposures below the teratogenic dose range.20 
 
During pregnancy, budesonide-formoterol should only be used when the benefits outweigh the 
potential risks. The lowest effective dose of budesonide needed to maintain adequate asthma 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 32 of 151                        
 
control should be used.20 
 
Breast-feeding 
Budesonide is excreted in breast milk. However, at therapeutic doses no effects on the 
suckling child are anticipated. It is not known whether formoterol passes into human breast 
milk. In rats, small amounts of formoterol have been detected in maternal milk. 
Administration of budesonide-formoterol to women who are breast-feeding should only be 
considered if the expected benefit to the mother is greater than any possible risk to the child.20 
 
3.4.4 Drug to drug interactions 
Potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, 
clarithromycin, telithromycin, nefazodone and HIV protease inhibitors) are likely to markedly 
increase plasma levels of budesonide and concomitant use should be avoided. If this is not 
possible the time interval between administration of the inhibitor and budesonide should be as 
long as possible.20 
 
The potent CYP3A4 inhibitor ketoconazole, 200 mg once daily, increased plasma levels of 
concomitantly orally administered budesonide (single dose of 3 mg) on average six-fold. 
When ketoconazole was administered 12 hours after budesonide the concentration was on 
average increased only three-fold showing that separation of the administration times can 
reduce the increase in plasma levels. Limited data about this interaction for high-dose inhaled 
budesonide indicates that marked increases in plasma levels (on average four-fold) may occur 
if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide 
(single dose of 1000 µg).20 
 
3.4.5 Summary of potential risks and benefits 
In a Phase 3 efficacy and safety study comparing budesonide-formoterol 160/9 pMDI vs. 
160/4.5 pMDI vs. budesonide 160mcg pMDI in 279 children, budesonide-formoterol 160/9 but 
not 160/4.5 resulted in increased baseline FEV1 changes compared to budesonide in children 
6-12 year of age, p=0.015. Incidence of protocol-defined asthma exacerbations and 
improvements in asthma symptom-related and quality-of-life outcomes were similar across 
treatments. There were no notable safety differences among treatments.21 In a safety, 12- 
week multi-centre randomised controlled trial comparing budesonide-formoterol pMDI and DPI 
compared to budesonide in 622 children 6-11 years of age, the pMDI showed equivalence to 
the DPI with regards to change in Peak Expiratory Flow Rates (PEFR) in both groups 29.5 vs 
30.2 l/min, 95%CI 6:0 to 4:6; p=0:78.22 
 
In a paediatric randomised controlled trial of 341 children aged 4-11 years, budesonide- 
formoterol reduced the number of exacerbations by 70-79% compared to high dose 
budesonide and also increased the time to first exacerbation, p=0.02. There was also 
improved quality of life with reduced night-time awakenings and increased growth in the 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 33 of 151                        
 
budesonide-formoterol group.23 In a randomised controlled study by Pohunek et al, in 630 
children, aged 4-11 years with asthma in a head-to-head study comparing; budesonide-
formoterol 80/4.5 vs. budesonide 100 vs. budesonide 100 and formoterol 4.5 (separate 
inhalers); budesonide/formoterol significantly improved morning PEFR, evening PEFR and 
FEV1 compared with budesonide (all p < 0.001); there was no significant difference between 
budesonide/formoterol and budesonide + formoterol in separate inhalers for these variables.24 
 
With regards to cost-effectiveness, a recent study by Buendia et al., comparing budesonide- 
formoterol SMART vs. budesonide-formoterol fixed dose combination and budesonide found 
mean QALY per patient was 0.57 and 0.56 QALYs per patient per year of SMART and fixed 
combination and 0.52 with fixed-dose budesonide.24, 25 The total mean of discounted costs per 
patient per cycle were US$111 for SMART, US$133 for fixed combination, and US$67 for 
fixed-dose budesonide. The net monetary benefit of SMART was US$12,549, US$12278 for 
fixed combination, and US$11,380 for fixed-dose budesonide.25 
 
Based on the above clinical trial data in young children 6-12 years of age and adult trial data 
which included adolescents 12-18 years in SYGMA, NOVEL START and PRACTICAL trials9, 
10, 15, 16, the evidence of benefit for use of budesonide-formoterol to improve lung function, 
reduce the number of exacerbations and improve quality of life of asthmatic children and 
adolescents indicate the benefit that potential trial participants would gain from the use of 
budesonide-formoterol compared to the current standard of care. 
  
To reduce the risk of complications and drug-to-drug interactions all volunteers with co- morbid 
conditions that will increase risk of side-effects from the IMP in a clinically significant way will 
be excluded from the study. All study participants will benefit from training on how to use the 
asthma devices i.e. pMDI and DPI and to rinse their mouths after medication use to minimise 
the most common side-effect of the IMP and standard of care inhaled corticosteroids, which is 
oral candidiasis. Appropriate inhaler technique and use of spacer devices in those on pMDI will 
also minimise the risk to study participants in both study arms for this most common side-
effect. 
 
Controlled clinical studies have shown that orally inhaled corticosteroids including budesonide, 
may cause a reduction in growth velocity in paediatric patients. This effect has been observed 
in the absence of laboratory evidence of HPA-axis suppression, suggesting that growth 
velocity is a more sensitive indicator of systemic corticosteroid exposure in paediatric patients 
than some commonly used tests of HPA-axis function. The long-term effect of this reduction in 
growth velocity associated with orally inhaled corticosteroids, including the impact on final 
height are unknown. The potential for “catch-up” growth following discontinuation of treatment 
with orally inhaled corticosteroids has not been adequately studied. 
 
In a study of asthmatic children 5 to 12 years of age, those treated with budesonide DPI 200 
mcg twice daily (n=311) had a 1.1 centimetre reduction in growth compared with those 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 34 of 151                        
 
receiving placebo (n=418) at the end of one year; the difference between these two treatment 
groups did not increase further over three years of additional treatment. By the end of 4 years, 
children treated with budesonide DPI and children treated with placebo had similar growth 
velocities.26 Conclusions drawn from this study may be confounded by the unequal use of 
corticosteroids in the treatment groups and inclusion of data from patients attaining puberty 
during the course of the study. 
 
The growth of paediatric patients receiving orally inhaled corticosteroids, including Symbicort, 
should be monitored. If a child or adolescent on any corticosteroid appears to have growth 
suppression, the possibility that he/she is particularly sensitive to this effect should be 
considered. The potential growth effects of prolonged treatment should be weighed against the 
clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, 
including Symbicort, each patient should be titrated to the lowest strength that effectively 
controls his/her asthma. 
 
 
4 
Objectives and Endpoints 
4.1 
Primary objective 
The primary objective is to assess the efficacy of a combination corticosteroid/rapid- onset long-
acting ß2 agonist (ICS/LABA) budesonide/formoterol inhaler ‘as required’ or, if clinically 
indicated, ‘both as required, and regularly’ to reduce asthma exacerbations compared to the 
standard of care for asthma. 
 
4.2 
Secondary objectives 
The secondary objectives are: 
a) To assess the cost-effectiveness of budesonide/formoterol compared to the standard of 
care from the individual, household, health system level and quality of life. 
b) To assess the quality of life of children and adolescents on budesonide/formoterol 
compared to standard of care. 
 
4.3 
Primary Endpoint 
The primary endpoint will be the number of severe asthma exacerbations in the treatment year, 
defined as “events requiring systemic corticosteroids for three or more days and/or a 
hospitalisation/emergency room visit for asthma requiring systemic corticosteroids”27. (ATS/ERS 
criteria for definition of asthma exacerbation for clinical trials). All participants will be given 
diaries to record any asthma related episodes as they occur. As an additional step to ensure that 
we capture all the primary endpoint data, as part of our data capturing all participants will receive 
SMS messages soliciting information about any exacerbations every month. A “yes” response to 
the SMS will trigger a call from the study team to capture the outcome data from the participants 
and capture any adverse events. A free call-me back system has also been developed where 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 35 of 151                        
 
participants can send a message should they experience an exacerbation.  
 
 
4.4 
Secondary Endpoints  
Clinical Endpoints 
The following clinical end points will be collected during visits 1, 2, 3, 4 and 5: any presence of 
asthma exacerbations, medication changes since the last visit, days lost from school for 
participants or work for parent(s) or legal guardians. Any presence of any adverse or serious 
adverse events will be reported. 
 
For visits 1, 3 and 5 outcome data to be collected will include the growth parameters i.e. weight 
and height. For the asthma outcomes: Asthma Control Test (>12 years) or child Asthma Control 
Test (6-11 years), peak expiratory flow measurements (PEFR) with electronic peak flow meter 
(Microlife AG Asthma Analyser Version 3.2.6) and the Paediatric Asthma Quality of Life 
Questionnaires (PAQLQ) to assess quality of life (QoL) will be completed at these scheduled 
visits. 
 
For the health economic endpoints in a sub-set of 200 participants i.e. 100 in each study arm, 
additional health economics questionnaire to capture data on time-to-first exacerbation, 
household labour absences, out-of-pocket expenditures, loss of household productivity time and 
income (productivity losses), borrowing, and education losses. Secondly, participants will 
complete the EQ-5D-Y to capture health-related quality of life using validated generic 
preference-based measures of health. We will use the EQ-5D-Y (and proxy) tool to collect the 
health profiles of respondents in our study sample. We will then use value sets pre-produced 
using standard preference (utility) elicitation methods. Each health profile of participants in our 
sample has a corresponding value set from the tables of values in the EQ-5D-Y. These values 
will then be used to analyse utility preference (quality of life that are weighted with preference 
(utility) weights) in the sample of interest. 
 
For the health systems costs, data collected from the facility level and pharmacist will include: 
health care costs related to in/out patient treatment of both the usual care and the intervention, 
including overhead costs at visits 1,3 and 5. These will be utilised to derive cost-savings from the 
intervention or standard treatment arm and to derive cost per quality-adjusted life year (QALY) 
gained. 
 
4.5 
Exploratory objectives 
To assess the change in FEV1 in the two study arms, pre and post study. 
 
 
 
5 
Study Design 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 36 of 151                        
 
5.1 
Overall Design 
This is a Phase 3 single-centre, pragmatic open-label randomised controlled trial with two equal 
sized groups to assess the efficacy of budesonide/formoterol 80/4.5 (6-11 years) and 160/4.5 
(12-18 years) compared to the standard of care in reducing asthma exacerbations over 52 
weeks compared to the standard of care. The budesonide/formoterol will be given according to 
the severity of asthma symptoms for all asthma severities i.e. mild, moderate or severe asthma, 
with those with mild asthma using the study drug as needed and those who are more 
symptomatic i.e. moderate or severe asthma using the study drug twice daily and as needed 
titrated to need. Severity assessment will be based on GINA steps of asthma severity14. 
 
Children and adolescents with a diagnosis of asthma will be screened for eligibility for enrolment. 
Those who had an asthma exacerbation in the previous year will be randomised 1:1, to either 
receive budesonide/formoterol inhaler for both symptom relief and for chronic anti-inflammatory 
maintenance therapy or the standard of care which is separate inhalers for symptom relief 
(short-acting bronchodilator-salbutamol) and chronic maintenance therapy with inhaled 
corticosteroids (anti-inflammatory beclomethasone or budesonide) and/or long-acting beta 
agonists or montelukast as determined by treating physicians. All asthma exacerbations and 
clinic/hospital admissions will be recorded for the duration of the 52-week follow-up. Participants 
will be followed up at 1,13, 26, 39 and 52 weeks. The 13- and 39- week visits will be telephonic 
visits to capture the primary end-points i.e. asthma review which will include: exacerbations, 
changes in medication, days lost at school or work for caregivers/guardians and serious adverse 
events and adverse events. 
 
An independent Data and Safety Monitoring Board (DSMB) will be convened for this study with 
expertise in asthma and asthma clinical trials. The purpose of the DSMB will be to monitor the 
study for safety and operational futility (see section 10.1.5) 
 
In addition to the usual regular required reporting to SAHPRA and the biomedical research 
ethics committee (BREC) of the University of KwaZulu-Natal (UKZN), a Trial Steering Committee 
(TSC) will also provide overall supervision of the trial and ensure the trial is delivered in 
accordance with South African Guidelines for Good Clinical Practice (SA GCP). The TMC will be 
established with an independent Chair and include additional independent members including an 
observer early career researcher, representatives of the Trial funder (NIHR) and Sponsor (AHRI) 
will be invited to all TMC meetings. 
 
5.2 
Investigational Product  
The study is an open label study with the comparator group being asthmatics on standard of 
care according to DOH guidelines. 
 
Age group 
Inhaler and dose 
6-11 years 
Budesonide formoterol 80/4.5 pMDI/DPI 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 37 of 151                        
 
12-18 years 
Budesonide formoterol 160/4.5 DPI 
 
For children 6- 11 years of age, the medication will be stepped up and down depending on 
asthma control every 6 months as per Figure 1. 
 
 
For adolescents 12-18 years, the medication dosing will be stepped up or down depending on 
symptom severity and asthma grading every 6 months as per Figure 2. 
 
 
 
5.3 
 Comparator  
Standard of care for children 6-11 years and adolescents 12-18 years. In the current Essential 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 38 of 151                        
 
Medicines List in South Africa the available drugs are as chronic anti- inflammatory agents: 
Budesonide or Beclomethasone, Fluticasone/Salmeterol (ICS/LABA) and Montelukast 
(leukotriene receptor antagonist). With the pragmatic nature of the trial, similar to the NOVEL 
and START trials15, 16 , the treatment options of medications used in the comparator arm will be 
at the discretion of the investigator. The comparator arm will be the standard therapy the patient 
is receiving and stepping up/down will be as per the GINA guidelines and the treating doctor’s 
assessment (track 2) 
 
For the standards of care arm treatment will be stepped up or down based on GINA track 2 
guidelines14. 
 
a) Children 6-11 years 
 
Step 1: Inhaled corticosteroid (Beclomethasone 100mcg OR Budesonide 100mcg) 2 puffs 
PRN and bronchodilator (Salbutamol 100mcg) 2 puffs PRN. 
 
Step 2: Inhaled corticosteroid (Beclomethasone 100mcg Budesonide 100mcg) 2 puffs twice 
daily and bronchodilator (Salbutamol 100mcg) 2 puffs PRN. 
 
Step 3: Inhaled corticosteroid (Beclomethasone 200mcg OR Budesonide 200mcg) 2 puffs 
twice daily and bronchodilator (Salbutamol 100mcg) 2 puffs PRN  
 
OR 
Leukotriene receptor antagonist (montelukast) 4mg Per os daily AND Inhaled corticosteroid 
(Beclomethasone 100mcg OR Budesonide 100mcg) 2 puffs twice daily and bronchodilator 
(Salbutamol 100mcg) 2 puffs PRN. 
 
OR 
Fluticasone/Salmeterol 25/50 2 puffs twice daily  
 
b) Adolescents 12-18 years 
 
Step 1 and 2: Inhaled corticosteroid (Beclomethasone 200mcg OR Budesonide 200mcg) 2 
puffs PRN and bronchodilator (Salbutamol 100mcg) 2 puffs PRN. 
 
Step 3: Inhaled corticosteroid (Beclomethasone 200mcg Budesonide 200mcg) 2 puffs twice 
daily and bronchodilator (Salbutamol 100mcg) 2 puffs PRN OR Fluticasone/Salmeterol 
25/125 2 puffs twice daily 
 
Step 4: 
Fluticasone/salmeterol 50/250 2 puffs twice daily and salbutamol 100mcg 2 puffs BD 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 39 of 151                        
 
OR 
Inhaled corticosteroid (Beclomethasone 200mcg OR Budesonide 200mcg) 2 puffs twice 
daily and bronchodilator (Salbutamol 100mcg) 2 puffs PRN AND Leukotriene receptor 
antagonist (montelukast) 4mg Per os daily 
 
Uncontrolled asthma 
Before considering any step up, we will first confirm that the symptoms are due to asthma and 
identify and address common problems such as inhaler technique, adherence, allergen 
exposure, multimorbidity and provide patient education. For adolescents, the preferred Step 3 
treatment is the Track 1 regimen with low-dose ICS-formoterol maintenance -and-reliver therapy 
(MART). This reduces the risk of severe exacerbations, with similar or better symptom control, 
compared with maintenance treatment using a combination of an ICS and a LABA as controller, 
plus as-needed SABA. If needed, the maintenance dose of ICS-formoterol can be increased to 
medium (step 4) by increasing the number of maintenance inhalations. MART is also a preferred 
option at Step 3 and 4 for children 6 – 11 years, with a lower dose ICS-formoterol inhaler. 
Hence, for the study participants in the intervention arm, they will benefit from use of this drug 
compared to the standard of care. 
 
5.4 
End of Study and Study Duration 
The study duration is 52 completed weeks per study participant. 
 
 
6 
Study Population 
Children and adolescents (6-18 years) with asthma have had ≥1 asthma exacerbation in the 
preceding 12 months. An exacerbation of asthma will be defined as an event requiring treatment 
with systemic corticosteroids for ≥3 days and/or a hospitalisation/emergency room visit for asthma 
requiring treatment with systemic corticosteroids. Participants will be enrolled if they have asthma 
of any severity i.e. mild, moderate or severe asthma. 
 
Written consent from a parent or guardian and assent from all the study participants. A 
“Parent/Guardian/Caregiver: will be regarded as the child's primary parent/Guardian/Caregiver if 
they are an adult who assumes the most responsibility in caring for the health and well-being of 
the child by providing for their food, shelter and clothing needs. In most instances, the 
Parent/Guardian will be the biological mother but may be the father, other legal guardian, 
grandparent or a child over 18 heading a household.” 
 
All participants who agree to comply with the study procedures, including the completion of the 
visits and be available for contact for telephonically for the non-contact visits. 
 
6.1 
Site and Participant Recruitment 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 40 of 151                        
 
Study participants will be recruited from a single centre the AHRI CTU with 6 satellite sites that 
will be located in 6 primary care clinics. AHRI CTU also has a group of general practitioners who 
practice in the study area, who will be contacted about the study protocol for the referral of 
potential study participants to the nearest clinic. 
 
In addition, active case finding will be employed. As an additional recruitment strategy, we will 
select a number of primary and secondary schools in collaboration with the local school health 
programs, where we will screen children for asthma symptoms with an internationally recognised 
asthma screening questionnaire (Global Asthma Network questionnaire addendum). Participants 
who are screened positive for asthma will be reviewed by the trial investigators who can confirm 
or exclude an asthma diagnosis in the potential participants and assess them for eligibility. 
 
We will recruit participants from the AHRI Somkhele Research Campus clinical trials unit (CTU) 
which is based in a poor rural community in uMkhanyakude in KwaZulu-Natal. AHRI operates a 
health and demographic surveillance system (HDSS)23 as part of the South African Population 
Research Infrastructure Network (SAPRIN) funded by the South African Department of Science 
and Innovation. AHRI’s HDSS follows approximately 20 000 households (140 000 household 
members) longitudinally, contacting them three times a year to update the status of each 
household member and to record any new births, in- or out-migrations, or deaths to establish 
and maintain a very accurate database containing every individual in the HDSS and assigns a 
unique Directory Services Identifier (DSID) to each person. 
 
Historically, population-based research at the Africa Centre for Population Health centred on a 
demographic surveillance system referred to as the Africa Centre Demographic Information 
System (ACDIS). ACDIS was established in 2000 to describe the demographic, social and 
health impact of the HIV epidemic in a population going through the health transition, and to 
monitor the impact of intervention strategies on the epidemic. The Africa Centre Demographic 
Surveillance Area (DSA) is situated in the Mtubatuba local municipality in the uMkhanyakude 
district of KwaZulu-Natal and within the Hlabisa health sub-district. The area is 438km2 in size 
and in mid-2015 there were approximately 90 000 (61 000 resident) household members of 11 
000 households in this area. Three primary subjects are observed longitudinally in ACDIS: 
physical structures (e.g. homesteads, clinics and schools), households and individuals. 
 
