A South African Multi-centre Pilot Trial to Assess the Feasibility and Clinical Efficacy of Preoperative Oral Iron to Treat Preoperative Iron-deficiency Anaemia in Children Undergoing Elective Noncardiac Surgery
Phase: PHASE4
Conditions: Paediatric Surgery, Anaemia, Iron Deficiency Anemia, Iron, Prospective Studies, Interventional Studies
Sponsor: University of Cape Town

Cover Page 
 
 
 
South African Paediatric Surgical Outcomes Study 2 (SAPSOS2) 
 
A South African multi-centre pilot trial to assess the feasibility and clinical efficacy of 
preoperative oral iron to treat preoperative iron-deficiency anaemia in children 
undergoing elective noncardiac surgery 
 
 
NCT05681871 
 
Unique Protocol ID: N20221001 
 
 
Study Document: Study Protocol V5.0 (Clean) 
 
Date: 05 August 2023 
 
Description: Study protocol V5.0 (Clean) submitted to University of Cape Town 
Human Research Ethics Committee 

 
FACULTY OF HEALTH SCIENCES 
Human Research Ethics Committee 
 
Form FHS015: Research Protocol – Section C 
 
 
South African Paediatric Surgical Outcomes Study-2 (SAPSOS-2) 
A South African multi-centre pilot trial to assess the feasibility and clinical efficacy 
of preoperative oral iron to treat preoperative iron-deficiency anaemia in children 
undergoing elective noncardiac surgery 
 
Protocol version 5.0 
05 August 2023 
 
 
 
 
   
 
Heidi Meyer   
Chief Investigator 
 
 
 
Chief Investigator contact details 
Dr Heidi Meyer 
Division of Paediatric Anaesthesia,  
Department of Anaesthesia & Perioperative Medicine 
University of Cape Town 
Western Cape, South Africa 
E-mail: heidi.meyer@uct.ac.za 
Telephone: +27 (0)799988858 

 
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Steering committee 
Heidi Meyer MBChB FRCA, Division of Paediatric Anaesthesia, Department of Anaesthesia & 
Perioperative Medicine, Red Cross War Memorial Children’s Hospital and University of Cape Town, 
South Africa 
 
Alexandra Torborg MBChB FCA(SA), Discipline of Anaesthesiology and Critical Care Medicine, 
Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa  
 
Bruce Biccard MBChB FCA(SA) FFARCS(I) MMedSci PhD, Professor and Second Chair, 
Department of Anaesthesia and Perioperative Medicine, Groote Schuur Hospital and University of 
Cape Town, South Africa 
 
Hyla Kluyts DMed (Anaest), Department of Anaesthesiology, Sefako Makgatho Health Sciences 
University, South Africa 
 
Susan Goobie, Professor, Department of Anaesthesiology, Boston Children’s Hospital 
 
Steven Staffa, PhD, Statistician, Department of Anaesthesiology, Boston Children’s Hospital 
 
Carmen Gerber MBChB FCA(SA), Medical Specialist Anaesthesia 
 
Vernon Louw, Professor, Department of Haematology, Groote Schuur Hospital and University of 
Cape Town, South Africa 
 
Sharon Cox, Professor, Division of Paediatric General Surgery, Red Cross War Memorial Children’s 
Hospital 
 
Shazia Peer, Associate Professor, Department of Otolaryngology, Red Cross War Memorial 
Children’s Hospital 
 
Marion Arnold, Division of Paediatric General Surgery, Red Cross War Memorial Children’s 
Hospital 
 