Since 1 October 2016 the DSA has been expanded, and a new structure referred to as the 
population intervention platform (PIP) has been established. PIP is a population-based platform 
for epidemiology and intervention research focused primarily on human immunodeficiency virus 
(HIV) and tuberculosis (TB). The HDSS incorporates a rural area of approximately 845 km2 with 
a mid-year population of 151 441 in 2015. The platform builds on the health and demographic 
surveillance system established in 2000 in this area. The purposes of this longitudinal platform 
are firstly to obtain accurate measures of population dynamics, disease burden, and utilisation of 
health and other services; secondly to measure clinical phenotypes and manifestations of ill 
health; and thirdly to provide a framework for the implementation and evaluation of individual 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 41 of 151                        
 
and population level interventions. The HDSS is served by 11 primary health clinics and one 
hospital. 
 
Written consent is obtained from all households to contact them both in person and 
telephonically to recruit household members into research studies conducted by AHRI. Two of 
the three households contacts are done telephonically using a modern call centre technology, 
this facility is available to all studies at AHRI to follow-up study participants where physical visits 
are not required. The homesteads where households are resident are all accurately geo-coded 
to allow easy navigation to selected households when physical contact is required.  
 
We intend to enrol participants from the AHRI CTU and at the following 6 Satellite Sites to 
ensure we reach the required sample size for the study: 
a) Hluhluwe Clinic  
b) Somkhele Clinic  
c) KwaMsane Clinic  
d) Mpukunyoni Clinic  
e) Mtubatuba Clinic  
f) Nkundusi Clinic 
 
The study will be enrolling children from 6 to 18 years therefore, most of the children are still at 
school. The pre- screening of potential participants be conducted in schools and qualifying 
participants will be referred to the enrolling clinic. On assessment by the investigator the 
diagnosis of asthma will be confirmed from the medical history with performance spirometry with 
bronchodilator reversibility testing and/or 2-week diurnal variation on peak flow measurements to 
confirm the diagnosis of asthma. Based on previous evidence, only 40% of children with an 
asthma diagnosis will have bronchodilator reversibility, a lack of bronchodilator reversibility will 
not be an exclusion criterion as almost 60% of children with asthma lack objective evidence of 
bronchodilator reversibility as per ERS asthma diagnosis guideline 2022. Below are the schools 
where the pre-screening for the potential participants will take place: 
 
 
 
 
 
 
 
 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 42 of 151                        
 
 
 
 
 
Table 2. List of schools and linked clinics for pre-screening  
 
 
The study will be conducted at the AHRI CTU and 6 Satellite Sites. The HDSS incorporates a 
rural area of approximately 845 km2 with a mid-year population of 151 441 in 2015. The platform 
builds on the health and demographic surveillance system established in 2000 in this area. The 
number of children between 6-18 years is 31 729 in 2021. With an asthma prevalence of 13% 
(i.e. an estimated 4 124 asthmatics) in the population, for the study to be feasible we need to 
KwaMsane Clinic 
Somkhele Clinic 
Mpukunyoni 
clinic 
Nkundusi clinic 
Hluhluwe clinic 
Mtubatuba 
clinic 
Mnotho Primary 
School 
Nqiwaneni Primary 
School 
Umfolozi High 
School 
ZiƟke Primary 
School 
Nkosikayingangathi 
High School 
Hill 70 Primary 
School 
Ngweni Primary 
School 
Ikusasalethu High 
School 
Siyathuthuka 
Primary School 
Syiyaqala High 
School 
Ophaphasi Primary 
School 
Nomathiya High 
School 
Mgwazeni High 
School 
Somkhele Primary 
School 
Mehlokubheka 
High School 
Mtuba Primary 
School 
NƟkili Primary 
School 
Welani Primary 
School 
Phola Primary 
School 
Umsizi wama 
Crestu 
Njojo Primary 
School 
Baswazini Primary 
School 
Mcebo Primary 
School 
Siyaphambili High 
School 
Mpukunyoni 
Primary School 
Veyane Primary 
School 
Nkodibe High 
School 
Ndukebandla 
High School 
Mandlesizwe 
Primary School 
Chwebebeni 
Primary School 
Mfekayi High 
School 
Ntulifakazi 
Primary School 
Mchakweni 
High School 
Mfekayi 
Primary School 
Gilonki High 
School 
Isihosabadletshe 
High School 
Duma Primary 
School 
Safari Primary 
School 
Bush Lands 
Primary School 
Siyembeni 
Nkonyane 
Primary School 
Sphelele 
Primary School 
Asiphikelele 
Primary School 
Mtubatuba 
Primary 
School 
Mfolozi 
Primary 
School 
Kingdom 
ChrisƟan 
College 
Combined 
School  
Mtuba 
ChrisƟan 
Academy 
Combined 
School 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 43 of 151                        
 
cover a large geographic area. 
 
The satellite sites are equipped and capacitated with appropriately trained personnel to conduct 
this clinical trial. The participants will be recruited and enrolled at each of the satellite site each 
with a full complement of trial staff i.e. trial investigators (x2), research nurses (RN) (x2), clinical 
research assistants (CRA) (x2), drivers, pharmacists. The satellite sites is supported by the full 
IT support infrastructure which is already in existence at all the 6 sites. IT provide oversight 
technical support to the clinic staff.  
IMP will be stored at the AHRI CTU pharmacy according to GCP and GPP guidelines. IMP will 
be dispensed to the enrolled participant once randomisation has been done and a prescriptions 
has been received.  IMP (prepared or unprepared) will be transported (within the recommended 
temperature range) to the satellite clinics. If the IMP was not prepared for the participant at the 
CTU pharmacy the IMP will be prepared at the satellite clinic (by the pharmacist) once a 
prescription is received. The IMP will be issued to the participant by the pharmacist A data team 
of two data managers is set up to monitor the data systems of the study.  
 
 
Figure 3: Map of Satellite sites for the study  
 
 
 
Equipment and resources 
 
Vehicle to transport the participants.  
 
Each site will have a room for screening and enrolment procedures.  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 44 of 151                        
 
 
Calibrated Scales  
 
Calibrated blood pressure machines  
 
Calibrated Thermometer  
 
Calibrated Oximeter  
 
Bed for examination  
 
Lockable cupboards for participants’ information  
 
Computers and tablets to capture patient information 
 
Access to AHRI network and data bundles for backup 
 
Stationery will be provided to satellite sites 
 
Working site files will be kept at each enrolling clinic  
 
Screening and enrolment logs will be kept at each enrolling clinic 
 
Emergency trolley with paediatric size equipment 
 
Emergency trolley for satellite sites 
 
The satellite sites will all have emergency trolleys with paediatric specific resuscitation 
equipment provided by AHRI. 
 
Emergency trolley checklist will be done on weekly basis and the RNs will email the 
emergency trolley checklist to the SC. 
 
Site monitoring and evaluation 
Clinical Research Satellite Sites will be monitored by an internal monitoring team according to 
AHRI Internal Monitoring Plan and the external monitoring will be contracted to a Clinical 
Research Organisation. The monitoring visits will be structured according to the following types 
of visits that will be done in combination and varied according to the observed risks, the stage of 
the study and the protocol requirements. 
 
Table 3. Site Monitoring Plan 
 
Monitoring activity 
Frequency 
Approach 
Investigators meeting 
1  
Remote 
Site Evaluation visit 
1 
Remote 
Site Initiation visit  
1 (2 days) 
Onsite 
First 18-24 participants enrolled in the study 
at each site (100% Review) (~3 per satellite 
site) 
3- 4 days 
Onsite 
Scheduled monitoring (10-20% Review of 
source -data verification, and 60-80% ICF 
review) 
Every 8 weeks in Year 1 
(while 
recruiting) 
and 
every 12 weeks thereafter 
Remote and onsite 
(alternating) 
Adverse event (100% Review) 
Per occurrence  
Remote and onsite 
For-cause-visit 
Per occurrence (budget 2) Remote and onsite 
 
 
Study Coordinator (SC) will be responsible for certifying and filing of the emergency 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 45 of 151                        
 
trolley checklists while the satellite sites keep the original electronic copies. 
 
SC will be responsible for operational meetings for the study to give an update and the 
progress of the study. 
 
SC and the quality team will be responsible for ensuring that the study sites are 
prepared for monitoring visits 
 
PIs and SC will be responsible for providing feedback and progress report to the 
partners (DOH), CAB, and the sponsor. 
 
6.2 
Inclusion criteria 
1) Age for inclusion children and adolescents 6-18 years at the time of consent 
2) Known asthmatic on treatment 
3) Newly diagnosed asthma based on investigator review and/or medical report 
4) All patients will have their asthma diagnosis confirmed (both new or known asthmatic patients) by 
either spirometry with reversibility or excessive diurnal variability by PEFR twice daily over 2 
weeks. 
5)  
6) Ability to perform spirometry and Peak Expiratory Flow rate and/or bronchodilator reversibility 
testing. 
7) Only mild, or moderate asthma severity, based on medical history 
8) At least one exacerbation of asthma in the past year as defined by an event requiring 
treatment with systemic corticosteroids for ≥3 days and/or a hospitalisation/emergency 
room visit for asthma requiring treatment with systemic corticosteroids. 
9) Written consent from the participant or parent/guardian and assent from study participants 
where applicable. 
10) Participant and/or parent/guardian agrees to comply with the study procedures, including 
the completion of the visits and be available for contact for telephonically for the non-
contact visits. 
 
6.3 
Exclusion criteria 
1) Tuberculosis: active TB disease and contact with people with active TB disease in the 
last 6 months. 
2) Chronic sputum expectoration, chest pain, shortness of breath (without any asthma 
symptoms), dizziness, or light- headedness in the last 2 months. 
3) Cardiac arrythmia 
4) Chronic conditions: thyrotoxicosis, phaeochromocytoma, cardiovascular disease, severe 
hypertension. 
5) Uncontrolled diabetes mellitus 
6) Patients with Peak Expiratory Flow Rate < 50% of predicted , as these would be 
classified as severe asthmatics. 
7) Patients with any history of life-threatening asthma, defined as any history of significant 
asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, 
hypoxic seizures, or asthma related syncopal episode(s). 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 46 of 151                        
 
8) Any use of biological therapy or immunomodulatory therapy such as methotrexate or 
regular oral prednisolone for the asthma management (STEP 5 GINA therapy). 
9) Any surgical or medical condition that would significantly alter the absorption, distribution, 
metabolism or excretion of the IMP which may jeopardise the safety of the participants. 
The investigator should make this determination in consideration of the volunteer’s 
medical history. 
10) Any physical, mental or social condition, laboratory abnormality of history of illness that in 
the investigator’s judgement might jeopardise the safety of the participant in the context 
of the study, or might interfere with study procedures or the ability of the participant to 
adhere to and complete the study. The investigator should make this determination 
consideration of the volunteer’s medical history. 
11) Inability to present for follow up or leaving the study area within 12 months of enrolment 
 
6.4 
Justification of inclusion and exclusion criteria 
The eligibility criteria were chosen to ensure that the study population selected include 
participants with asthma diagnosis or symptoms and no other chronic lung diseases in which 
asthma therapies are not recommended and may potentially be harmful.  
 
6.5 
Participant identification 
All volunteers who are screened for eligibility to participate in the study will be allocated a unique 
sequential screening number. On enrolment the study participants will be allocated participant 
identifier number for the duration of the study. 
 
6.6 
Screen Failures 
All participants who fail the screening process will be continued on the normal care at the clinics 
and hospital. Those who may be symptomatic identified at the schools will be referred to the 
local clinic or hospital for management of asthma symptoms and follow-up care. 
 
6.7 
Co-enrolment 
Participants will be considered for enrolment in this study if they are involved in other research 
studies that are observational or include behavioural interventions only. Participants who are 
enrolled in other clinical trials will be excluded unless prior approval is provided after review by 
the Principal Investigators. BCEPS and IDS are put in place to prevent co-enrolment. 
Participants will be required to produce their identity documents and fingerprints to verify that 
they are not enrolled in another clinical trial.  
 
6.8 
Endpoint Case Definitions 
The primary endpoint will be the number of severe asthma exacerbations in the treatment year, 
defined as “events requiring systemic corticosteroids for three or more days and/or a 
hospitalisation/emergency room visit for asthma requiring systemic corticosteroids.” based on 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 47 of 151                        
 
medical history or records. The primary end point will be assessed at every visit, for the 
preceding 3 months. Participants will be offered diaries at the initial visit so they can record all 
exacerbations. There will be a study monitor in place to review all study safety and clinical data 
monthly in conjunction with the PI. The DSMB board is also in place to review for any safety 
concerns on a 6-monthly basis. As per the SAHPRA requirements any SAE and AEs will be 
reported and reviewed by the PI and study monitor and should any safety concerns arise, these 
will be immediately reported to all ethical committees, SAHPRA and the DSMB. 
 
6.8.1 Clinical Endpoints 
a) Asthma exacerbations (visit 1-5) 
b) Asthma Control Test (ACT) for ≥ 12 years and Childhood ACT (cACT) for children 6-11 
years (Visit 1,3 and 5) 
c) Paediatric Asthma Quality of Life Questionnaire (PAQLQ) (Visit 1, 3 and 5) 
d) Peak Expiratory Flow Rate (Visit 1) 
e) Spirometry (Visit 1,3 and 5) 
f) School absence for participants (Visit 1-5) 
g) Work absence for parents/guardians to take care of children due to asthma. (Visit 1-5) 
h) Adverse events (AE) (Visit 1-5) 
i) 
Serious Adverse Events (SAEs) (Visit 1-5) 
 
6.8.2 Health economics Endpoints (N=200 participants). 
These endpoints will be collected in a sub-set of a convenience representative sample 200 
participants i.e. 100 in each study arm at study entry and exit. Questionnaires will be 
administered to the study participants to capture the relevant economic data including the 
completion of the EQ-5D-Y tool (Addendum B). 
j) Quality of survival estimates: time to first exacerbation, health-related quality of life using 
validated generic preference-based measures of health (EQ-5D-Y), adverse effects, 
school, work, household labour absences. (Visit 1,3 and 5) 
k) Household-level economic impact by socio-economic stratum (World Bank approach): 
out-of-pocket expenditures, loss of household productivity time and income (productivity 
losses), borrowing, and education losses. (Visit 1, 3 and 5) 
l) Health system: health care costs related to in/out patient treatment of both the usual care 
and the intervention, including overhead costs, as well as cost savings from reduced 
exacerbations due to intervention and cost per quality-adjusted life year (QALY) gained. 
(Visit 1,3 and 5) 
m) Utility preferences as derived from the EQ-5D-Y (Visit 1, 3 and 5) 
 
7 
Discontinuation/Withdrawal 
A study participant may withdraw from the study at any time and for any of the following reasons: 
a) At the participant’s request (withdrawal of consent), irrespective of the reason for this. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 48 of 151                        
 
b) At the request of the parent or guardian, irrespective of the reason for this. 
c) At the discretion of the investigator if he/she believes that the continuation of the 
participant in the study will be detrimental to their well-being in any way. 
d) At the discretion of the REC, SAHPRA, Funder or Medical monitor if they believe that 
continuation in the study would be detrimental to the participants well-being in any way. 
e) Any protocol non-conformance that results in a significant risk to the participants safety. 
 
The investigator will make every effort to determine the primary reason for the participant’s 
withdrawal from the study and record this information in the electronic case report form (eCRF). If 
the participant withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data before such withdrawal of consent. For those participants who withdraw, 
if possible and agreed to, all the Visit 5 assessments (week 52) will be completed at the time of 
discontinuation. Participants who withdraw or are withdrawn will not be replaced if the participant 
has completed at least 6 months follow-up time in the study. 
 
7.1 
Loss to Follow-up 
Participants lost to follow-up or who fail to return will be considered to be withdrawn from the 
study under the following scenarios: 
a) Missed two consecutive study visits. 
b) Study team unable to contact via three telephone calls or one home visit. 
All attempts to contact the participants, parents and or guardians will be recorded in the source 
documents. The investigator will make every effort to determine the primary reason for the 
participants to be lost to follow-up and will attempt to trace the participant and will demonstrate 
due diligence by documenting all the steps taken to contact the participant. 
 
8 
Study assessments and procedures 
No study-specific assessments will be performed, or information gathered, until the potential 
participant or parent/guardian has given written, informed consent for screening procedures and 
(if found to be eligible) for procedures and assessments to be conducted during the study period. 
The timing of all assessments and procedures is detailed in the Schedule of Events (Section 1). 
 
8.1 
Screening and Baseline Assessments 
Screening evaluations will be completed, and the results reviewed by the investigator to confirm 
eligibility of participants. Screening and enrolments can be completed on the same day, unless 
there are further evaluations required to confirm asthma diagnosis by the investigator. 
 
8.1.1 Demographics 
Demographic and baseline characteristic data to be collected for all participants includes but 
not limited to: age, sex, self-reported ethnicity. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 49 of 151                        
 
8.1.2 Relevant medical and surgical history/current medical conditions including 
treatment 
Information related to past and current relevant medical conditions and surgical procedures will 
be collected, including age at diagnosis of asthma and current asthma medication. At 
screening a list of chronic diseases and current medications both over the counter and 
prescribed medication will be recorded. 
 
No special investigations or laboratory measures will be performed as part of study 
procedures. 
 
8.2 
Safety Assessments 
8.2.1 Physical examination 
Abbreviated, symptom-directed physical examinations will be performed at screening, at the 
end of study (EOS) visit, and during unscheduled visits if deemed necessary by the 
investigator or primary health care nurse. At a minimum these examinations will include: 
general appearance, skin, blood pressure, chest and lungs. Significant findings present at 
screening will be recorded in the relevant medical history/current medical conditions section of 
the participant’s eCRF. At follow-up visit significant findings, or worsening of pre-existing 
findings, detected after dosing will be recorded as AEs in the participant’s eCRF. 
 
8.2.2 Height and weight 
Height in centimetres (cm) and body weight (to the nearest 0.1 kg in light indoor clothing, but 
without shoes) will be measured. The stadiometer available at all the clinic and hospital 
research sites will be used. 
 
Body Mass Index (BMI) will be calculated using the formula: BMI = weight (kg) / height (m)2. 
 
8.2.3 Vital signs 
Vital signs include body temperature, pulse rate, blood pressure assessments and SpO2. 
Blood pressure, pulse rate and SpO2 will be measured after the participant has been at rest for 
at least 5 minutes. An appropriately sized cuff will be used to ensure accurate blood pressure 
determination. 
 
8.3 
Efficacy Assessments 
8.3.1 Patient Reported Outcomes 
For each participants the following questionnaires will be completed: 
a) Study designed questionnaire (All visits) 
b) Paediatric asthma quality of life questionnaire (visit 1, 3 and 5) 
c) EQ-5D-Y (visit 1 and 5) 
d) Asthma Control Test (ACT or cACT) score (visit 1, 3 and 5) 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 50 of 151                        
 
e) Health economics questionnaire (Visit 1,3 and 5) 
These questionnaires will be completed on e-source or paper-based source documents. 
Participants will be contacted via telephone call or text/direct messaging or web-based 
conference on visits 2 and 4 by the study team to confirm any AE occurrence, general well-
being and record of asthma review. 
 