Patient advocate 
TBC 
 
Sponsor 
University of Cape Town 
 
Funders 
Society for the Advancement of Patient Blood Management 
 

 
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Table of Contents 
1. 
LIST OF ABBREVIATIONS ................................................................................................... 4 
2. 
SUMMARY ................................................................................................................................ 5 
3. 
INTRODUCTION ...................................................................................................................... 6 
4. 
STUDY OBJECTIVES .............................................................................................................. 7 
4.2  
PRIMARY OBJECTIVE ............................................................................................................. 7 
4.2  
SECONDARY OBJECTIVES ...................................................................................................... 7 
5. 
STUDY AIMS ............................................................................................................................. 7 
5.2  
PRIMARY OUTCOME MEASURE .............................................................................................. 7 
5.2  
SECONDARY OUTCOME MEASURES ........................................................................................ 7 
6. 
METHODS ................................................................................................................................. 8 
6.1 
STUDY DESIGN ...................................................................................................................... 8 
6.2 
INCLUSION CRITERIA ............................................................................................................. 8 
6.3 
EXCLUSION CRITERIA ............................................................................................................ 8 
6.4 
SITE REQUIREMENTS ............................................................................................................. 8 
6.5 
RESEARCH ETHICS AND INFORMED CONSENT ........................................................................ 9 
6.6 
SUBJECT WITHDRAWAL ......................................................................................................... 9 
6.7 
RECRUITMENT AND SCREENING ............................................................................................ 9 
6.8 
ENSURING ADEQUATE RESOURCES ...................................................................................... 10 
6.9 
CRITERIA FOR IRON DEFICIENCY ......................................................................................... 11 
6.10 
SUPPLEMENTAL IRON DOSING REGIMEN .............................................................................. 11 
6.11 
EMPIRIC TREATMENT FOR WORMS ....................................................................................... 12 
6.12 
RESEARCH PROCEDURES, DATA COLLECTION AND COLLATION ........................................... 13 
6.13 
DATASET ............................................................................................................................. 14 
6.14 
CASE RECORD FORMS .......................................................................................................... 15 
6.15 
COLLECTION AND STORAGE OF BLOOD SAMPLES ................................................................. 15 
6.16 
MONITORING MEDICAL ADHERENCE ................................................................................... 15 
6.17 
SAFETY REPORTING ............................................................................................................. 16 
5.10 
EXPECTED BENEFITS TO INDIVIDUAL PARTICIPANTS AND POTENTIAL SOCIETAL BENEFITS .. 16 
5.10 
SAMPLE SIZE CALCULATION ................................................................................................ 17 
5.10 
POWER ANALYSES ............................................................................................................... 17 
5.11 
STATISTICAL ANALYSIS ....................................................................................................... 18 
7. 
STUDY ORGANISATION AND MANAGEMENT  ........................................................... 19 
7.1 
STUDY STEERING COMMITTEE ............................................................................................. 19 
7.2 
PATIENT ADVOCATE ............................................................................................................ 19 
7.3 
LOCAL CO-ORDINATORS ...................................................................................................... 19 
7.4 
TRAINING OF INVESTIGATORS ............................................................................................. 19 
8 
DATA MANAGEMENT AND OWNERSHIP ...................................................................... 20 
9 
PUBLICATION PLAN ............................................................................................................ 20 
10 MANAGEMENT OF PREMATURE TERMINATION OF THE TRIAL ........................ 20 
11 REFERENCES ......................................................................................................................... 21 
10. 
APPENDICES ...................................................................................................................... 24 
 
 
 
 

 
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1. List of abbreviations 
 
DHb 
Delta haemoglobin (pre-treatment haemoglobin – post-treatment 
haemoglobin) 
Hb 
 
 
Haemoglobin 
IDA 
 
 
Iron deficiency anaemia 
SAPSOS 
 
South African Paediatric Surgical Outcomes Study 

 
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2. Summary 
 
Short title 
SAPSOS-2: Pilot Study 
Methodology 
Prospective national multi-centre interventional study 
Research sites 
Hospitals undertaking paediatric surgery in South Africa 
Objective 
To evaluate the efficacy of oral iron supplementation in children diagnosed 
with preoperative iron-deficiency anaemia undergoing noncardiac surgery. 
Primary 
outcome 
The delta Hb (DHb) (pre-intervention Hb –post-intervention Hb) 
Number of 
patients 
1110 patients 
Inclusion 
criteria 
Paediatric patients aged >6 months and <16 years admitted to participating 
hospitals undergoing elective non-cardiac surgery 
Anaemia as per WHO criteria1 
Exclusion 
criteria 
Patient or parent refusal 
Surgery planned in not less than 4 weeks from surgical outpatient visit 
Known history of acquired iron overload, family history of haemochromatosis 
or thalassemia 
Known reason for anaemia (e.g. untreated vitamin B12 or folate deficiency or 
haemoglobinopathy) 
Treatment with oral iron, erythropoietin, IV iron therapy or blood transfusion 
in the previous 12 weeks 
Known hypersensitivity to oral iron or other contraindication to oral iron 
Temperature > 38.0 °C or receiving non-prophylactic antibiotics 
Statistical 
analysis 
The primary outcome measure is comparison of pre-intervention and post-
intervention haemoglobin 
Proposed start 
date 
08 February 2023 
Proposed end 
date 
26 July 2024 
Trial duration  
Recruitment in outpatient clinic and follow-up until day of surgery 
 
 

 
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3. Introduction 
 
Studies in both paediatric and adult patients have shown an association between preoperative anaemia 
and increased postoperative morbidity and mortality, and transfusion rates2-7. The incidence of 
preoperative anaemia in the secondary analysis of the SAPSOS cohort of children who underwent 
noncardiac surgery was 46.2%4. Iron deficiency anaemia (IDA) has been shown to represent up to 
30% of preoperative anaemia in adults8. Iron deficiency and IDA are of even greater concern in 
children, because of the negative impact it may have on cognitive performance9. 
 
A recent Cochrane review on the role of preoperative iron in reducing perioperative blood transfusion 
in adult patients found no significant reduction in the administration of allogeneic blood transfusion 
in patients who had received preoperative iron compared with those who did not10. These findings 
were supported by the Preoperative intravenous iron to treat anaemia before major abdominal surgery 
(PREVENTT) trial which found no difference in blood transfusion or death between the patients who 
did and did not receive intravenous iron11. However, these findings have generated much discussion 
in the literature and concerns have been raised about the clinical application of this study. The mean 
Hb difference between the two groups post intervention (0.47g.dl-1) highlights the need for greater 
understanding of the impact of an intervention on the absolute or relative increase in Hb when 
designing trials looking at the impact of iron treatment on perioperative outcomes. Dosing regimens 
of preoperative oral iron varies widely between studies further complicating the ability to draw 
conclusions of the role of oral iron in the treatment of preoperative anaemia12-16. 
 
In contrast with the findings of the Cochrane review and the PREVENTT trial, a meta-analysis of 
patient blood management programme (PBM) studies, many of which include preoperative iron 
treatment as a component, found that there was a reduction in exposure to red cell transfusions17. 
Although, the meta-analysis also found the implementation of PBM was not associated with a 
reduction on in-hospital mortality or 30-day mortality, there was no additive benefit from multiple 
interventions and no trial showed that PBM were cost-effective.  
 
Not included in this meta-analysis were recently published studies on the implementation of 
preoperative anaemia screening clinics in adults in elective colorectal surgery and major surgery 
which demonstrated reductions in red cell transfusions18,19, length of stay18,19, and net costs18 in 
patients with IDA who were treated with preoperative intravenous iron. Similarly, a large study from 
Western Australia reported significant reductions in cost associated with the use of blood products, 
and improved patient outcomes, after implementation of a PBM20. 
 
Studies investigating the impact of increasing preoperative haemoglobin on perioperative outcomes 
in children are primarily focused on blood loss and blood transfusion rates in surgery in which 
significant bleeding and frequent blood transfusion are anticipated and most children in these studies 
received preoperative erythopoeitin21-27. The impact of preoperative oral iron as a stand-alone 
intervention to increases preoperative Hb are limited to 2 studies28,29. A single retrospective study has 
reported on the impact of the introduction of preoperative oral iron without EPO in children 
undergoing spinal surgery28. They found a significant difference in intraoperative transfusion rates in 
patients who received a longer duration of preoperative oral iron therapy. The major limitation of the 
study was a lack of preintervention Hb, precluding the ability to assess the effect of iron 
supplementation on delta Hb.  

 
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A subsequent study reviewing the impact of preoperative oral iron in paediatric cardiac patients found 
that iron supplementation resulted in an increase in preoperative haemoglobin levels which was 
associated with reduced red blood cell transfusion volumes29. 
 