 
9 
Study treatment/Investigational products/devices 
9.1 
Budesonide-Formoterol 
Budesonide-formoterol is a combination of a corticosteroid and a fast acting long acting β2 
agonist. Budesonide is an agonist of glucocorticoid receptors. Among its effects are it controls 
the rate of protein synthesis, depresses the migration of polymorphonuclear leukocytes and 
fibroblasts, reverses capillary permeability and lysosomal stabilization at the cellular level to 
prevent or control inflammation and it has a potent glucocorticoid activity and weak 
mineralocorticoid activity. Formoterol is a relatively selective long-acting agonist of beta2-
adrenergic receptors, although it does carry some degree of activity at beta1 and beta3 
receptors. Beta 2 receptors are found predominantly in bronchial smooth muscle (with a 
relatively minor amount found in cardiac tissue) whereas beta1 receptors are the predominant 
adrenergic receptors found in the heart - for this reason, selectivity for beta 2 receptors is 
desirable in the treatment of pulmonary diseases such as asthma. Formoterol has demonstrated 
an approximately 200-fold greater activity at beta 2 receptors over beta1 receptors. On a 
molecular level, activation of beta receptors by agonists like formoterol stimulates intracellular 
adenylyl cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP). The 
increased levels of cAMP in bronchial smooth muscle tissue result in relaxation of these muscles 
and subsequent dilation of the airways, as well as inhibition of the release of hypersensitivity 
mediators (e.g. histamine, leukotrienes) from culprit cells, especially mast cells. 
 
The IMP that will be administered in the study either in dry powder form (Symbicort ) turbuhaler 
and a metered dose inhaler pMDI (Vannair). 
 
9.1.1 Packaging, labelling, storage and accountability 
There will be adequate quantities of budesonide-formoterol (both DPI and pMDI) supplied to 
the study site in sufficient amounts with each participant being provided with at least a 6-month 
supply of medication to cover for all physical once approvals from SAHPRA and UKZN BREC 
have been obtained. The drug will be packed, labelled, and shipped together with the 
respective Certificates of Analysis containing the batch numbers. The label content will be in 
accordance with South African legal requirements. 
 
The PI is responsible for ensuring that the study drug is stored in a secure location with 
restricted access to unauthorised personnel. Budesonide-formoterol should be stored at room 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 51 of 151                        
 
temperature. Storage conditions will be adequately monitored, and appropriate temperature 
logs maintained throughout the study at the trial pharmacy. 
 
Upon receipt of the budesonide-formoterol shipment, the study pharmacist (or designee) will 
immediately inspect the shipment for damage, acknowledge receipt and confirm the shipment 
condition and content. Any damage or discrepancies from the packing list will be documented 
and promptly discussed with the supplier and study monitor to determine the appropriate 
action. 
 
The study pharmacist (or designee) is responsible for maintaining accurate study drug 
accountability records. Instructions and the necessary forms for completion will be detailed in 
the Pharmacy Manual. Study drug accountability records will be reviewed by the study monitor 
during interim site visits and upon completion of the study. On study completion, copies of all 
study drug management records will be provided to the Sponsor. The originals must be 
maintained at the study site with the rest of the study records. 
 
 
9.1.1.1 Cohorts 
Eligible participants will be randomised 1:1 to receive either Budesonide-formoterol or 
Standard of Care for a total duration of 52 weeks. 
 
9.1.1.2 Blinding 
This study is an open labelled study but the PI (or designee) who will be assessing the AEs 
will  know the treatment assignment of the participants.  
 
9.1.1.3 Dispensing 
The study drug will be dispensed by the study pharmacist and dispatched to the clinic for 
administration to study participants. 
 
9.1.1.4 IMP administration 
The study drug are inhalers both pMDI and DPI. All the participants will be trained on how to 
use the pMDI (Vannair) which will be administered together with a spacer device for 
participants who are unable to co-ordinate inhalation of the medication and actuation at the 
same time. For the participants who will be receiving Symbicort Turbuhaler, all participants 
will be taught how to use the DPI and technique will be confirmed with the use of a DPI 
training device. The technique for device use will be checked at each physical study visit to 
ensure correct technique. For the participants in the control arm, similar checks on correct 
use of inhaler devices and provision of spacer devices will be checked at all physical study 
visits to ensure good inhaler technique. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 52 of 151                        
 
9.1.1.5 Treatment adherence 
The trial medication adherence of participants who require chronic use of medication as well 
as the comparator arm will be reviewed at all study visits. With each visit, the study staff will 
enquire on whether use of medication is as needed  and this will be recorded in the source 
documents. 
 
9.1.2 Overdose 
An overdose of formoterol would likely lead to effects that are typical for β2 adrenoceptor 
agonists: tremor, headache, palpitations. Symptoms reported from isolated cases are 
tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc-interval, arrhythmia, nausea and 
vomiting. Supportive and symptomatic treatment may be indicated. A dose of 90 micrograms 
administered during three hours in patients with acute bronchial obstruction raised no safety 
concerns. 
 
Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical 
problem. When used chronically in excessive doses, systemic glucocorticosteroid effects, such 
as hypercorticolism and adrenal suppression may appear. As per the budesonide/formoterol 
package insert, for adolescent a maximum of 12 doses per day and for children 6-11 year 8 
doses per day. Should participants overdose, as per regulatory requirements, any adverse 
events will be reported to the regulator and ethics committees should adverse events occur 
and the study participants will have a SMART action plan with maximum daily allowable doses 
stated.  
 
Treatment of overdose is supportive measures and correction of electrolyte abnormalities. 
 
9.1.3 Returns 
After completion of the study, any study drug that is remaining will be returned to the Sponsor. 
Empty and returned pumps will be destroyed according to Good Pharmacy Practice Guideline 
and destruction certificate will be filed.  
 
9.1.4 Concomitant treatments 
Participants will be asked about any concomitant medication at the screening evaluation. At 
each contact visit i.e. telephonic and physical visits the investigator will question the 
participants on any medication takes (including over-the-counter) or prescription medication, 
vitamins or other supplements they may be taking. Participants will be assessed and 
depending on whether the over-the-counter drug causes drug-to-drug interactions with any of 
the drugs mentioned in section 3.4.4. 
 
9.1.5 Post-trial access 
There will be no post-trial access to the study drug for any of the participants as this is an 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 53 of 151                        
 
investigator-initiated study. Should the findings of the trial be positive for the budesonide-
formoterol arm including the cost-effectiveness analysis, these findings will be shared with the 
Department of Health in particular the Ministry of Health Chronic Diseases Unit, as part of 
advocacy efforts to improve access to the budesonide-formoterol. 
 
The PI will also ensure that should that advocacy efforts to allow for access to the treatment 
post -trial. The advocacy efforts nationally will include recommendation of the addition of the 
use of budesonide/formoterol in the South African Paediatric Guidelines for chronic asthma 
treatment. Global efforts will include recommendation of use of this approach through the 
GINA Scientific Committee and through the WHO Integrated Management of Childhood 
Illnesses (IMCI) Guideline Development Group. 
 
9.2 
Research Capacity Strengthening 
This study will provide much needed research capacity by graduation of 3 PhD students through 
this clinical trial. These will be two South African PhD students (Black African) with a PhD 
(Health economics) and two PhD (Paediatrics).  
 
 
10 Safety Considerations 
10.1 Responsibilities for Ensuring the Safety of Study Participants 
10.1.1 Principal investigator 
The PI has a personal responsibility to closely monitor the study participants and an inherent 
authority to take whatever measures necessary to ensure their safety, including ensuring that 
procedures and expertise are available to cope with the medical emergencies during the study. 
The PI has the authority to terminate, suspend or require changes to a clinical study for safety 
concerns and may pause or delay the administration of the study drug to an individual or 
across the study. If the PI has concerns that the study drug may place participants at 
significant risk. 
 
10.1.2 Study Sponsor 
The Sponsor (AHRI) has the institutional responsibility to ensure participant safety and 
undertakes to promptly notify the concerned Investigator/Ethics committee and SAHPRA of 
findings that could adversely affect the safety of participants included in the study, impact the 
conduct of the study, alter the BREC’s approval of, or favourable opinion to continue the study. 
This included the expedited reporting to these parties of all adverse events that are both 
serious and unexpected. 
 
10.1.3 Study Funder 
The Funder National Institute of Health and Care Research (NIHR) has a responsibility to 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 54 of 151                        
 
immediately inform the Sponsor and PI of any existing risk assessment of the study or new 
information that could impact adversely on the participant safety. 
 
10.1.4 Safety Review Committee 
The Medical Monitor, in consultation with the Safety Review Committee (SRC). The SRC will 
comprise of at least the following personnel: 
a) The Principal Investigator 
b) The Medical Monitor 
c) The Safety Physician 
d) Another medically qualified paediatrician 
The timing of the SRC data review and a detailed description of the operational aspect of the 
SubRip Text (SRT) will be documented in the SRT Charter. 
 
10.1.5 Data and Safety Monitoring Board 
 
An independent DSMB will be convened for this study with expertise in asthma clinical trials. A 
biostatistician will also form part of the DSMB. The purpose of the DSMB is to monitor the 
study for safety and operational futility. The board will provide recommendations to the 
Sponsor regarding ongoing study conduct. 
 
Roles and responsibilities of the DSMB 
The DSMB is responsible for reviewing study documentation (e.g., study protocol, the informed 
consent and other participant handouts, etc.) and ensuring that it has adequate information to 
assess the safety of the study participants and the efficacy of the intervention during both the 
treatment and follow-up periods. The DSMB will review the data and safety monitoring plan, 
safety and operating procedures. The DSMB will meet six-monthly or earlier should 
recruitment targets be faster with at least one mid-study interim analysis meeting or safety 
concerns. The DSMB must ensure that the data and safety monitoring plan is sufficient given 
the complexity of the study and patient population. The Board shall have the option for 
expedited meetings to review unexpected SAE or other urgent issues that may arise during the 
course of the trial. Unscheduled meetings may be recommended and initiated by the DSMB 
Chairperson, the clinical trial Sponsor, or the PI. Clinical trial documentation and data will be 
available to the Board members at least two weeks prior to the meeting. 
  
The DSMB will evaluate participant safety data throughout the duration of the trial; evaluate the 
efficacy of the study intervention(s) at intervals specified in the DSMB charter; and 
independently provide recommendations to the study Sponsor to either continue, amend or 
terminate a clinical trial based on this information. The presence of 
early unanticipated therapeutic results, side effects, or AE are all reasons that a DSMB might 
recommend termination of a clinical trial early due to safety or efficacy matters. 
  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 55 of 151                        
 
In addition, the DSMB is responsible for monitoring the performance of each clinical site (e.g., 
protocol violations, improper participant enrolment criteria, slow accrual rate, low participation 
rate, failure of randomisation, inadequate treatment adherence, inadequate follow-up rate, 
severely compromised validity). The DSMB will independently make recommendations for 
improving the performance of the clinical trial or terminating the trial if it determines the study 
would be unable to provide useful data, regardless of modifications. A summary of each board 
meeting and the board recommendation will be provided to the clinical trial sponsor for 
distribution to each participating clinical site.  
 
In addition to meeting at pre-determined, scheduled time points, the DSMB will also be called 
upon to perform evaluations of relevant data should any of the study pause criteria be met at 
any stage, and make recommendation about study stopping or continuation, or amended 
circumstances under which the study may proceed. 
 
The objectives and responsibilities of the DSMB will be detailed in the DSMB Charter which 
will be ratified by the DSMB members prior to the study start. 
 
DSMB 
Chair: Prof Chen-Yuan Chiang (Taiwan)  
 
Members: 
Prof Richard Van Zyl Smit (UCT-Asthma expert and Pulmonologist) 
Mr Jacob Busang: Biostatistician 
Prof Marielle Pijnenburg (Netherlands- Paediatric pulmonologist expert in asthma clinical trials) 
(TBC) 
Dr Sanelisiwe Ngaka (Early career researcher and observer non-voting member) 
 
The objectives and responsibilities of the DSMB will be detailed in the DSMB Charter which 
will be ratified by the DSMB members prior to the study start. 
 
AHRI the Site, NIHR the Funder, the PI, UKZN BREC and Regulatory Authority independently 
reserve the right to discontinue the study at any time for safety or other reasons. This will be 
done in consultation with the Funder, Sponsor and PIwhere practical. 
 
Trial Steering Committee 
Chair: Prof Chakaya Muhwa (Kenya) Members 
Prof Refiloe Masekela (Principal investigator) Prof Kevin Mortimer (UK) 
Prof Asma El-Sony (Sudan) 
Dr Rebecca Nantanda (Uganda) 
Dr Reratilwe Mphahlele (Early career researcher and observer non-voting member) Lay 
member: Mtubatuba Community Advisory Board Member 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 56 of 151                        
 
 
10.2 Adverse events 
10.2.1 Definitions 
The following definitions are based on those described in the SAHPRA Safety Reporting 
Guidelines for Clinical Trials conducted in South Africa. 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical trial 
participant administered an investigational product that may present during treatment with that 
investigational product, but which does not necessarily have a causal relationship with this 
treatment. 
 
A treatment emergent adverse event (TEAE) is any new AE that begins, or any pre- existing 
condition that worsens in severity, after at least one dose of study product has been 
administered. 
 
An adverse drug reaction (ADR) is a response to a medicine in humans which is noxious and 
unintended,  
and which occurs at any dose, and which can also result from overdose, misuse, or abuse of a 
medicine. “Response” in this context means that a causal relationship between a medicine and 
an adverse event is at least a reasonable possibility. 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that: 
 
• 
Results in death 
• 
Is life-threatening (the term "life-threatening" in the definition of "serious" refers to an event 
in which the participant was at immediate risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe) 
 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation unless this is 
for: 
- 
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
trial and has not worsened since the start of the investigational product 
- 
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission 
- 
An acute asthma exacerbation 
- 
cosmetic surgery or for social reasons or respite care in the absence of any 
deterioration in the participant’s general condition 
 
• 
Results in persistent or significant disability/incapacity 
 
• 
Results in a congenital anomaly/birth defect 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 57 of 151                        
 
 
• 
Is medically significant or important event or reaction. 
 
An Unexpected Adverse Drug Reaction is one in which the nature, specificity, severity, and 
outcome is not consistent with the applicable product information. An expected ADR with a 
fatal outcome should be considered unexpected. 
 
A suspected unexpected serious adverse reaction (SUSAR) is an unexpected adverse 
drug reaction which also meets the criteria for a serious adverse event. 
 
10.2.2 Assessment and recording of adverse events 
All AEs regardless of seriousness or relationship to the study drug are to be recorded in the 
eCRF. AEs can be spontaneously reported by the participant, observed by the investigator 
(either directly, or through an objective assessment) or elicited by general questioning. 
Whenever possible, symptoms should be grouped as a single syndrome or diagnosis. 
 
The following information will be recorded for each AE: 
 
a) a description of the adverse event (verbatim term) 
b) the dates of onset and resolution of the event (and whether the event started prior to or after 
start of study drug) 
c) the characteristics of the event (seriousness, severity) 
d) the action taken in response to the event (including treatment required) 
e) the outcome of the event 
f) the relationship of the event to the study drug (causality assessment). 
 
Vital signs abnormalities will be recorded as AEs only if they are considered clinically 
significant, are symptomatic, require corrective treatment or fulfil a seriousness criterion. Day-
to-day fluctuations in pre-existing conditions that do not represent a clinically significant 
change in the participant’s status (including fluctuation in symptoms of asthma) will not be 
reported as AEs. 
 
10.2.2.1 Reporting time period 
For the purpose of this study, all non-serious AEs will be reported from the time of granting 
main study informed consent until the participant’s EOS visit (Week 52). Events reported prior 
to this will be recorded as medical history unless the symptoms worsen during the follow-up 
period. 
 
SAEs will be reported for the same period. SAEs occurring after the reporting period that the 
Investigator becomes aware of will be reported to the Sponsor within 24 hours of being aware 
of the event. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 58 of 151                        
 
 
10.2.2.2 Severity grading 
The medical assessment of AE severity will be recorded in accordance with the classification 
detailed in the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Paediatric Adverse Events Version 2.1, Jul 2017.25 
 
AEs not specifically referenced in the DAIDS classification will be graded in accordance with 
the following general guidelines detailed in the classification document: 
 
• 
Grade 1: Mild symptoms causing no or minimal interference with usual social and 
functional activities with intervention not indicated 
• 
Grade 2: Moderate symptoms causing greater than minimal interference with usual 
social and functional activities with intervention indicated 
• 
Grade 3: Severe symptoms causing inability to perform usual social and functional 
activities with intervention or hospitalisation indicated 
• 
Grade 4: Potentially life-threatening symptoms causing inability to perform basic self-
care functions with intervention indicated to prevent permanent impairment, persistent 
disability, or death 
•  
Grade 5: Death related to the AE. 
•  
10.2.2.3 Relationship to study drug 
The investigator will assess the relationship of each event to the study drug and decide 
whether, in his or her medical judgment, there is a reasonable possibility that the event may 
have been caused by the study drug. This should be documented in the participant’s source 
documentation and eCRF. 
 
The following may guide this assessment: 
 
• Related: 
 
o The event has a reasonable temporal relationship to study drug administration 
 
o The event is more likely to be explained by the study drug than by another cause 
 
o This includes events considered possibly related to the study drug 
 
• Not related: 
 
o Events not meeting the “related” criteria. 
 
Where possible, a distinction will be made between events considered related to the study 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 59 of 151                        
 
drug and those related to study-specific procedures. 
 
10.2.2.4 Outcome 
The investigator will follow up all AEs wherever possible until they have attained an 
acceptable outcome. 
 
The date of the outcome will be recorded, and the course of the AE will be assessed in 
accordance with the following classification: 
 
• Recovered/resolved: the AE has resolved, and the participant returned to their condition 
prior to onset 
 
• Recovered/resolved with sequelae: the AE resolved, but the participant has sequelae 
 
• Recovering/resolving: the AE has almost resolved, and the participant is returning to his 
condition prior to onset 
 
• Death: the participant died 
 
• Not recovered/not resolved: the AE had not resolved, and the participant’s condition 
remained unchanged at the last time of observation. 
 
In case of death from a different cause, events ongoing at the time of death will be classified 
as such. 
 
10.2.2.5 Action taken and follow-up of events 
All adverse events will be followed up by the Investigator until: 
 
• the event is resolved, or stable 
 
• no further medically relevant information in relation to the event can be expected, and 
 
• the investigator considers it justifiable to terminate the follow-up. 
 
Events that are ongoing at the time of the participant’s EOS visit should be indicated as “not 
recovered/not resolved” or “recovering/resolving” (whichever applicable) if considered 
unrelated to the study drug. AEs that are considered related to the study drug and are 
ongoing at the time of the participant’s EOS visit will continue to be followed up by the 
Investigator until the event has resolved or the Investigator, Sponsor and Medical Monitor 
consider it justifiable to terminate the event follow-up. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 60 of 151                        
 
All AEs should be treated appropriately. The Investigator will decide upon the appropriate 
action to be taken in response to an AE, which may include one or more of the following: 
 
• no action taken (i.e., further observation only) 
 
• administration of a concomitant medication or other treatment 
 
• hospitalisation or prolongation of current hospitalisation (event to be reported as an SAE) 
 
• other. 
 
10.2.3 Reporting of serious adverse events 
The investigator will report all SAEs to the Sponsor within 24 hours of the site personnel 
becoming aware of the event in accordance with the procedures described in the Safety 
Management Plan. The report should be in writing by email with the Medical Monitor on copy 
and documented on a standard SAE Reporting Form. In addition to this, fatal or life-threatening 
SAEs must be reported immediately to the Sponsor and the Medical Monitor, irrespective of 
the extent of available AE information. 
 
For all SAEs, the investigator is obligated to pursue and provide information in accordance with 
the timeframes for reporting specified above. In addition, an investigator may be requested to 
obtain specific additional follow-up information in an expedited fashion. This information may 
be more detailed than that captured on the AE case report form. In general, this will include a 
description of the AE in sufficient detail to allow for a complete medical assessment of the case 
and independent determination of possible causality. Information on other possible causes of 
the event, such as concomitant medications and illnesses must be provided. In the case of a 
participant death, a summary of autopsy findings (if available) must be submitted as soon as 
possible to the Sponsor. 
 
All SAEs will be followed-up until resolution, or until in the opinion of the PI and the Medical 
Monitor, no further improvement can be reasonably expected on medical grounds. 
 
The UKZN BREC and SAHPRA will be notified of all SAEs in accordance with their 
requirements. Reporting and follow-up procedures are described in the Safety Management 
Plan (SMP). 
 
All the research sites have an emergency trolley which is checked daily, and a log of the 
equipment is kept on site to ensure that all the emergency equipment and medication is 
available in case of an emergency. 
 
10.2.4 Pregnancy 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 61 of 151                        
 
All women of reproductive potential will be advised on contraceptives. Should a participant 
become pregnant during the study (at any stage), she will be counselled regarding the use of 
budesonide-formoterol during pregnancy or asthma standard of care. 
 
Pregnancies occurring in participants enrolled in this study will be reported. Follow-up will 
include, but is not limited to, the following: 
 
• Ultrasound at approximately 20 weeks’ gestation 
 
• Pregnancy complications 
 
• Outcome ascertainment 
 
• Information related to live births 
 
• Follow-up of infants to approximately 3 months of age. 
 
Reporting will be performed using a standard Pregnancy Reporting Form. The reporting 
procedure follows that described for SAEs in Section 10.2.3. 
 
Pregnancy alone is not regarded as an AE. Elective abortions without complications should not 
be considered AEs unless they were therapeutic abortions. Hospitalisation for normal delivery 
of a healthy Newborn should not be considered an SAE. Pregnancy is not considered an SAE 
unless there is an associated outcome that meets one or more of the SAE criteria. 
Spontaneous abortions should always be reported as SAEs. 
 
Any pregnancy outcome considered to be an SAE should be reported within the timelines and 
using the procedures described in Section 10.2.3. 
 
10.2.5 Assessment and recording of adverse events 
All AEs regardless of seriousness or relationship to the study drug are to be recorded in the 
eCRF. AEs can be spontaneously reported by the participant, observed by the investigator 
(either directly or through objective assessment) or elicited by general questioning. 
Whenever possible, symptoms should be grouped as a single syndrome or diagnosis. 
 
 
11 Study Limitations 
The study will be limited due to it not being double-blind but open label in design. The pragmatic 
nature of the study comparing standard of care and budesonide-formoterol necessitates this 
methodology, as well as being similar to other real-world studies NOVEL and START studies. The 
reliance on self-reporting for our outcomes and study end-points. There may also be recall bias 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 62 of 151                        
 
due to timing of the study visits. Lastly, there may be social desirability bias by study participants 
and parents/guardians from the self-reporting of symptoms. 
 
 
12 Statistical considerations 
We will enroll 1038 participants. Assuming a 10% loss to follow-up, 1142 participants will 
complete the trial (571 experimental, 571 control; 286 children, 286 adolescents). Sample size 
has been performed for the primary endpoint of severe asthma exacerbations based on the 
assumption that approximately 40% of participants under the standard of care will experience at 
least one such exacerbation in a 52-week period giving an anticipated rate of 
0.7 severe exacerbations per year (conservative assumptions). The severe exacerbation rate of 
0.7 in the control group was estimated based on studies with similar study populations. A recent 
meta-analysis reported a 36% reduction in exacerbations with ICS/LABA.28 The sample size 
calculations was based on a clinically relevant 25% reduction in severe exacerbations (equivalent 
to average rate of 0.525 severe exacerbations/year) between the control and experimental 
groups. Sample size was calculated using the negative binomial distribution with the 
"power.nb.test" function in R, based on work by Zhu and Lakkis.29, 30 The negative binomial allows 
a degree of ‘over dispersion’ meaning that individuals differ in their underlying propensity to (i.e. 
rate of) exacerbations. This over dispersion is reflected by the dispersion parameter k.30 At 90% 
power, a two-sided significance level of 0.05, and assuming k =0.7, a minimum sample size of n = 
519 subjects per arm. Calculations were undertaken with different estimates of k to ensure 
robustness (k= 0.9, 646 per arm; k = 0.5, 544 per arm) and noting that we are powered for a 
relatively small rate reduction, if the true dispersion is 0.9 then at n = 443 subjects per arm we will 
retain 85% power to detect a 25% reduction and 95% power to detect a 30% reduction in severe 
asthma exacerbations. A sample size of n = 387 per arm will have 80% power to detect a 25% 
difference in the rate of severe exacerbations between arms. For the study analysis plan the 
following populations are defined and will be described in greater detail in the trial Statistical 
Analysis Plan (SAP). An intention to treat analysis approach will be adopted to on all enrolled 
randomised participants. A per-protocol analysis plan will be performed for all participants who 
completed the study protocol procedures without any major protocol deviations. For the safety 
analysis, all participants who received at least one dose of the study drug will be analysed. 
 
Based on previous GAN data of 3957 children in Durban, the asthma prevalence of adolescents 
age 12-14 year of age is 13.8%.3 Based on this and from engagement with the AHRI 
Biostatistician, the population of uMkhanyakude, we will therefore recruit children and 
adolescents in AIR-South Africa from all the Somkhele Research Campus from 6 drainage clinics 
and the Hlabisa District Hospital which serves a community of 137 000 which has been followed 
up for the past 20 years as part of the Health and Demographic Survey System (HDSS) with 
excellent data management systems. This is a relatively stable population with low levels of 
migration in a rural community in uMkhanyakude. The current paediatric population of 6–18-year-
olds is 31 729 children. Based on our calculations we should have a minimum of 4 128 asthmatic 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 63 of 151                        
 
children in the population, and we will be using an active recruitment strategy at schools to 
identify any undiagnosed children in the community. Based on this, we should be able to recruit 
the required sample size. 
 
13 Ethical considerations 
13.1 Regulatory and Ethical Considerations 
The study will be done according to South African GCP Guidelines , the Belmont Report, the 
Declaration of Helsinki, and South Africa legal requirements regarding clinical trials.31 The study 
protocol and relevant supporting documents will be submitted for review and approval by 
SAHPRA and UKZN BREC. The study protocol has been registered with the South African 
National Clinical Trial Registry (www.sanctr.gov.za), National Human Research Ethics 
Committee (www.ethicsapp.co.za) and www.ClinicalTrial.gov. Six-monthly progress reports will 
be submitted to SAHPRA and BREC for the duration of the study, and as requested. Upon 
completion or premature termination of the study, the investigator will provide BREC and 
SAHPRA with a summary of the study’s outcome, and any reports required. Administrative 
approvals will also be requested from the district and provincial departments of health and 
education.  
 
13.2 Informed Consent Process 
The principles of informed consent in the current edition of the Declaration of Helsinki will be 
implemented before any protocol-specified procedures or interventions are carried out. The 
active case finding consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. 
 
As per the South African National Department of Health guide on “Ethics in Health Research: 
Principles, Processes and Structures (2015),” all participants <18 years of age will have to 
provide assent and consent from the parent or Parent/Guardian. In South Africa, children ≥18 
years of age are able to independently consent for medical and surgical procedures. In the 
South African context, “Parent/Guardian” means a person who factually cares for a child (s 1 
Children’s Act, 38 of 2005; a Parent/Guardian is obliged (in terms of s 32(1)) to safeguard the 
child’s health, well-being and development; and to protect the child from abuse and other harms. 
Further, a Parent/Guardian may exercise the parental right to consent to medical examination or 
treatment of the child (in terms of s 32(2)). We will adhere to the guidelines for all minors 
(children and adolescents) considering, amongst others, special precautions for children 
(including orphans) living in child headed households and children who are taken care of by a 
legal guardian. Furthermore, parental permission and permission from orphans without legal 
guardians, will be obtained according to the guidelines. We do not envisage that child headed 
households and orphans without legal guardians would be recruited into this study based on our 
previous experience conducting studies in this setting. If a child turns 18 years during the course 
of the study, he/she will be re-consented to obtain their permission to continue participation in 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 64 of 151                        
 
this study. According to South African law, an unmarried minor mother may not agree to the 
participation of her child in research without assistance. Her guardian (usually her parent) is also 
the guardian of her child while she is a minor and must consent to the child’s participation. In 
other words, pregnancy and childbirth do not change the legal status of the minor mother. When 
the mother reaches the age of majority (18 years), she may consent to her child’s participation in 
research. However, we do not anticipate recruiting mothers who are also minors based on 
previous experience in this setting. 
 
Participants and or guardian/parent will be counselled about the available data regarding the 
efficacy of budesonide-formoterol in improving asthma control and preventing exacerbations but 
also that data is limited in children between the age of 6 and 11 years of age. Potential 
participants and or guardian/parent will have the opportunity to have any questions answered 
before and after signing the informed consent forms (ICFs). The informed consent process and 
all questions raised will be documented. 
 
The study staff who conduct the informed consent process will also sign the ICFs. A copy of the 
consent form(s) will be given to the participant and or guardian/parent, and this fact will be 
documented in the participant’s record. 
 
Any participant who is rescreened should be re-consented and eligibility for the study must be 
re-checked prior to enrolment with regard to all other screening procedures. 
 
13.3 Study Records and Confidentiality 
The study site will establish a standard operating procedure for confidentiality protection. The 
site will ensure that study records including administrative documentation and regulatory 
documentation as well as documentation related to each participant enrolled in the study, 
including ICFs, locator forms, case report forms, notations of all contacts with the participant, 
and all other source documents are stored in a secure manner. 
 
All records will be kept in a secure storage area with limited access. Clinical information will not 
be released without the written permission of the participant, except as necessary for monitoring, 
and auditing by the Regulatory Authority or the Institutional Review Board (IRB)/ BREC. 
 
The PI or designee and all employees and co-workers involved with this study may not disclose 
or use, for any purpose other than performance of the study, any data, record, or other 
unpublished confidential information disclosed to those individuals for the purpose of the study. 
• 
Electronic source documents will be kept in the designated secured server which is 
password protected. 
• 
All computers used during the study conduct will be password-protected, and records will 
only be accessible to authorised study staff delegated on the delegation log. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 65 of 151                        
 
13.4 Compensation for Injury 
The Sponsor will ensure that compensation is provided for reasonable medical expenses 
incurred because of study-related injury, illness, or death, as determined according to the 
guidelines laid down by the Association of the British Pharmaceutical Industry (ABPI) 
compensation guidelines Version 2014, and Guidelines for Good Practice in the Conduct of 
Clinical Trials in Human Participants in South Africa.32 
 
13.5 Participant Remuneration 
For each day of protocol-related study procedures, the participants will receive compensation for 
travel costs to and from the clinic and inconvenience incurred, as per local regulating body 
recommendations at R400 per clinic visit for the participant and parent/guardian for any 
scheduled visit which is less 3 hours as per SAHPRA Guideline for clinical trial participants time, 
inconvenience and expense (TIE) Compensation model July 2022. Should the visits extend 
beyond 3 hours participants and parents/guardians will be provided with an additional R50 to 
cover meals. 
 
13.6 Budget 
The Research site will be funded by NIHR for the clinical trial for a total amount of ZAR 42 
885519.00 for 5 years. UKZN has sub-contracted the AHRI Clinical Trials unit as Sponsor and 
an independent clinical trial monitor has been commissioned to assist with trial oversight. AHRI 
will be compensated by UKZN for all trial related renumeration including site staff, equipment, 
consumables and infrastructural requirements.  
 
The PI will not receive any renumeration for the study as her salary is recycled through the grant 
for payment of a clinician to assist with her clinical duties and as a PhD student.  
 
1. UKZN PhD students (100% FTE):  
a. 1 Clinical salary: for 5 years (R 1 304 023/year) 
b. 1 Health economics PhD salary for 3 years (R 1 05 000/year) 
c. 1 clinical PhD for 3 years (R 1 308 000/year) 
d. 1 Clinical PhD for 3 year (R 1 160 000/year) 
 
2. AHRI salary: Staff costs  
a. CTU administrator (FTE 25% year 1 and 50% year 2-5): R356 168 per year 
b. Trial co-ordinator (50% FTE): R 715 000 per year  
i). Medical officers (25% FTE): R 317 311 per year (year 1-5) 
ii). Enrolled nurses (FTE 300%): R 1 7 00 234 per year (Year 1-5) 
iii). Research pharmacists (25% FTE): R 144 4500 per year (Year 1-5) 
iv). Database manager (25% FTE): R 356 168 per year 
v). Clinical research assistants (300% FTE): R 738 312 per year (Year 1-5) 
vi). Grants officer (5% FTE): R 30 607 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 66 of 151                        
 
 
3. Trial monitor: R1 808 860.00 monitoring professional and pass-through costs. 
4. Trial insurance: R219 537.00 annual premium for 1038 participants. 
The investigator-initiated research approval for funding the supply of IP and spacers has been 
approved by the AstraZeneca Global team, so we have secured funds for the IP. 
 
We will randomise 519 study participants to the active arm. The study drug requested for 
participants is for 260 pMDI (6-11-year-old) and 260 DPI (12-18 adolescents)  
 
a) Vannair 80/4.5 pMDI= a total of (130 X 12) 1560 of 3120 
b) Vannair 160/4.5 pMDI = total of (130X 12) 1560 of 3120 
c) Symbicort 160/4.5 DPI = total of (260 X 12) 3120   
d) Spacers = 519. 
Should there be the requirement to source additional IP, the budget would accommodate 
additional purchasing of IP. 
 
 
13.7 Protocol Amendments 
Any protocol amendments will be prepared by the Sponsor and submitted to UKZN BREC and 
SAHPRA in accordance with local requirements. 
Approval must be obtained from the UKZN BREC and SAHPRA (as required) before the 
implementation of any changes, except for changes necessary to eliminate an immediate hazard 
to participants, or changes that involve logistical or administrative aspects only (e.g., change in 
contact information). 
 
13.8 Clinical Data Records 
A log of names, signatures and initials of all staff authorised to enter data into a participant’s 
clinic file and eCRF will be kept. 
 
The investigator will maintain paper or electronic source documentation in a locked place and 
password encrypted electronic device for all study participants. Protocol-specific participant 
information will be captured in an eCRF. The Clinical Data Management System (CDMS) will 
comply with regulatory guidelines and requirements for electronic systems. Data validation and 
quality control procedures will be detailed in the Data Management Plan (DMP). 
 
All deviations from this study protocol will be documented in the Trial Master File (TMF) and 
included in the final study report. An assessment of the significance of each protocol deviation 
will be presented in the clinical study report. 
 
13.9 Record Retention 
All source data and clinical records relating to the study will be archived for a minimum 15 year-

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 67 of 151                        
 
period after completion of the study in accordance with South African GCP guidelines, Sponsor 
and Funder requirements. Data will be available for retrospective review or audit by arrangement 
with the appropriate representative at the archiving organisation (e.g., Sponsor Head). Written 
agreement from the Funder NIHR, must precede destruction of the same. 
 
13.10 Discontinuation of the Study 
AHRI the Sponsor, NIHR the Funder, the PI, UKZN BREC and Regulatory Authority 
independently reserve the right to discontinue the study at any time for safety or other reasons. 
This will be done in consultation with the Funder, Sponsor and PI where practical. In the event of 
premature termination or suspension of the study, the above-mentioned parties will be notified in 
writing by the terminator/suspender stating the reasons for early termination or suspension (with 
the exception of the Sponsor’s responsibility for notifying the Regulatory Authority). Following 
such a decision, the Sponsor and the investigator will ensure that adequate consideration is 
given to the protection of the participants’ interest and safety. All ongoing participants will be 
followed up for a minimum of 28 days post initiation of the study drug and will be scheduled for 
an EOS visit. At this visit all assessments scheduled in accordance with the Schedule of Events 
will be performed. 
 
13.11 Publication Policy 
A dissemination plan will be developed with all project partners prior to study completion. After 
study completion, results will be disseminated using the following strategies: written methods 
(i.e., publications in peer reviewed scientific journals), presentations at scientific conferences 
and workshops, in person dissemination of results to the research participants, the ministry of 
health and using electronic methods such as the project website and electronic media to publish 
results. 
 
13.12 Study Audits 
Audits may be carried out by the Sponsor quality assurance representatives, local authorities, or 
authorities to whom information on this study has been submitted. All documents pertinent to 
this study must be made available for such inspections after adequate notice of the intention to 
audit is provided. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 68 of 151                        
 