Given the high incidence of preoperative anaemia in children having surgery in South Africa in the 
public sector and its association with poorer postoperative outcomes, it is important to assess the 
feasibility of a pragmatic intervention to treat preoperative anaemia in the context of a resource-
constrained setting. Although intravenous iron in combination with EPO may be more effective and 
have fewer side effects, oral iron is relatively inexpensive and widely available in South Africa. 
Regular deworming may also play an important role in the treatment of preoperative anaemia and has 
been shown to be an effective intervention to increase baseline Hb in school age children from low- 
and middle- income countries30.  
 
We hypothesise that the implementation of preoperative anaemia screening and treatment of anaemic 
patients with a minimum of 6 weeks supplementation with oral iron will have a clinically significant 
effect on increasing the haemoglobin in patients with preoperative IDA. 
 
 
4. Study objectives 
 
4.2  
Primary objective 
 
To evaluate the efficacy of oral iron supplementation in children diagnosed with preoperative IDA 
undergoing noncardiac surgery. 
 
4.2  
Secondary objectives 
 
Describe the incidence of preoperative IDA. 
 
5. Study aims 
 
5.2  
Primary outcome measure 
 
DHb (pre-intervention Hb – post-intervention Hb) 
 
5.2  
Secondary outcome measures 
 
Incidence of preoperative IDA in the elective paediatric surgical population in South Africa. 
 
 
 
 

 
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6. Methods 
 
6.1 Study design 
 
Prospective interventional quasi-experimental pre-post study across multiple hospitals in South 
Africa. Patients will be screened for trial eligibility at a normal routine outpatient clinic visit. Those 
patients with a screening Hb meeting the criteria for anaemia according to the WHO definition30 and 
able to receive the oral iron for a minimum of 6 weeks prior to their planned operation, will be eligible 
for inclusion.  
 
The formal laboratory blood test results will be reviewed within 48-76 hours by the research nurse to 
diagnose those patients who meet the pre-defined criteria for IDA. Parents & legal guardians will be 
contacted via telephone by the research nurse to inform them about their child’s results and to instruct 
them to either discontinue or continue taking the oral iron supplementation dependent on whether the 
results meet the pre-defined criteria for iron-deficiency anaemia. 
 
Prior to inclusion, freely given written informed consent must be obtained from all parents or legal 
guardians and assent from patients where appropriate.  
 
6.2 Inclusion criteria 
 
- 
Age > 6 months to <16 years 
- 
Noncardiac surgery 
- 
Elective surgery 
- 
Anaemic as per WHO criteria1 
 
6.3  Exclusion criteria 
 
- 
Patient or parent refusal 
- 
Unable to obtain written consent at the surgical outpatient clinic 
- 
Surgery planned in not less than 4 weeks from surgical outpatient visit 
- 
Known history of acquired iron overload, family history of haemochromatosis or 
thalassemia 
- 
Known reason for anaemia (e.g., untreated vitamin B12 or folate deficiency or 
haemoglobinopathy) 
- 
Treatment with oral iron, erythropoietin, IV iron therapy or blood transfusion in the previous 
12 weeks 
- 
Known hypersensitivity to oral iron or other contraindication to oral iron 
- 
Temperature > 38.0 °C or receiving non-prophylactic antibiotics 
- 
Acute liver failure 
 
6.4 Site requirements 
 
Hospital sites will include public hospitals in South Africa performing elective paediatric surgery and 
each site must meet the following requirements: 
 

 
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1) Appointed research nurse able to obtain consent and perform finger-prick test at the surgical 
outpatient clinic. 
2) On-site phlebotomy service. 
3) On-site pharmacy able to provide the patient and parent or legal guardian with the oral iron 
supplementation and deworming medication where appropriate. 
 
6.5 Research ethics and informed consent 
 
Research ethics and regulatory approvals will be sought before starting the study at each site, in 
accordance with national research legislation/guidelines. Hospitals will not be permitted to record 
data unless ethics approval is in place. 
 
Written informed consent (Appendix A) will be required for all study participants prior to screening 
haemoglobin is performed, with translators where necessary, from the primary parent or legal 
guardian or legally authorised representative and should include assent (Appendix B) of the child 
where appropriate. Two consent ± assent forms will be completed. One copy of the form(s) will be 
given to the parent or legal guardian to keep, and the other copy(s) will be kept in a study folder in a 
secure location. 
 