14 References 
1. 
Adeloye D, Chan KY, Rudan I, Campbell H. An estimate of asthma prevalence in Africa: a 
systematic analysis. Croat Med J. 2013;54(6):519-31. 
2. 
Meghji J, Mortimer K, Agusti A, Allwood BW, Asher I, Bateman ED, et al. Improving lung 
health in low-income and middle-income countries: from challenges to solutions. Lancet. 
2021;397(10277):928-40. 
3. 
Mphahlele RE, Kitchin O, Masekela R. Barriers and determinants of asthma control in 
children and adolescents in Africa: a systematic review. BMJ Open. 2021;11(10):e053100. 
4. 
WHOsdg. http://www.who.int/sdg/en/. 
5. 
GAR2018. http://globalasthmareport.org/. 
6. 
Baard CB, Franckling-Smith Z, Munro J, Workman L, Zar HJ. Asthma in South African 
adolescents: a time trend and risk factor analysis over two decades. ERJ Open Res. 2021;7(2). 
7. 
Hatter L, Bruce P, Braithwaite I, Holliday M, Fingleton J, Weatherall M, et al. ICS-
formoterol reliever versus ICS and short-acting β(2)-agonist reliever in asthma: a systematic 
review and meta-analysis. ERJ Open Res. 2021;7(1). 
8. 
Crossingham I, Turner S, Ramakrishnan S, Fries A, Gowell M, Yasmin F, et al. 
Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with 
mild asthma. Cochrane Database Syst Rev. 2021;5(5):Cd013518. 
9. 
O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, et al. Inhaled 
Combined Budesonide-Formoterol as Needed in Mild Asthma. N Engl J Med. 2018;378(20):1865-
76. 
10. 
O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al. 
Budesonide/formoterol combination therapy as both maintenance and reliever medication in 
asthma. Am J Respir Crit Care Med. 2005;171(2):129-36. 
11. 
Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in 
combination with formoterol for reliever therapy in asthma exacerbations: a randomised 
controlled, double-blind study. Lancet. 2006;368(9537):744-53. 
12. 
Bateman ED, Reddel HK, O'Byrne PM, Barnes PJ, Zhong N, Keen C, et al. As-Needed 
Budesonide-Formoterol versus Maintenance Budesonide in Mild Asthma. N Engl J Med. 
2018;378(20):1877-87. 
13. 
Masekela R, Mortimer K, Aluoch J, Ozoh OB. Building research capacity to correct global 
health's wrongs. Lancet Glob Health. 2022;10(2):e175-e6. 
14. 
GINA. https://ginasthma.org/. 
15. 
Beasley R, Holliday M, Reddel HK, Braithwaite I, Ebmeier S, Hancox RJ, et al. Controlled 
Trial of Budesonide-Formoterol as Needed for Mild Asthma. N Engl J Med. 2019;380(21):2020-
30. 
16. 
Hardy J, Baggott C, Fingleton J, Reddel HK, Hancox RJ, Harwood M, et al. Budesonide-
formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in 
adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, 
superiority, randomised controlled trial. Lancet. 2019;394(10202):919-28. 
17. 
Manjra AI, Van Niekerk A, White DA, Kling S, Zar HJ, Masekela R, et al. Summary of 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 69 of 151                        
 
childhood asthma guidelines, 2021: A consensus document. South African Medical Journal. 
2021;111(5):395. 
18. 
drugs.com. https://www.drugs.com/pregnancy/budesonide-formoterol.html. 
19. 
FDA. chrome-
extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.accessdata.fda.gov/drugsatfda_docs/l
abel/2023/216579s000lbl.pdf. 
20. 
ema.europa. https://www.ema.europa.eu/en/documents/product-information/duoresp-
spiromax-epar-product-information_en.pdf. 
21. 
Pearlman DS, Eckerwall G, McLaren J, Lamarca R, Puu M, Gilbert I, et al. Efficacy and 
safety of budesonide/formoterol pMDI vs budesonide pMDI in asthmatic children (6-<12 years). 
Ann Allergy Asthma Immunol. 2017;118(4):489-99.e1. 
22. 
Morice AH, Peterson S, Beckman O, Kukova Z. Efficacy and safety of a new pressurised 
metered-dose inhaler formulation of budesonide/formoterol in children with asthma: a superiority 
and therapeutic equivalence study. Pulm Pharmacol Ther. 2008;21(1):152-9. 
23. 
Bisgaard H, Le Roux P, Bjåmer D, Dymek A, Vermeulen JH, Hultquist C. 
Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. 
Chest. 2006;130(6):1733-43. 
24. 
Pohunek P, Kuna P, Jorup C, De Boeck K. Budesonide/formoterol improves lung function 
compared with budesonide alone in children with asthma. Pediatr Allergy Immunol. 
2006;17(6):458-65. 
25. 
Antonio Buendía J, Lindarte EF, Patiño DG. Comparison of three alternatives for the 
management of moderate asthma in children aged 6-11 years: a cost-utility analysis. J Asthma. 
2023;60(4):761-8. 
26. 
Szefler S, Weiss S, Tonascia J, Adkinson NF, Bender B, Cherniack R, et al. Long-term 
effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343(15):1054-
63. 
27. 
Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al. Management of 
severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir 
J. 2020;55(1). 
28. 
Kirenga BJ, de Jong C, Mugenyi L, Katagira W, Muhofa A, Kamya MR, et al. Rates of 
asthma exacerbations and mortality and associated factors in Uganda: a 2-year prospective 
cohort study. Thorax. 2018;73(10):983-5. 
29. 
Keene ON, Calverley PM, Jones PW, Vestbo J, Anderson JA. Statistical analysis of 
exacerbation rates in COPD: TRISTAN and ISOLDE revisited. Eur Respir J. 2008;32(1):17-24. 
30. 
Zhu H, Lakkis H. Sample size calculation for comparing two negative binomial rates. Stat 
Med. 2014;33(3):376-87. 
31. 
Safety S. South African Health Products Regulatory Authority. Safety Reporting During 
Clinical Trials in South Africa.; 2021. https://www.sahpra.org.za/wp-
content/uploads/2021/10/Safety- Reporting-During-Clinical-Trials_-August-2021_V4.pdf. 
32. 
SA_GCP. South African Department of Health. South African Good Clinical Practice: 
Clinical Trial Guidelines.; 2020. https://www.sahpra.org.za/wp-content/uploads/2021/06/SA-GCP- 
2020_Final.pdf. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 70 of 151                        
 
15 APPENDICES 
15.1 Appendix 1: Study screening questionnaire  
Unique Study ID Number: 
 
 
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
Protocol Version and 
Approval Date: 
Version 1.1; 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela, uMkhanyakude 
Institution: 
Africa Health Research Institute 
 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I 
am a ______________________________ (INSERT DESIGNATION) at ____________________ (INSERT 
SITE). 
 
We would like to invite your child to consider taking part in a research study called “Anti-
Inflammatory Reliever therapy for asthma using inhaled budesonide/formoterol as-needed with or 
without maintenance in South African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial”.  
We are currently recruiting participants for a trial involving budesonide/formoterol and regular asthma 
therapy.  The purpose of the study is to check whether using a newer asthma pump 
(Budesonide/formoterol) will lead to reduced asthma attacks compared to the normally used asthma 
pump in South African children and adolescents and to see if this will reduce the costs of asthma care. 
Would you be willing for your child to be part of the study? 
Yes ☐ 
No ☐ 
If No, please sign below. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 71 of 151                        
 
If you are willing for your child to participate, you will be asked some questions about your child for us to 
check if he/she would be a potential participant for the study.  
 
If you decide for your child to take part in this study, you will be given the document about the study and 
be guided through the next steps. You will also be given a copy to keep and refer to.  
 
PARENT/GUARDIAN: 
_________________________________________________________________________ 
Printed Name(s) and Surname 
 
_________________________________________________________________________ 
Signature / Mark or Thumbprint                                                           Date and Time 
 
WITNESS (If applicable): 
_________________________________________________________________________ 
Printed Name(s) and Surname 
 
_________________________________________________________________________ 
Signature / Mark or Thumbprint                                                              Date and Time 
 
INVESTIGATOR: 
_________________________________________________________________________ 
Printed Name(s) and Surname 
 
_________________________________________________________________________ 
Signature 
 
 
 
 
 
 
 
    Date and Time 
 
 
 
  
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 72 of 151                        
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 73 of 151                            
 
15.2 Appendix 3: Patient information and consent form 
 
PARTICIPANT INFORMATION LEAFLET AND INFORMED CONSENT 
 
Each participant must receive, read and understand this document before any study-related procedure is 
performed 
 
Study  Uniqe ID : 
 
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
 
Protocol Version and 
Approval Date: 
Version 1.1 21 Aug 2023;  
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela  
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
To the potential participant: This consent form may contain words that you do not understand. Please ask the 
study doctor or the study staff to explain any words or information that you do not clearly understand. You may 
take home an unsigned copy of this consent form to think about or discuss with family or friends before making 
your decision. 
 
 
ICF administration starting time: _________________ ICF administration finish time: ___________________ 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 74 of 151                            
 
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I am a 
______________________________ (INSERT DESIGNATION) at ____________________ (INSERT SITE). 
I would like to invite you to consider having your child taking part in a research study called “Anti-
Inflammatory Reliever therapy for asthma using inhaled budesonide/formoterol as-needed with or without 
maintenance in South African children: A Pragmatic Open Label Phase 3 Randomised Controlled Trial. “ 
• 
Before you decide if you want your child to be part of this study, we would like to give you information to 
help you decide if you would like to be part of the study.  
• 
Please take the time to think through the following information and discuss it with others if you wish. 
Knowing what is involved will help you decide if you want your child to take part.  
• 
If you have any questions, do not hesitate to ask me.   
• 
You should not agree to take part unless you are happy about all the procedures involved.  
• 
Please be open with me regarding your child’s health history since you may otherwise harm your child by 
taking part in this study. 
• 
If you decide for your child to take part in this study, you will be asked to sign this document to confirm that 
you understand the study. You will also be given a copy to keep and refer to. 
• 
Should you agree for your child to take part in the study we will do so without revealing his/her study 
identity. 
 
What is the purpose of the study? 
 
• 
The purpose of the study is to check whether using a newer asthma pump will lead to reduced asthma 
attacks compared to the normally used asthma pump in South African children and adolescents and 
to see if this will not cost a lot of money.  
 
Why has my child been invited? 
• 
Your child have been selected to participate in this study because he/she has asthma symptoms and 
have been diagnosed with asthma. We got your child’s details from Somkhele Campus of the African 
Health Research Institute (AHRI) database which includes all people living in your area. We are 
planning to include 1142 participants who will be divided into 2 age groups (6 -11 years) and (12 – 18 
years). Your child will either be in the group that will be taking normal asthma medication dispensed 
at the clinic (standard medication) or he/she will receive the study asthma pump (new medicine 
called Vannair or Symbicort) 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 75 of 151                            
 
Does my child have to take part? 
• Taking part in this study is entirely voluntary. You do not have to have your child take part if you would 
not like to. If you choose to have your child take part and you change your mind later about 
participation in the study, you can withdraw from the study at any point, without giving a reason. 
Withdrawal from the study will not affect your child’s clinical care at the clinic or hospital and you will 
not incur any penalties 
 
What will happen to me if I decide for my child to take part? 
• 
When you decide to have your child take part, you will be asked to sign the consent form to confirm 
that you have received enough information about the what the study is about and that and you are 
willing for him/her to take part. 
• 
You will be asked few questions so that we get to know you and your child’s background better. 
• 
Your child will be allocated one of the groups then be given asthma pump (standard one or new one) 
to use for his/her asthma management.  
• 
Once allocated, your child will stay in that group for the duration of the study. 
• 
The number of participants in the standard asthma pump and the new asthma pump will be the same. 
• 
Your child will be involved in this study for 12 months. During this period, he/she will have checkups 
every 3 months. The check-up will be either by one of the nurses/investigator at the clinic/hospital or 
will be done telephonically. 
• 
The checkups are to check how he/she is feeling  and whether he/she has had any asthma attacks or 
any undesired harmful effects from the medication or any concerns. 
• 
Your child can go to the clinic at any point if he/she is unwell or you have any concerns, you don’t 
have to wait for the scheduled appointments. 
 
What should I consider? 
• 
Your child cannot participate in the study if he/she do not have asthma or if he/she has active 
tuberculosis on treatment. If he/she is taking any other medication, you will be expected to let us 
know what these are. If he/she is taking the medicine that can interact with any medicine in the new 
pump, he/she will not be expected to participate in the study.  If your child is involved in any other 
research studies, we will request that you let us know as this ma also not allow us to enroll your child 
in this current study without discussion with the principal investigator of that study. 
 
Are there any possible disadvantages or risks from taking part? 
• The risks expected during the study are adverse events (side-effects) from the drugs being given, 
otherwise the project itself is not associated with any risks. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 76 of 151                            
 
 
For the new medication that we will be giving for the study. 
• The medicine is already recommended for use for the moderate to severe asthma treatment for 
children 6 to 11 years and for mild asthma treatment in adolescents over the age of 12 years.  
• There may be side effects from the drugs. The most common side effects are minor and well-described 
and include headache, throat irritation, nausea, vomiting, diarrhoea, blocked nose, changes in voice, 
oral candidiasis, nasopharyngitis and upper respiratory tract infections. These side effects especially 
the throat irritation, change in voice and candida can be avoided by rinsing out the mouth after using 
the medicine. 
 
What are the possible benefits of taking part? 
• 
All trial participants will benefit from the asthma education and training provided at all health centres, 
from individualised advice about what action to take in the event of deteriorating asthma and an 
asthma attack. Your child will also be guaranteed availability of first-line asthma treatments during 
the study. If the study findings are positive, we will use the findings to recommend to the health 
policy makers to make the new medicine available for all children in South Africa.   
 
Will my family doctor/ General Practitioner be informed of my child’s participation? 
• Your family doctor (should you have one) will be provided with the study information sheet and will be 
informed that your child is taking part in the study. We will require him/her to fill out information for 
us should your child experience an asthma attack and present to him/her for treatment. 
• Your family doctor may be contacted if there are any other health concerns that may be picked up 
during the study. 
 
Will my child’s taking part in the study be kept confidential? 
• Your child’s  participation to the study will be known by the relevant people such as clinical team at the 
clinic you will be attending. 
• All trial staff will protect the rights of your child’s information and privacy of his/her information will be 
maintained, including the informed consent  or assent.  
• Arrangements have been made to ensure that information is kept secure, in a locked cupboard 
accessible on the to the study team. 
• Devices with participants details will be encrypted with the password. AHRI and UKZN will maintain all 
trial records and documents and retain these for at least 15 years.  
• For the analysis of data, all direct identifiers to your child will be removed, and participants will be 
identified only by numbers. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 77 of 151                            
 
Will me and my child be reimbursed for taking part? 
• You will be reimbursed for travel expenses and inconvenience for you and your child. Your child’s 
involvement in the study should not cost you any amount. 
 
What will happen to the data? 
• 
The information received will be kept in a password crypted devices. Numbers will be used instead of 
personal identifiers during the data analysis and reporting. The information will be kept by the UKZN 
and AHRI for 15 years. 
• 
We will be using information from AHRI to undertake this study. Research is a task that we perform in 
the public interest.  
• 
We will use the minimum personally identifiable information.  
• 
We will keep identifiable information about your child for 15 years after the study has finished.  
• 
We will store the anonymized research data and any research documents with personal information, 
such as      consent forms, securely at UKZN and AHRI.  
 
You can find out more about how we use your information by contacting UKZN 031 26 04399/ 
masekelar@ukzn.ac.za or AHRI 035 251 0650 . 
 
What will happen if I don’t want to carry on with the study? 
• 
Participation is voluntary and you may change your minds at a later stage. 
• 
Withdrawal will not affect the care you receive from any health service  
• 
If you withdraw from the study, we will destroy all identifiable samples, but will use the data up to 
your withdrawal.  
 
What happens at the end of the study? 
• Your child will not be identified from any report or publication placed in the public domain.  
• We intend to publish the findings of the study, present it at conferences and give feedback to the 
community and policy makers.  
• Some of the research being undertaken will also contribute to the fulfilment of an educational           
requirement (e.g. a doctoral thesis). 
 
What if we find something unexpected? 
• 
If there are unexpected clinical findings, your child will be referred to the local clinic/ district hospital. 
We will need to report these findings, so please inform the study team should these happen.  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 78 of 151                            
 
 
What if there is a problem? 
• 
In the event of any problems or concerns/questions you may contact Professor Masekela, at 031 260 
4399/ masekelar@ukzn.ac.za or the UKZN Biomedical Research Ethics Committee and the South African 
Health Regulatory Authority on the contact details as follows:  
 
BIOMEDICAL RESEARCH ETHICS ADMINISTRATION 
 
Research Office, Westville Campus 
 
Govan Mbeki Building 
Private Bag X 54001  
Durban  
4000 
KwaZulu-Natal, SOUTH AFRICA 
Tel: 27 31 2602486 - Fax: 27 31 2604609 
Email: BREC@ukzn.ac.za  
 
SOUTH AFRICAN HEALTH PRODUCTS REGULATORY AUTHORITY:  
The Chief Executive Officer 
South African Health Products Regulatory Authority 
Loftus Park 
Building A 
402 Kirkness Street 
Arcadia, Pretoria 
0083 
  
E-mail: Boitumelo.Semete@sahpra.org.za 
Tel: 012 501 0413 
 
 
 
• 
Trial participants and staff will be covered by clinical trial indemnity and insurance for the study.  
 
How have patients and the public been involved in this study? 
• 
We plan ongoing involvement of local patient and community advisory board and consultation groups 
through trial set-up, implementation, and dissemination phases. For example, during the trial set-up 
phase we have sought input into trial plans and wording of participant information and consent forms 
from the uMkhanyakude District Community Advisory Board and patient representatives. During trial 
implementation we will share progress reports, discuss, and troubleshoot problems that arise. When 
the study results are available these will be presented and pathways to impact discussed and planned. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 79 of 151                            
 
 
Who is organizing and funding the study 
• The National Institute of Health and Care Research (United Kingdom) via a Global Health Research 
Professorship Grant has awarded grant to Professor Refiloe Masekela  
• Your doctor will not be paid for their role in the study (if contacted to verify information or follow up 
updates) and there will be no conflicts of interest.  
 
Who has reviewed the study? 
• 
We will request ethical review of the trial protocol and other documents by the University of KwaZulu 
Natal Biomedical Research Ethics Committee and the South African Health Products Regulating 
Authority (SAHPRA). The trial will not commence until we have ethical approval. The final approved 
version of the protocol will be registered with Current Controlled Trials Ltd and published in an open 
access format. Trial oversight committees will be established.  
 
Further information and contact details: 
• 
Please contact Professor Refiloe Masekela 031 260 4399, masekelar@ukzn.ac.za or in writing to: 
4th floor Dept of Paediatrics and Child Health 
Nelson R Mandela School of Medicine 
Durban  
4013 
 
Thank you for considering taking part. 
DECLARATION OF CONSENT  
 
I ……………………………………………………………………………… have been informed about the study entitled ‘Anti-
Inflammatory Reliever therapy for asthma using inhaled budesonide/formoterol as-needed with or without 
maintenance in South African children: A Pragmatic Open Label Phase 3 Randomised Controlled Trial’ by 
……………………………………………………………………. 
 
I understand the purpose and procedures of the study is to compare different types of medicine in controlling 
asthma and preventing acute asthma episodes. 
 
I have been given an opportunity to ask questions about the study and have had answers to my satisfaction. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 80 of 151                            
 
I declare that the participation of my child in this study is entirely voluntary and that I may withdraw him/her  
at any time without affecting any treatment or care that he/she would usually be entitled to. 
 
I have been informed about any available compensation or medical treatment if injury occurs to him/her as a 
result of study-related procedures. 
  
If we have any further questions/concerns or queries related to the study we understand that we may contact 
the researcher at UKZN/AHRI. 
 
If I have any questions or concerns about my child’s rights as a study participant, or if I am concerned about an 
aspect of the study or the researchers then I may contact: 
 BIOMEDICAL RESEARCH ETHICS ADMINISTRATION 
Research Office, Westville Campus 
Govan Mbeki Building 
Private Bag X 54001  
Durban  
4000 
KwaZulu-Natal, SOUTH AFRICA 
Tel: 27 31 2602486 - Fax: 27 31 2604609 
Email: BREC@ukzn.ac.za  
 
SOUTH AFRICAN HEALTH PRODUCTS REGULATORY AUTHORITY:  
The Chief Executive Officer 
South African Health Products Regulatory Authority 
Loftus Park 
Building A 
402 Kirkness Street 
Arcadia, Pretoria 
0083 
  
E-mail: Boitumelo.Semete@sahpra.org.za 
Tel: 012 501 0413 
 
PARTICIPANT NAME 
 
____________________________________ 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 81 of 151                            
 
PARENT/GUARDIAN: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INFORM CONSENT ADMINISTRATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
                              Date and Time 
 
 
WITNESS (If applicable): 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INVESTIGATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 82 of 151                            
 
Signature 
 
 
 
 
 
 
                                              Date and Time 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 83 of 151                            
 
 
15.3 Appendix 4: Patient information and parents/guardian consent 
 
PARENT/LEGAL GUARDIAN PARTICIPANT INFORMATION LEAFLET AND INFORMED 
CONSENT 
 
Each participant must receive, read and understand this document before any study-related procedure is 
performed 
 
Study Number: 
 
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
 
Protocol Version and 
Approval Date: 
Version 1.0; 23 January 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela  
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Somkhele +27 (0)35 550 7500 
 
To the potential participant: This consent form may contain words that you do not understand. Please ask the 
study doctor or the study staff to explain any words or information that you do not clearly understand. You may 
take home an unsigned copy of this consent form to think about or discuss with family or friends before making 
your decision. 
 
 
ICF administration starting time: _________________ ICF administration finish time: ___________________ 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 84 of 151                            
 
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I am a 
______________________________ (INSERT DESIGNATION) at ____________________ (INSERT SITE). 
I would like to invite you to consider taking part in a research study called “Anti-Inflammatory Reliever 
therapy for asthma using inhaled budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled Trial. “ 
• 
Before you decide if you want to be part of this study, we would like to give you information to help you 
decide if you would like to be part of the study.  
• 
Please take the time to think through the following information and discuss it with others if you wish. 
Knowing what is involved will help you decide if you want to take part.  
• 
If you have any questions, do not hesitate to ask me.   
• 
You should not agree to take part unless you are happy about all the procedures involved.  
• 
Please be open with me regarding your health history since you may otherwise harm yourself by taking part 
in this study. 
• 
If you decide to take part in this study, you will be asked to sign this document to confirm that you 
understand the study. You will also be given a copy to keep and refer to. 
• 
Should you agree to take part in the study we will do so without revealing your study identity. 
 
What is the purpose of the study? 
• 
The purpose of the study is to check whether using a newer asthma pump will lead to reduced asthma 
attacks compared to the normally used asthma pump in South African children and adolescents and 
to see if this will not cost a lot of money.  
 
Why have I been invited? 
• 
You have been selected to participate in this study because you have asthma symptoms and has been 
diagnosed with asthma. We got your details from Somkhele Campus of the African Health Research 
Institute (AHRI) database which includes all people living in your area. We are planning to include 
1142 participants who will be divided into 2 age groups (6 -11 years) and (12 – 18 years). You will 
either be in the group that will be taking normal asthma medication dispensed at the clinic (standard 
medication) or you will receive the study asthma pump (new medicine called Vannair or Symbicort) 
 
Do I have to take part? 
• Taking part in this study is entirely voluntary. You do not have to take part if you would not like to. If 
you choose to take part and you change your mind later about participation in the study, you can 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 85 of 151                            
 
withdraw from the study at any point, without giving a reason. Withdrawal from the study will not 
affect your clinical care at the clinic or hospital and you will not incur any penalties 
 
What will happen to me if I decides to take part? 
• 
When you decide to take part, you will be asked to sign the consent form to confirm that you have 
received enough information about the what the study is about and that and you are willing to take 
part. 
• 
You will be asked few questions so that we get to know your background better. 
• 
You will be allocated one of the groups then be given asthma pump (standard one or new one) to use 
for your asthma management.  
• 
Once allocated, you will stay in that group for the duration of the study. 
• 
The number of participants in the standard asthma pump and the new asthma pump will be the same. 
• 
You will be involved in this study for 12 months. During this period, you will have checkups every 3 
months. The check-up will be either by one of the nurses/investigator at the clinic/hospital or will be 
done telephonically. 
• 
The checkups are to check how you are feeling whether you had any asthma attacks or any undesired 
harmful effects from the medication or any concerns. 
• 
You can go to the clinic at any point if you are unwell or you have any concerns, you don’t have to 
wait for the scheduled appointments. 
 
What should I consider? 
• 
You cannot participate in the study if you do not have asthma or if you have active tuberculosis on 
medication. If you are taking any other medication, you will be expected to let us know what these 
are. If you are taking the medicine that can interact with any medicine in the new pump, you will not 
be expected to participate in the study.  If you are involved in any other research studies, we will 
request that you let us know as this may not allow us to enroll you in this current study without 
discussion with the principal investigator of that study. 
 
Are there any possible disadvantages or risks from taking part? 
• The risks expected during the study are adverse events (side-effects) from the medicines being given, 
otherwise the project itself is not associated with any risks. 
 
For the new medication that we will be giving for the study. 
• The medicine is already recommended for use for the moderate to severe asthma treatment for 
children 6 to 11 years and for mild asthma treatment in adolescents over the age of 12 years.  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 86 of 151                            
 
• There may be side effects from the drugs. The most common side effects are minor and well-described 
and include headache, throat irritation, nausea, vomiting, diarrhoea, blocked nose, changes in voice, 
oral candidiasis, nasopharyngitis and upper respiratory tract infections. For the most common side 
effects, candida, throat irritation and voice changes these can be avoided by rinsing out the mouth 
after using the medicine.  
 
What are the possible benefits of taking part? 
• 
All trial participants will benefit from the asthma education and training provided at all health centres, 
from individualised advice about what action to take in the event of deteriorating asthma and an 
asthma attack. You will also be guaranteed availability of first-line asthma treatments during the 
study. If the study findings are positive, we will use the findings to recommend to the health policy 
makers to make the new medicine available for all children in South Africa.   
 
Will my family doctor/ General Practitioner be informed of my participation? 
• Your family doctor (should you have one) will be provided with the study information sheet and will be 
informed that you are taking part in the study. We will require him to fill out information for us should 
you experience an asthma attack and present to him/her for treatment. 
• Your family doctor may be contacted if they are any other health concerns that may be picked up 
during the study. 
 
Will my taking part in the study be kept confidential? 
• Your participation to the study will be known by the relevant people such as clinical team at the clinic 
you will be attending. 
• All trial staff will protect the rights of your information and privacy of your information will be 
maintained, including the informed consent or assent.  
• Arrangements have been made to ensure that information is kept secure, in a locked cupboard 
accessible on the to the study team. 
• Devices with participants details will be encrypted with the password. AHRI and UKZN will maintain all 
trial records and documents and retain these for at least 15 years.  
• For the analysis of data, all direct identifiers to you will be removed, and participants will be identified 
only by numbers. 
 
Will I be reimbursed for taking part? 
• You will be reimbursed for travel expenses and inconvenience. Your involvement in the study should 
not cost you any amount. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 87 of 151                            
 
What will happen to the data? 
• 
The information received will be kept in a password crypted devices. Numbers will be used instead of 
personal identifiers during the data analysis and reporting. The information will be kept by the UKZN 
and AHRI for 15 years. 
• 
We will be using information from AHRI to undertake this study. Research is a task that we perform in 
the public interest.  
• 
We will use the minimum personally identifiable information.  
• 
We will keep identifiable information about you for 15 years after the study has finished.  
• 
We will store the anonymized research data and any research documents with personal information, 
such as      consent forms, securely at UKZN and AHRI.  
 
You can find out more about how we use your information by contacting UKZN 031 260 4399/ 
masekelar@ukzn.ac.za or AHRI 035 251 0650 . 
 
What will happen if I don’t want to carry on with the study? 
• 
Participation is voluntary and you may change your minds at a later stage. 
• 
Withdrawal will not affect the care you receive from any health service  
• 
If you withdraw from the study, we will destroy all identifiable samples, but will use the data up to 
your withdrawal.  
 
What happens at the end of the study? 
• Your will not be identified from any report or publication placed in the public domain.  
• We intend to publish the findings of the study, present it at conferences and give feedback to the 
community and policy makers.  
• Some of the research being undertaken will also contribute to the fulfilment of an educational           
requirement (e.g. a doctoral thesis). 
 
What if we find something unexpected? 
• 
If there are unexpected clinical findings, you will be referred to the local clinic/ district hospital. We 
will need to report these findings, so please inform the study team should these happen.  
 
What if there is a problem? 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 88 of 151                            
 
• 
In the event of any problems or concerns/questions you may contact Professor Masekela, at 031 260 
4399/ masekelar@ukzn.ac.za or the UKZN Biomedical Research Ethics Committee and the South African 
Health Products Regulatory Authority on contact details as follows:  
 
BIOMEDICAL RESEARCH ETHICS ADMINISTRATION 
 
Research Office, Westville Campus 
 
Govan Mbeki Building 
Private Bag X 54001  
Durban  
4000 
KwaZulu-Natal, SOUTH AFRICA 
Tel: 27 31 2602486 - Fax: 27 31 2604609 
Email: BREC@ukzn.ac.za  
SOUTH AFRICAN HEALTH PRODUCTS REGULATORY AUTHORITY:  
The Chief Executive Officer 
South African Health Products Regulatory Authority 
Loftus Park 
Building A 
402 Kirkness Street 
Arcadia, Pretoria 
0083 
  
E-mail: Boitumelo.Semete@sahpra.org.za 
Tel: 012 501 0413 
 
 
 
• 
Trial participants and staff will be covered by clinical trial indemnity and insurance for the study.  
 
How have patients and the public been involved in this study? 
• 
We plan ongoing involvement of local patient and community advisory board and consultation groups 
through trial set-up, implementation, and dissemination phases. For example, during the trial set-up 
phase we have sought input into trial plans and wording of participant information and consent forms 
from the uMkhanyakude District Community Advisory Board and patient representatives. During trial 
implementation we will share progress reports, discuss, and troubleshoot problems that arise. When 
the study results are available these will be presented and pathways to impact discussed and planned. 
 
Who is organizing and funding the study 
• The National Institute of Health and Care Research (United Kingdom) via a Global Health Research 
Professorship Grant has awarded grant to Professor Refiloe Masekela  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 89 of 151                            
 
• Your doctor will not be paid for their role in the study (if contacted to verify information or follow up 
updates) and there will be no conflicts of interest.  
 
Who has reviewed the study? 
• 
We will request ethical review of the trial protocol and other documents by the University of KwaZulu 
Natal Biomedical Research Ethics Committee and the South African Health Products Regulating 
Authority (SAHPRA). The trial will not commence until we have ethical approval. The final approved 
version of the protocol will be registered with Current Controlled Trials Ltd and published in an open 
access format. Trial oversight committees will be established.  
 
Further information and contact details: 
• 
Please contact Professor Refiloe Masekela 031 260 4399, masekelar@ukzn.ac.za or in writing to: 
4th floor Dept of Paediatrics and Child Health 
Nelson R Mandela School of Medicine 
Durban  
4013 
 
 
Thank you for considering taking part. 
 
DECLARATION OF CONSENT  
 
I ……………………………………………………………………………… have been informed about the study entitled ‘Anti-
Inflammatory Reliever therapy for asthma using inhaled budesonide/formoterol as-needed with or without 
maintenance in South African children: A Pragmatic Open Label Phase 3 Randomised Controlled Trial’ by 
……………………………………………………………………. 
 
I understand the purpose and procedures of the study is to compare different types of medicine in controlling 
asthma and preventing acute asthma episodes. 
 
I have been given an opportunity to ask questions about the study and have had answers to my satisfaction. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 90 of 151                            
 
I declare that my participation in this study is entirely voluntary and that I may withdraw at any time without 
affecting any treatment or care that I would usually be entitled to. 
 
I have been informed about any available compensation or medical treatment if injury occurs to me as a result 
of study-related procedures. 
  
If we have any further questions/concerns or queries related to the study we understand that we may contact 
the researcher at UKZN/AHRI. 
 
If I have any questions or concerns about my rights as a study participant, or if I am concerned about an aspect 
of the study or the researchers then I may contact: 
 BIOMEDICAL RESEARCH ETHICS ADMINISTRATION 
Research Office, Westville Campus 
Govan Mbeki Building 
Private Bag X 54001  
Durban  
4000 
KwaZulu-Natal, SOUTH AFRICA 
Tel: 27 31 2602486 - Fax: 27 31 2604609 
Email: BREC@ukzn.ac.za  
 
SOUTH AFRICAN HEALTH PRODUCTS REGULATORY AUTHORITY:  
The Chief Executive Officer 
South African Health Products Regulatory Authority 
Loftus Park 
Building A 
402 Kirkness Street 
Arcadia, Pretoria 
0083 
  
E-mail: Boitumelo.Semete@sahpra.org.za 
Tel: 012 501 0413 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 91 of 151                            
 
 
PARTICIPANT: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INFORM CONSENT ADMINISTRATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
                              Date and Time 
 
 
WITNESS (If applicable): 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INVESTIGATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 92 of 151                            
 
 
__________________________________________________________________________________________ 
Signature 
 
 
 
 
 
 
 
 
Date and T

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 93 of 151                            
 
 
15.4 Appendix 5: Patient information and assent 
 
 
PARTICIPANT INFORMATION LEAFLET AND INFORMED CONSENT 
 
Each participant must receive, be informed and/or read and understand this document before any study-
related procedure is performed 
 
Study Number: 
 
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
 
Protocol Version and 
Approval Date: 
Version 1.1; 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela  
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
To the potential participant: This consent form may contain words that you do not understand. Please ask the 
study doctor or the study staff to explain any words or information that you do not clearly understand. You may 
take home an unsigned copy of this consent form to think about or discuss with family or friends before making 
your decision. 
 
 
ICF administration starting time: _________________ ICF administration finish time: ___________________ 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 94 of 151                            
 
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I am a 
______________________________ (INSERT DESIGNATION) at ____________________ (INSERT SITE). 
I would like to invite you to consider taking part in a research study called “Anti-Inflammatory Reliever 
therapy for asthma using inhaled budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled Trial. “ 
• 
Before you decide if you want to be part of this study, we would like to give you information to help you 
decide if you would like to be part of the study.  
• 
Please take the time to think through the following information and discuss it with others if you wish. 
Knowing what is involved will help you decide if you want to take part.  
• 
If you have any questions, do not hesitate to ask me.   
• 
You should not agree to take part unless you are happy about all the procedures involved.  
• 
Please be open with me regarding your health history since you may otherwise harm yourself by taking part 
in this study. 
• 
If you decide to take part in this study, you will be asked to sign this document to confirm that you 
understand the study. You will also be given a copy to keep and refer to. 
• 
Should you agree to take part in the study we will do so without telling anyone who you are or your study 
identity. 
 
What is the study about? 
• 
The reason for the study is about my asthma and to check whether using a newer asthma pump will 
may cause fewer asthma attacks compared to the normally used asthma pump and will cost less. You 
will either get the new pump or use the normal (regular) asthma medication from the clinic. 
 
Why have I been invited? 
• 
You have been invited because you have asthma. We are going to compare those who will be on 
medication the normally used at your clinic or hospital (standard) asthma pump and new asthma 
pump (Vannair or Symbicort).  
 
Do I have to take part? 
• No, you do not have to take part. If you agree to take part you are also free to quit the study at any 
time and this will not affect your care at the clinic or hospital. 
 
What will happen to me if I decide to take part? 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 95 of 151                            
 
• 
When you decide to take part, you will be given the asthma medicine that you have been allocated to. 
You will take the medicine for a year in the group you are allocated to. You will have check-ups at the 
clinic twice and you will have two telephone visit with the study team.  
• 
The nurses will ask you questions about your asthma, your medicines you used and any attacks you 
may have had. 
 
 
Will I have bad effects from the medicine? 
• The new medicine for asthma can make you feel slightly ill. You can feel feel unwell, want to vomit or 
have a blocked nose, sore head or change in your voice. If you are unwell let the study team know you 
are not well. Should you feel very bad from the medicine the doctor will check you and decide if the 
medicine should be stopped or not. 
 
How will the study help? 
 
 
• 
If we see that the new medicine works better that the normal medicine in the clinic, we will 
recommend that the new medicine should be given to children with asthma in South Africa. 
 
 
Will my taking part in the study be kept confidential? 
• 
No one but the study team will know what answers you have given and all the your name and 
information will not be available to anyone but the study team. 
 
 
What if there is a problem or questions? 
• 
In the event of any problems or concerns/questions you can speak to Professor Masekela, at 
0312604399/ masekelar@ukzn.ac.za or the UKZN Biomedical Research Ethics Committee and the South 
African Health Regulatory authority on contact details as follows:  
 
BIOMEDICAL RESEARCH ETHICS ADMINISTRATION 
 
Research Office, Westville Campus 
 
Govan Mbeki Building 
Private Bag X 54001  
Durban  
4000 
KwaZulu-Natal, SOUTH AFRICA 
Tel: 27 31 2602486 - Fax: 27 31 2604609 
Email: BREC@ukzn.ac.za  
 
SOUTH AFRICAN HEALTH PRODUCTS REGULATORY AUTHORITY:  
The Chief Executive Officer 
South African Health Products Regulatory Authority 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 96 of 151                            
 
Loftus Park 
Building A 
402 Kirkness Street 
Arcadia, Pretoria 
0083 
  
E-mail: Boitumelo.Semete@sahpra.org.za 
Tel: 012 501 0413 
 
 
 
    
 
 
PARTICIPANT ASSENT: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INFORM CONSENT ADMINISTRATOR: 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
                              Date and Time 
 
 
WITNESS (If applicable): 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 97 of 151                            
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INVESTIGATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature  
 
 
 
 
 
 
 
 
 
Date and Time

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 98 of 151                        
 
15.5 Appendix 6: Asthma screening questionnaire  
 
Study Number: 
AIR-SA-001  
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
Protocol Version and 
Approval Date: 
Version 1.1 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela-uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
ASTHMA SCREENING QUESTIONNAIRE 
Dear Potential participant, 
You are kindly requested to answer to following 6 questions regarding your breathing. The 
parent/guardian is requested to assist in answering these questions. 
 
1. Have you ever had wheezing or whistling in the chest at any time in the past? 
Yes ☐ or No ☐ 
2. Have you had wheezing or whistling in the chest in the past 12 months? 
Yes ☐ or No ☐ 
 
 
3. Have you ever had asthma? 
Yes ☐ or No ☐ 
 
 
4. Was asthma confirmed by a doctor? 
Yes ☐ or No ☐ 
 
5. Have you used any inhaled medicines e.g. pumps or nebuliser to help your breathing problems at any time 
in the past 12 months? (when you didn’t have a cold) 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 99 of 151                        
 
Yes ☐ or No ☐ 
6. How many attacks of wheezing have you had in the past 12 months? 
☐ None 
☐ 1 – 3 
☐ 4 – 12 
☐ More than 12  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 100 of 151                            
 
15.6 Appendix 7: Background information  
BACKGROUND INFORMATION 
 
Study Unique ID Number: 
 
 
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
Protocol Version and 
Approval Date: 
Version 1.1; 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof  Refiloe Masekela: uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
To the potential participant: This form may contain words that you do not understand. Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly understand. 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 101 of 151                        
 
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I 
am a ______________________________ (INSERT DESIGNATION) at ____________________ (INSERT 
SITE). 
I would like you to help me understand your / your child’s background information by answering these 
questions. 
 
Background information 
 
1. How old are you in years:___________ 
 
2. What is your date of birth: ____/___/________ 
 
3. What is your sex:  
☐  Male     
☐ Female 
4. Do you have a chronic condition/s? Yes☐ or No ☐ 
State the name of the condition ……………………………………………………………………..…….. 
 
5. Are you taking any chronic medications? Yes☐ or No ☐ 
 
6. If yes to question 5, what is the name of the medication (s)?____________________________ 
 
______________________________________________________________________ 
 
 
Asthma diagnosis 
7. Who diagnosed the asthma? 
☐ Doctor 
☐ Nurse 
☐ Self 
☐Other 
 
8. Age at diagnosis 
☐ Less than 4 years 
☐ 4 – 11 years 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 102 of 151                        
 
☐ 12 years and above 
 
Asthma medication 
9. Are you taking any asthma medication currently? Yes ☐ or No ☐ 
 
10. Which medication? Tick appropriate medication below: 
☐ Budesonide 
☐ Beclomethasone 
☐ Fluticasone/salmeterol 
☐ Montelukast 
☐ Theophylline  
☐ Salbutamol 
☐ Symbicort 
☐ Vannair, 
☐ Other…………………………………………………………………………….. 
 
11. How often do you use..? ( NAEP poster to choose from) 
Anti-inflammatory 
☐ Only when needed 
☐ In short courses 
☐ Everyday  
☐ Never 
Salbutamol 
☐ Only when needed 
☐ In short courses 
☐ Everyday  
☐ Never 
Other ( specify)……………………………………………………………………. 
☐ Only when needed 
☐ In short courses 
☐ Everyday  
 
Asthma severity 
12. How many attacks of asthma in the last year? (Required to go to clinic with wheezing, miss school, 
admission to hospital, nebulization at a doctor/clinic, medication (steroids)) indicate the number of times. 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 103 of 151                        
 
13. Peak expiratory flow rate 
 
Blow 1                                   Blow 2                                 Blow 3                                Best blow  
 
 
 
 
 
PARTICIPANT: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INFORM CONSENT ADMINISTRATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
                              Date and Time 
 
 
WITNESS (If applicable): 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 104 of 151                        
 
 
 
INVESTIGATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 105 of 151                            
 
15.7 Appendix 8: Childhood Asthma Control Test 
 
CHILDHOOD ASTHMA CONTROL TEST 
 
Study Number: 
AIR-SA-001  
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
Protocol Version and 
Approval Date: 
Version 1.1 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela-uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
To the potential participant: This form may contain words that you do not understand. Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly understand. 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 106 of 151                        
 
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I 
am a ______________________________ (INSERT DESIGNATION) at ____________________ (INSERT 
SITE). 
I would like you to help me understand your / your child’s asthma control by answering these questions. 
 
How old is your child in years?______________ 
 
Parent/guardian is required to assist in completing this form. 
 
c-ACT (ages 4-11) 
 
1. How was your Asthma today?  
☐ 0    Very Bad 
☐ 1 
Bad 
☐ 2 
Good 
☐ 3 
Very Good 
 
2. How much of a problem is your asthma when you run, exercise or play sports? 
☐ 0 
It's a big problem, I can't do what I want to do.  
☐ 1 
It's a problem and I don't like it. 
☐ 2 
It's a problem but it's okay. 
☐ 3 
It's not a problem. 
 
3. Do you cough because of your asthma?  
☐ 0 
Yes, all the time. 
☐ 1 
Yes, most of the time. 
☐ 2 
Yes, some of the time. 
☐ 3 
No, none of the time. 
 
4. Do you wake up during the night because of your asthma? 
☐ 0 
Yes, all of the time. 
☐ 1 
Yes, most of the time. 
☐ 2 
Yes, some of the time. 
☐ 3 
No, none of the time. 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 107 of 151                        
 
The following questions are directed to the caregiver or parent. 
 
5. During the last 4 weeks, on average, how many days per month did your child have any daytime 
asthma symptoms?  
☐ 5  
 Not at all 
☐ 4  
 1-3 days/month 
☐ 3  
4-10days/month 
☐ 2  
 11-18 days/month 
☐ 1  
 19-24 days/month 
☐0  
 Everyday 
 
6. During the last 4 weeks, on average, how many days per month did your child wheeze during the 
day because of asthma? 
☐ 5  
Not at all 
☐ 4  
 1-3 days/mo 
☐ 3  
4-10days/mo 
☐ 2  
11-18 days/mo 
☐ 1  
19-24 days/mo 
☐ 0  
Everyday 
 
7. During the last 4 weeks, on average, how many days per month did your child wake up during the 
night because of asthma? 
☐ 5  
 Not at all 
☐ 4  
1-3 days/mo 
☐ 3  
 4-10days/mo 
☐ 2  
 11-18 days/mo 
☐ 1  
19-24 days/mo 
☐ 0  
Everyday 
 
 
C-ACT Score: 
__________________________________ 
PARTICIPANT: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 108 of 151                        
 
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INVESTIGATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 109 of 151                            
 
15.8 Appendix 9: Asthma Control Test 
 
ASTHMA CONTROL TEST 
 
Study Number: 
AIR-SA-001  
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
Protocol Version and 
Approval Date: 
Version 1.1 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela-uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
To the potential participant: This form may contain words that you do not understand. Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly understand. 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 110 of 151                            
 
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY 
STAFF), I am a ______________________________ (INSERT DESIGNATION) at 
____________________ (INSERT SITE). 
I would like you to help me understand your asthma control by answering these questions. 
 
How old are you in years?__________ 
 
ACT (ages > 12 years) 
 
1. In the past 4 weeks, how much of the time did your asthma keep you from getting as much 
done at work, school or at home? 
☐ 1  
 All of the time 
☐ 2  
Most of the time 
☐ 3 
Some of the time 
☐ 4  
 A little of the time 
☐ 5  
None of the time 
 
2. During the past 4 weeks, how often have you had shortness of breath? 
☐ 5   
Not at all 
☐ 4   
 Once or twice a week 
☐ 3   
3- 6 times a week 
☐ 2   
Once a day 
☐1    
More than once a day 
 
3. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, 
shortness of breath, chest tightness, or pain) wake you up at night or earlier than usual in 
the morning? 
☐ 5  
 Not at all 
☐ 4  
Once or twice 
☐ 3  
 Once a week 
☐ 2  
2 or 3 nights a week 
☐ 1  
 4 or more nights a week 
 
4. During the past 4 weeks, how often have you used your rescue inhaler or nebulizer 
medication (such as salbutamol)? 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 111 of 151                            
 
☐ 5  
 Not at all 
☐ 4  
 Once a week or less 
☐ 3  
2 or 3 times per week 
☐ 2  
 1 or 2 times per day 
☐ 1   
 3 or more times per day 
 
5. How would you rate your asthma control during the past 4 weeks? 
☐ 5  
Completely Controlled 
☐ 4  
Well Controlled 
☐ 3  
Somewhat Controlled 
☐ 2  
Poorly Controlled 
☐ 1   
 Not Controlled at all 
 
 
ACT Score: 
__________________________________ 
 
 
PARTICIPANT: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INVESTIGATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 112 of 151                            
 
 
15.9 Appendix 10: Quality of life questionnaire 
PAEDIATRIC ASTHMA QUALITY OF LIFE QUESTIONNAIRE  
 
 
Study Number: 
AIR-SA-001  
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
Protocol Version and 
Approval Date: 
Version 1.1 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela-uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
To the potential participant: This form may contain words that you do not understand. Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly understand. 
 
 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 113 of 151                            
 
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I am a 
______________________________ (INSERT DESIGNATION) at ____________________ (INSERT SITE). 
I would like you to tell me about all the things you do in which you are bothered by your asthma. 
Record identified activities. 
Together, we are going to look at a list of things that you may have done during the last week. Because of 
your asthma, you may have found some of these activities difficult to do or not so much fun. Let’s look at the 
list and you tell me in which activities you’ve been bothered by your asthma during the past week. If you 
haven’t done something on the list or if it hasn’t bothered you, just say ‘no’. 
Read activities, omitting those which the patient has identified spontaneously. Pause after each activity to 
give the patient a chance to reply. 
 
Activities 
 
 
1.Ball hockey 
13. Sleeping 
25. Shouting 
2. Baseball 
14.  Soccer 
26. Gymnastics 
3. Basketball 
15. Swimming 
27. Rollerblading 
4. Dancing 
16. Volleyball 
28. Skateboarding 
5. Football 
17. Walking 
29. Track and field 
6. Playing at recess 
18. Walking uphill 
30. Tobogganing 
7. Playing with pets 
19. Walking upstairs 
31. Skiing  
8. Playing with friends 20. Laughing 
32. Ice skating 
9. Riding a bicycle 
21. Studying 
33. Climbing 
10. Running 
22. Doing Household chores 34. Getting up in the morning 
11. Skipping rope 
23. Singing 
35. Talking 
12.Shopping 
24. Doing Crafts or hobbies 
 
 
Of the activities you have listed, I would like you to tell me which three bother you the most. 
Read together the list of identified activities. Write the three activities in Questions 1–3 of the Questionnaire. 
I now would like you to tell me how much you were bothered by your asthma while doing these activities. I 
will tell you which card to use. Pick the number which best describes how much you were bothered by your 
asthma in doing each activity during the past week. 
1. How much have you been bothered by your asthma in (Activity 1: 
. . .) during the past week? ☐ (BLUE CARD) 
2. How much have you been bothered by your asthma in (Activity 2: 
. . .) during the past week? ☐ (BLUE CARD) 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 114 of 151                            
 
3. How much have you been bothered by your asthma in (Activity 3: 
. . .) during the past week? ☐ (BLUE CARD). 
 
4. How much did COUGHING bother you in the past week? ☐ (BLUE CARD) 
5. How much did ASTHMA ATTACKS bother you during the past week? ☐ (BLUE CARD) 
6. How much did WHEEZING bother you during the past week? ☐ (BLUECARD) 
7. How much did TIGHTNESS IN YOUR CHEST bother you during the past week? ☐ (BLUE CARD) 
8. How often did you feel DIFFERENT or LEFT OUT because of your asthma during the past week? ☐ 
(BLUE CARD) 
9. How much did SHORTNESS OF BREATH bother you during the past week? ☐ (BLUE CARD) 
10. Think about all the activities that you did during the past week. How much were you bothered by your 
asthma doing these activities? ☐ (BLUE CARD) 
11. How often did your asthma make you feel FRUSTRATED during the past week? ☐ (GREEN CARD) 
12. How often did your asthma make you feel TIRED during the past week? ☐ (GREEN CARD) 
13. How often did you feel WORRIED, CONCERNED OR TROUBLED because of your asthma during the past 
week? ☐ (GREEN CARD) 
14. How often did your asthma make you feel ANGRY during the past week? ☐ (GREEN CARD) 
15. How often did you feel IRRITABLE (cranky) during the past week?  ☐ (GREEN CARD) 
16. How often did you feel FRUSTRATED BECAUSE YOU COULDN’T KEEP UP WITH OTHERS during the past 
week? ☐ (GREEN CARD) 
17. How often did your asthma WAKE YOU UP DURING THE NIGHT during the past week? ☐  (GREEN 
CARD) 
18. How Often did you feel UNCOMFORTABLE because of your asthma during the past week? ☐  (GREEN 
CARD) 
19. How often did you feel OUT OF BREATH during the past week? ☐ (GREEN CARD) 
20. How often did you feel YOU COULDN’T KEEP UP WITH OTHERS because of your asthma during the 
past week? ☐ (GREEN CARD) 
21. How often did you have trouble SLEEPING AT NIGHT because of your asthma during the past week? ☐ 
(GREEN CARD) 
22. How often did you feel FRIGHTENED BY AN ASTHMA ATTACK during the past week? ☐ (GREEN CARD) 
23. How often did you have difficulty taking a DEEP BREATH during the past week? ☐ (GREEN CARD). 
 
Response options 
Domain Questions 
Symptoms  
Activities  
Emotions  
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 115 of 151                            
 
BLUE CARD  
1. Extremely bothered  
2. Very bothered  
3. Quite bothered  
4. Somewhat bothered  
5. Bothered a bit  
6. Hardly bothered at all  
7. Not bothered  
 
GREEN CARD 
1. All of the time 
2. Most of the time 
3. A good bit of the time 
4. Some of the time 
5. A little of the time 
6. Hardly any of the time 
7. None of the time 
 
Four scores, including 3 main topics and 1 total, are obtained from the scale. Each question on the scale is 
evaluated over 7 points. While 1 indicates excessive discomfort or constant complaining, 7 indicates absence 
of complaints in relation to scoring. A high score shows a higher quality of life. 
 
 
PARTICIPANT: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INFORM CONSENT ADMINISTRATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 116 of 151                            
 
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
                              Date and Time 
 
 
WITNESS (If applicable): 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INVESTIGATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 117 of 151                            
 
15.10 Appendix 11: Scheduled telephonic follow-up 
 
SCHEDULED VISIT 2 and VISIT 4  
Study Number: 
AIR-SA-001  
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
Protocol Version and 
Approval Date: 
Version 1.1 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela-uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
 
To the potential participant: This form may contain words that you do not understand. Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly understand. 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 118 of 151                        
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I 
am a ______________________________ (INSERT DESIGNATION) at ____________________ (INSERT 
SITE). 
I would like you to help me understand your / your child’s asthma control by answering these questions. 
 
 
Telephonic / clinic visits 
1. How many times in the past three months have you had: cough, wheeze, difficulty in 
breathing 
☐ zero  
☐ less than 2 per month 
☐ 2- 4 per month 
☐ more than 4 per month 
2. Have you gone to a doctor or a clinic to receive nebulizer for your asthma? 
Yes ☐ or No ☐ 
3. Did you receive a syrup or tablet for the asthma attack? 
Yes ☐ or No ☐ 
4. If yes how many days did you take the syrup or tablet for? 
☐ less than 3 
☐ 3 – 7 
☐ more than 7 
5. Have you changed any of your asthma medications in the last three months 
Yes ☐ or No ☐ 
6. Did you miss any days of school because of your asthma 
Yes ☐ or No ☐ 
7. Did your parent or guardian miss days of work because of your asthma 
Yes ☐ or No ☐ 
8. Did you have any side effects from the medication? 
Yes ☐ or No ☐ 
9. If yes state what you experienced 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 119 of 151                        
 
……………………………………………………………………………………………………………………………………………………
………………………… 
10. How long was this side-effect for? 
☐ less than 3 days 
☐ 3 – 7 days 
☐ more than 7 days 
11. Did you use any treatment for this side-effect 
Yes ☐ or No ☐ 
STUDY STAFF: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature  
 
 
 
 
 
 
 
 
Date 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 120 of 151                            
 
15.11 Appendix 12: Schedule follow-up visit 
 
SCHEDULE VISIT 3 AND VISIT 5  
 
Study Number: 
AIR-SA-001  
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
Protocol Version and 
Approval Date: 
Version 1.1 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela-uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
To the potential participant: This form may contain words that you do not understand. Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly understand. 
 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 121 of 151                        
 
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I 
am a ______________________________ (INSERT DESIGNATION) at ____________________ (INSERT 
SITE). 
I would like you to help me understand your / your child’s asthma control by answering these questions. 
 
Follow up 6 months and 12 months  
 
Asthma medication 
1. Are you taking any asthma medication currently? Yes ☐ or No ☐ 
 
2. Which medication? Tick appropriate medication below: 
☐ Budesonide 
☐ Beclomethasone 
☐ Fluticasone/salmeterol  
☐ Montelukast 
☐ Theophylline  
☐ Salbutamol 
☐ Symbicort 
☐ Vannair, 
☐ Other…………………………………………………………………………….. 
 
3. How often do you use..? ( NAEP poster to choose from) 
Anti-inflammatory (Symbicort/Vannair OR Inhaled corticosteroid) 
☐ only when needed 
☐ In short courses 
☐ Everyday  
☐ Never 
Salbutamol 
☐ only when needed 
☐ In short courses 
☐ Everyday  
☐ Never 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 122 of 151                        
 
Other ( specify)……………………………………………………………………. 
☐ only when needed 
☐ In short courses 
☐ Everyday  
 
4. Have you gone to a doctor or a clinic to receive nebulizer for your asthma? 
Yes ☐ or No ☐ 
5. Did you receive a syrup or tablet for the asthma attack? 
Yes ☐ or No ☐ 
6. If yes how many days did you take the syrup or tablet for? 
☐ less than 3 
☐ 3 – 7 
☐ more than 7 
7. Have you changed any of your asthma medications in the last three months 
Yes ☐ or No ☐ 
8. Did you miss any days of school because of your asthma 
Yes ☐ or No ☐ 
9. Did your parent or guardian miss days of work because of your asthma 
Yes ☐ or No ☐ 
10. Did you have any side effects from the medication? 
Yes ☐ or No ☐ 
11. If yes state what you experienced 
……………………………………………………………………………………………………………………………………………………
………………………… 
12. How long was this side-effect for? 
☐ less than 3 days 
☐ 3 – 7 days 
☐ more than 7 days 
13. Did you use any treatment for this side-effect 
Yes ☐ or No ☐ 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 123 of 151                        
 
 
Asthma severity 
 
14. How many attacks of asthma in the 3 months? (Required to go to clinic/hospital with 
wheezing, miss school, admission to hospital, nebulization at a doctor/clinic) indicatethe 
number of times. 
 
 
 
15. Peak expiratory flow rate 
 
Blow 1                           Blow 2                           Blow 3                          Best blow  
 
 
  
INVESTIGATOR: 
 
 
__________________________________________________________________________________________ 
 Printed Name(s) and Surname  
 
 
__________________________________________________________________________________________ 
Signature  
 
 
 
 
 
 
 
 
Date 
 
 
        
         
        

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 124 of 151                        
 
 
15.12 Appendix 13: Asthma Diary National Asthma Education Programme (NAEP) 
 
Study Unique ID 
Number: 
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in 
South African children: A Pragmatic Open Label Phase 3 
Randomised Controlled Trial. 
Protocol Version and 
Approval Date: 
Version 1.0; 21 August 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal 
& 
Site): 
Prof Refiloe Masekela, uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
Daytime and After-
Hours Telephone 
Number(s): 
Somkhele +27 (0)35 550 7500 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 125 of 151                                
 
 
Month 
SYMPTOMS 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 31 
Cough – Day 
 
Cough – Night 
 
Wheeze I tight chest 
 
Used reliever 
 
Clinic/ Hospital visit for nebulizer 
 
Controller 
Day 
 
Night 
 
Other 
Day 
 
Night 
 
Month 
SYMPTOMS 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 
Cough – Day 
Cough – Night 
Wheeze/ tight chest 
Used reliever 
Clinic/ Hospital visit for nebulizer 
Controller 
Day 
Night 
Other 
Day 
Night 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 126 of 151                                
 
 
 
Month 
SYMPTOMS 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
 
12 
 
13 
 
14 
 
15 
 
16 
 
17 
 
18 
 
19 
 
20 
 
21 
 
22 
 
23 
 
24 
 
25 
 
26 
 
27 
 
28 
 
29 
 
30 
 
31 
 
Cough – Day 
Cough – Night 
Wheeze / tight chest 
Used reliever 
Clinic/ Hospital visit for nebulizer 
Controller 
Day 
Night 
Other 
Day 
 
Night 
 
 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 127 of 151                            
 
15.13 
Appendix 14: The economic impact of Asthma tool  
(Youth Proxy version) 
Study Unique ID 
Number: 
AIR-SA-001 
 
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in 
South African children: A Pragmatic Open Label Phase 3 
Randomised Controlled Trial.  
Protocol Version and 
Approval Date: 
Version 1.1; 21 Aug 2023  
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal 
& Site): 
Prof Refiloe Masekela-uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
 
Daytime and After-
Hours Telephone 
Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
This questionnaire aims to determine Asthma's economic impact/burden (child patient 
perspective). Asthma is a chronic disease, but the economic impact data will be collected over 
a short time period (from a month up to 6 months). 
 
The tool includes:  
       Part 1: Child Socioeconomic and demographic information  
       Part 2: Direct costs for asthma services  
     2.1 Outpatient services  
     2.2 Inpatient services   
       Part 3: Indirect costs for asthma services 
     3.1 Outpatient services  
     3.2 Inpatient services   
     3.3 Productivity loss by Child and Caregivers 
 
 
 
PART 1: CHILD SOCIOECONOMIC AND DEMOGRAPHIC INFORMATION  
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 128 of 151                            
 
1.1 Individual child 
Please fill in the following information about yourself as a parent/guardian and the child you 
represent  
 
1) Please indicate whom you are answering these questions on behalf of 
 ☐ I am answering these questions on behalf of a child with asthma aged between 6-
11 years old  
☐ I am answering these questions on behalf of a child with asthma aged between 12-
18 years old 
 
2) What is your relationship with the child? Choose one from the list 
☐ Parent 
☐ Legal Guardian 
☐ Relative 
 
1.2 Household of the child  
Note: The questions must be answered by someone who knows about the child patient's 
household income. This must be the sum of all people in the household who are working and 
contribute to the household's spending.  
 
3) Does someone in the household work for pay/income?  
☐ Yes  
☐ No  
[If yes, continue with Question 4; If no, skip to Questions 5 and 6] 
 
4) How much is your household income a month? _________ 
 
5) Who supports the household with income (tick all that apply)?  
☐ Family (not living in the child’s household) 
☐ Government/social grant 
☐ No one 
☐ Others, specify ____________________ 
 
6) How much does the household get monthly from the supporter/s in question 5?     ____
 
____ 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 129 of 151                            
 
7) How much does your household spend monthly on essential items, excluding medicines 
for asthma? (Essential items are items you cannot live without, like food, cooking, energy, 
etc.) 
       Food: _________  
            Clothing:_________ 
            Accommodation: _______ 
            Transportation: _________ 
            Education:_______  
            The household energy source (e.g. fuel, electricity):______ 
           Other: specify  
                      Item1 (name item________), state the amount _________________ 
                      Item2 (name item_______), state the amount, ________________ 
 
8) Where do you buy/get the child’s medicine for asthma? 
☐  Local Pharmacy                 
☐  Hospital/Clinic     
☐  I don't use medicine for the child’s treatment of asthma 
Others (specify) ________________________________ 
 
[If selected ‘I don't use medicine for the child’s treatment’, skip to Question 10] 
 
9) How much do you spend monthly on the child’s medication for asthma?  
 
 
 
10) If the child does not use medicine, why not? 
☐  I don't have money to buy it                     
☐  The pharmacy/clinic/hospital is too far 
☐  I choose not to use medicine for the child                     
Others (specify)_______________________________________________ 
 
11) Is the child covered by any kind of private or government health/medical insurance 
scheme? 
☐  Yes 
☐  No 
[If yes, continue with Question 12; If no, skip to Question 16] 
 
12)  What type? 
 
☐  Private medical insurance 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 130 of 151                            
 
☐  National health insurance 
 
☐  Other (specify) 
 
13) If the child is covered by private medical insurance, how much do you or the main 
insurance member pay monthly for cover?   
 
 
14) Does the insurance cover all the child’s treatment costs (tests, consultation fees) for their 
asthma?  
☐  Yes 
☐  No 
 
15) Does the insurance cover all the child’s medicines for their asthma?  
☐  Yes 
☐  No 
 
16) In the past 6 months, did you borrow any money to cover costs due to the child’s asthma?  
☐  Yes      
☐  No  
[If yes, continue with Question 17; If no, skip to Question 20] 
 
17) In the past 6 months, how much did you borrow?  
  Amount borrowed________ 
 
 
 
18) From whom did you borrow?  
☐  Family                   
☐  Neighbors/friends   
☐  Bank  
☐  Local social club, e.g. cooperative society or Stokvel  
☐  Other (specify)____________ 
 
19) What is the interest rate on the loan (in %)?  
      ☐  less than 5%         
      ☐  5% to 10%  
      ☐  more than 10%     
      ☐  I don't know     
      ☐  I do not need to pay back the money  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 131 of 151                            
 
 
20) In the past 6 months, have you sold any of your property to pay for the child’s treatment 
costs for asthma? 
☐  Yes 
☐  No 
[If yes, continue with Question 21; If no, skip to Question 23] 
 
21) Did you have to sell the asset in a hurry (rush)? 
☐  Yes  
☐  No   
 
22) What did you sell?  
☐  Land 
☐  Livestock/farm products   
☐  Car/Vehicle   
☐  Household item     
☐  Personal electronics 
☐  Other (specify): ________  
 
PART 2: DIRECT COSTS OF ASTHMA SERVICES FOR CHILD AND THEIR CAREGIVERS 
Please fill in the following information about yourself as a parent/guardian and the child you 
represent. 
 
2.1 Outpatient services  
23) For how long has the child been receiving treatment for asthma?  
  
Years 
 
24) Where does the child get health care when there is an asthma attack or cough/breathing 
emergency problem?   
☐   Clinic/local health centre   
☐   Hospital       
☐   Alternative providers       
☐   They don't go anywhere  
Others (specify) _________________________________________ 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 132 of 151                            
 
[If selected ‘clinic/local health centre’ or ‘hospital’, continue with Question 25 through to 
question 28; If selected ‘They don’t go anywhere, skip to Question 29] 
 
25) How much do you pay per visit for   
         Consultation? _____ 
         Medicine? ___  
         Transportation? ____  
         Food whilst seeking health care?___ 
         Other medical services?_____  
 
26) How many visits does the child make to the healthcare facility per month for treatment of 
asthma?    
 
 
27) How far is that facility    
         
 minutes/_________hours walking,  
       
 
 minutes/_________hours with public transportation   
 
28) List the latest visits (in the last six months) the child made to that facility for asthma and 
the cost related to these visits   
  
Visit  Purpose of 
visits   
Time spent 
(hours at the 
facility, 
including 
travelling 
time) 
Waiting time 
(where 
visited)  
Administration 
cost (e.g. card 
fees)  
Cost of 
medical 
services  
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
     
29) If the answer to Question 24 is “They don't go anywhere”, what is the reason for not 
seeking health care (tick all that apply)  
☐   We self-treat at home  
           ☐   Distance to the health facility is too far  
           ☐   Too expensive  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 133 of 151                            
 
           ☐   Waiting time at the facility  
           ☐   Lack of facilities 
           ☐   Other reasons (specify) _______________________________ 
 
2.2  Inpatient services  
 
30) In the past 6 months, was the child hospitalized as part of treatment for asthma?  
☐ Yes 
☐ No  
[If yes, continue with Questions 31 and 32; If no, skip to Question 33] 
 
31) How many days did the child spend in the hospital during the last hospital stay?  
 
 
days 
 
32) How much money did you spend during the child’s last stay in the hospital on:  
Hospital admin fees _____ 
Food (not provided by the hospital)____  
Medicine_____  
Tests ____ 
Others_____  
    
PART 3: INDIRECT COSTS FOR CHILD OR CAREGIVERS OF A CHILD 
Please fill in the following information about yourself as a parent/guardian and the child you 
represent  
 
3.1 Outpatient care  
 
33) Do you or someone else in the household go with the child to the healthcare facility when 
they receive treatment for asthma? 
☐ Yes 
☐ No 
[If yes, continue with Question 34; If no, skip to Question 35] 
 
34) Please indicate how much you or the caregiver (the person who went to the facility with 
the child) spent on the last visit 
Cost per visit on transport ____ 
Cost per visit on food ______  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 134 of 151                            
 
 
3.2  Inpatient care  
 
35) Did you or the child’s caregiver spend time in the hospital with the child during the child’s 
last hospitalisation? 
☐ Yes 
☐ No  
[If yes, continue with Questions 36; If no, skip to Question 37] 
 
36) While in the hospital, how much did you/they spend on 
      Food______ 
                Accommodation____  
     Transport____  
           Other_____  
 
3.3 Productivity Loss by Child and Caregivers 
 
School/Work Days Lost 
 
37) How many days per week does the child go to school?  ____ days 
 
 
38) Did the child miss school during the past 6 months due to their asthma?  
☐ Yes 
 
☐ No 
 
 
[If yes, continue with Question 39; If no, skip to Question 40] 
 
39) During the past 6 months, how many days was the child unable to go to school due to 
their asthma?  _______days 
 
40) During the past 6 months, did you or someone else (caregiver) stay home from work or 
school to care for the child due to their asthma or go with them to receive treatment?  
☐ Yes  
☐ No  
[If yes, continue with Question 41; If no, skip to Question 44] 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 135 of 151                            
 
41) How many days in a month did you or the caregiver miss work or school to care for the 
child?            days 
 
42) In the past 6 months, did you or the caregiver lose any income on the days you/they 
stayed home to care for the child?  
☐ Yes 
☐ No 
[If yes, continue with Question 43; If no, skip to Question 44] 
 
43) How much income did you/they lose per day?  
 
 
Non-School Activities Missed 
 
44) During the past 6 months, did the child’s asthma prevent them from participating in one or 
more non-school activities (such as playing, visiting friends/relatives, or other activities)?   
☐ Yes 
☐  No 
 
[If yes, continue with Question 45] 
 
45) During the past 6 months, how many total days did they not participate in non-school 
activities due to their asthma? ____days 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 136 of 151                            
 
15.14 Appendix 15: CHILD-FRIENDLY EQ-5D-Y  
 
Study Number: 
AIR-SA-001  
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled Trial. 
Protocol Version and 
Approval Date: 
Version 1.1 21 Aug 2023 
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela-uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
To the potential participant: This form may contain words that you do not understand. Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly understand. 
 
 
ICF administration starting time: _________________ ICF administration finish time: ___________________ 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 137 of 151                        
 
 
INTRODUCTION 
 
Good day, my name is _____________________________________ (INSERT NAME OF STUDY STAFF), I 
am a ______________________________ (INSERT DESIGNATION) at ____________________ (INSERT 
SITE). 
I would like you to describe your health TODAY 
Under each heading, mark ONE box that best describes your health TODAY 
 
Mobility (walking about) 
☐ I have no problems walking about because of my asthma 
☐ I have some problems walking about because of my asthma 
☐ I have a lot of problems walking about because of my asthma 
 
Looking after myself 
☐ I have no problems washing or dressing myself because of my asthma 
☐ I have some problems washing or dressing myself because of my asthma 
☐ I have a lot of problems washing or dressing myself because of my asthma 
 
Doing usual activities (for example, going to school, hobbies, sports, playing, doing things with family 
or friends) 
☐ I have no problems doing my usual activities because of my asthma 
☐ I have some problems doing my usual activities because of my asthma 
☐ I have a lot of problems doing my usual activities because of my asthma 
 
Having pain or discomfort 
☐ I have no pain or discomfort because of my asthma 
☐ I have some pain or discomfort because of my asthma 
☐ I have a lot of pain or discomfort because of my asthma 
 
Feeling worried, sad or unhappy 
☐ I am not worried, sad or unhappy because of my asthma 
☐ I am a bit worried, sad or unhappy because of my asthma 
☐ I am very worried, sad or unhappy because of my asthma 
 
How good is your health TODAY 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 138 of 151                        
 
We would like to know how good or bad your health is TODAY 
The line is numbered from 0 to 100 
100 means the best health you can imagine 
0 means the worst health you can imagine 
 
Please mark X on the line that shows how good or bad your health is TODAY 
 
The worst 
health  
you can 
imagine 
0…………………..25……………………50…………………75……………………100 
The best 
health 
 you can 
imagine 
 
PARTICIPANT/GUARDIAN: 
 
 
____________________________________________________________________________________
______ 
 Printed Name(s) and Surname  
 
 
____________________________________________________________________________________
______ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INFORM CONSENT ADMINISTRATOR: 
 
 
____________________________________________________________________________________
______ 
 Printed Name(s) and Surname  
 
 
____________________________________________________________________________________
______ 
Signature / Mark or Thumbprint 
 
 
 
 
                              Date and Time 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 139 of 151                        
 
 
WITNESS (If applicable): 
 
 
____________________________________________________________________________________
______ 
 Printed Name(s) and Surname  
 
 
____________________________________________________________________________________
______ 
Signature / Mark or Thumbprint 
 
 
 
 
 
 
Date and Time 
 
 
INVESTIGATOR: 
 
 
____________________________________________________________________________________
______ 
 Printed Name(s) and Surname  
 
 
____________________________________________________________________________________
______ 
Signature / Mark or Thumbprint 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 140 of 151                        
 
15.15 Appendix 16: Health facility costing tool for asthma  
HEALTH FACILITY COSTING TOOL FOR ASTHMA  
Study Unique ID Number: 
AIR-SA-001 
 
Study Title: 
Anti-Inflammatory Reliever therapy for asthma using inhaled 
budesonide/formoterol as-needed with or without maintenance in South 
African children: A Pragmatic Open Label Phase 3 Randomised Controlled 
Trial.  
Protocol Version and 
Approval Date: 
Version 1.1; 21 Aug 2023  
Sponsor: 
Africa Health Research Institute. 
Investigator (Principal & 
Site): 
Prof Refiloe Masekela-uMkhanyakude sites 
Institution: 
Africa Health Research Institute 
 
Daytime and After-Hours 
Telephone Number(s): 
Daytime:+27 (0)35 550 7500 After-Hours 079 056 4232 
 
This questionnaire is filled by the Health facility manager who has overall 
information. The data collector would leave the questionnaire and ask for an 
appointment to collect it. 
 
A. GENERAL FACILITY INFORMATION 
Question1: Describe your facility:  
A1 
Name of the facility  
 
A2 
City 
 
A3 
District  
 
A4  
Type/level of facility 
 
A5 
Operating Hours  
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 141 of 151                        
 
Question 2: List the number of staff (medical and non-medical) working with 
asthma services. Include staff who might be working there part time or a few 
hours. The cost centre referred here can be the mainstream department 
providing asthma services or support department like the admin/finance 
department staff providing support to asthma medical personnel or patients.   
Number 
of staff 
Position  
Time dedicated to 
asthma services a 
week 
Department or cost 
centre where staff is 
located   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Question 3:  What is the average number of asthma patients served per day? 
 
 
 
  patients 
 
B. HEALTH PROFESSIONAL TIME 
Please provide the following information for the staff that work at your facility in 
providing asthma services. 
Staf
f 
title  
Numbe
r of 
staff 
with 
this 
title  
Staff 
monthl
y 
salary  
Averag
e 
trainin
g costs 
for 
staff 
per 
month  
Housing 
allowanc
e per 
month  
Value 
of 
Other 
benefit
s per 
month 
Total 
days 
worke
d per 
month  
Time 
used 
daily 
to 
serve 
asthm
a 
Time 
used 
daily 
to 
serve 
non-
asthm
a 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 142 of 151                        
 
patient
s  
patient
s  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C. SUPPLIES TYPICALLY USED IN ASTHMA TREATMENT 
Please provide the following information for supplies such as masks, syringes and 
other supplies used to treat asthma patients.  
Please list the 
supplies used 
in a typical 
visit during 
asthma service  
Unit for 
measurement  
Year 
purchased 
Number of 
items used 
per visit  
How long the 
item is used 
for asthma 
service  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D. Medicines, drugs, laboratory tests for user of asthma services  
Medicines, tests and other services rendered to asthma patients in the month of 
 
 
 
 
 202  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 143 of 151                        
 
Serial 
number 
Type of medicine/ lab 
test or other service  
Quantities per 
month  
Average number of 
asthma patients 
served per day  
 
 
 
 
 
 
 
 
 
 
 
 
 
E. Equipment used for the provision of asthma services   
Please provide the following information for medical equipment used such as x-
ray machines etc.  
Serial 
numbe
r 
Type of 
equipme
nt 
Year, 
month 
and 
date of 
purchas
e 
Total 
initial 
expens
e 
Repair/Maintenan
ce  
expense per year  
Numb
er of 
asthm
a 
patient
s 
served 
a day  
Number 
of non-
asthma 
patients 
served by 
equipme
nt a day  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F. Transportation costs   
Please provide the following information on vehicles and ambulances used in 
transporting patients from a place to another. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 144 of 151                        
 
Registratio
n number 
Type 
of 
vehicl
e   
Year, 
month 
and 
date of 
purchas
e 
Total 
initial 
expens
e 
Repair/Maintenan
ce expense per 
year 
Numbe
r of 
asthma 
patient
s 
served 
by 
vehicle 
a 
month  
Numbe
r of 
non-
asthma 
patient
s 
served 
by 
vehicle 
a 
month  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G. Costs for building facilities used  
Please provide information regarding the number of rooms serving asthma 
patients, the area of these rooms and whether or not the rooms serve other non-
asthma patients  
Serial 
number 
Room 
name   
Medical 
department 
where 
room/hall 
is located  
Area 
of the 
room, 
hall 
(m2) 
Area of 
building 
where 
room is 
located 
(m2) 
Cost (or 
rental) 
of the 
building 
where 
room is 
located  
Number 
of 
asthma 
patients 
served 
in a 
room 
per day  
Number 
of non-
asthma 
patients 
served 
in a 
room 
per day  

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 145 of 151                        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
 
Version 1.5; 14 Dec 2023  
 
Page 146 of 151                        
 
15.16 Appendix 17: Asthma Advert 
 
 
 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
Page 147 of 151                               Version 1.1; 21 Aug 2023 
VV 
15.17 Appendix: 18 SMART ACTION Plan  
 
For participants on budesonide/formoterol  
 
(Example of action plan template for budesonide/formoterol. A similar action plan could be constructed for other ICS/formoterol formulations, e.g., 
mometasone/formoterol) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal mode 
 
Asthma Flare-up 
 
Asthma Emergency 
 
My Asthma Action Plan 
For Single Inhaler Maintenance and 
Reliever Therapy (SMART)  
with budesonide/formoterol 
      My SMART Asthma Treatment is: 
☐ budesonide/formoterol 160/4.5 (12 years or 
older) 
☐ budesonide/formoterol 80/4.5 (6-11 years) 
 
      My Regular Treatment Every Day: 
 
(Write in or circle the number of doses prescribed for this 
patient) 
 
Take [1, 2] inhalation(s) in the morning 
and [0, 1, 2] inhalation(s) in the evening, every 
day 
 
      Reliever 
Use 1 inhalation of budesonide/formoterol 
whenever needed for relief of my asthma 
symptoms 
I should always carry my budesonide/formoterol 
inhaler 
 
Name: 
________________________________________ 
 
Date: 
_________________________________________ 
 
Action plan provided by: 
______________ 
 
Doctor: 
____________________________ 
 
     If over a Period of 2-3 Days: 
• My asthma symptoms are getting worse OR NOT 
improving 
     OR 
• I am using more than 6 budesonide/formoterol 
reliever inhalations a day (if aged 12 years or 
older) or more than 4 inhalations a day (if aged 6-
11 years) 
I should: 
☒Continue to use my regular everyday treatment 
PLUS 1 inhalation budesonide/formoterol 
whenever needed to relieve symptoms 
☐ Start a course of prednisolone 
☐ Contact my doctor 
 Course of Prednisolone Tablets: 
Take _____________mg prednisolone 
tablets per day for ________days OR 
_______________________________  
________________________________
 
      Signs of an Asthma Emergency: 
• Symptoms getting worse quickly 
• Extreme difficulty breathing or speaking 
• Little or no improvement from my 
budesonide/formoterol reliever inhalations 
If I have any of the above danger 
signs, I should dial _____ for an 
ambulance and say I am having a 
severe asthma attack. 
      While I am waiting for the 
ambulance start my asthma first aid 
plan: 
 
• Sit upright and stay calm. 
 
• Take 1 inhalation of budesonide/formoterol. 
Wait 1-3 minutes. If there is no 
improvement, take another inhalation of 
budesonide/formoterol (up to a maximum of 
6 inhalations on a single occasion). 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
Page 148 of 151                               Version 1.1; 21 Aug 2023 
VV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    My asthma is stable if: 
• I can take part in normal physical activity 
without asthma symptoms 
AND 
• I do not wake up at night or in the 
morning because of asthma 
Other Instructions 
__________________________________ 
 
      If I need more than 12 
budesonide/formoterol inhalations 
(total) in any day (or more than 8 
inhalations for children 6-11 years), I 
MUST see my doctor or go to the hospital 
the same day. 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
Page 149 of 151                               Version 1.1; 21 Aug 2023 
VV 
15.18 Appendix 19: NAEP Asthma Action Plan 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
Page 150 of 151                               Version 1.1; 21 Aug 2023 
VV 
 
 
 

Confidential 
Africa Health Research Institute (AHRI)                               Protocol Version 1.5; 14 Dec 2023 
University of KwaZulu-Natal (UKZN)                                    Protocol number: AIR-SA-001 
 
Page 151 of 151                               Version 1.1; 21 Aug 2023 
VV 
15.19 
Appendix 20: NAEP Medicine poster