The investigators will perform the study in accordance with this protocol, will obtain consent, and 
will report unanticipated problems involving risks to subjects or others in accordance with local ethics 
committee requirements. Collection, recording, and reporting of data will be accurate and will ensure 
the privacy, health, and welfare of research subjects during and after the study. 
 
6.6 Subject withdrawal 
 
Subjects may withdraw from the study at any time without prejudice to their care and will still be 
treated for their anaemia in accordance with standard treatment protocols. 
 
6.7  Recruitment and screening 
 
Eligible subjects will be identified at routine surgical outpatient appointments. Paper informed 
consent will be obtained prior to a finger-prick screening haemoglobin (Hemacue) is performed, with 
translators where necessary, from the primary parent or legal guardian or legally authorised 
representative and included assent of the child where appropriate. Broadcasting through an 
appropriate hospital notice will inform the patients, their parents/guardians and the public that the 
hospital is participating in the study (Appendix C). 
 
The total patients planned to be recruited for screening is 1110 patients and these will be divided 
across 7 sites: 
 
 

 
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Sites 
Number of 
patients to be 
screened 
Estimated 
number of 
patients with 
IDA 
Western Cape 
460 
18 
Red Cross War Memorial Children's Hospital 
310 
12 
Tygerberg Hospital 
150 
6 
KwaZulu-Natal 
250 
10 
Inkosi Albert Luthlui Hospital 
150 
6 
Greys Hospital 
100 
4 
Gauteng 
400 
16 
Steve Biko Hospital 
100 
4 
Kalafong Hospital 
100 
4 
Chris Hani Baragwanath Hospital 
100 
4 
Charlotte Maxeke Johannesberg Academic Hospital 
100 
4 
Total 
1110 
44 
 
 
6.8 Ensuring adequate resources 
 
To conduct a sound and valid study the investigators will ensure to the best of their ability that the 
following criteria are met: 
 
1) Reasonable potential to recruit 1110 individuals to the study over a cumulative 9-month period. 
 
 
2) An appropriate amount of time to complete recruitment, intervention, and data collection (9 
months). 
 
3) An adequate supply of suitably qualified staff at each facility including: 
 
a) Appointed research nurse at each research site able to carry out the following responsibilities 
3 days per week:  
 
08:00 to 10:00 
 
Checking National Health Laboratory Services Results (NHLS) for blood tests at outpatient 
clinic 
Telephonic follow-up with recruited patients to discontinue iron supplementation if they do 
not meet criteria for IDA 
 
10:00 to 16:00 
 
Recruitment of patients for study 
Obtaining written informed consent and assent where appropriate 
Performing finger-prick Hb (Hemacue) 
Applying EMLA for venepuncture for anaemic patients  

 
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Giving drug script signed by clinic doctor for oral iron supplementation ± deworming 
medication for collection at the hospital pharmacy 
 
b) Appointed research assistant for all sites to complete weekly telephonic survey for all IDA 
patients assessing medical adherence and side-effects, referring onto study nurse or doctor 
where appropriate. 
 
3) Appropriate training on the study protocol, about any investigational product and about their 
duties to allow the staff to carry out their tasks safely and effectively. 
 
4) Appropriate supervision of any individual or group to whom the investigator assigns trial-related 
duties at the trial site 
 
5) Assurance that any person or party retained to perform trial-related duties is suitably qualified to 
perform those duties.  
 
 
 
6.9 Criteria for iron deficiency 
 
The patient will be allocated to iron-deficiency group if they meet one or more of the following 
criteria. 
 
1. Serum Ferritin WHO Definitions31 
2. Transferrin saturation (TSAT) <11%32 
 
6.10 
Supplemental iron dosing regimen 
 
All patients diagnosed with anaemia on the point of care Hemacue test will be given an oral iron 
supplement to take every day prior to surgery for a maximum of 3 months. 
 
The recommended treatment dose of elemental iron for IDA is 3-6mg-1kg-1day-1 33. This can be 
increased to 12mg-1kg-1day-1. The recommendation from Red Cross War Memorial Hospital 
Pharmacy is that iron syrup is preferred in children up to 4 years old or in older children unable to 
take tablets (Table 1). 
 
Table 1. Ferrous gluconate (350mg/5ml) Elemental Iron 8mg/ml Dosing 
 
Weight (kg) 
BD dose (mL) 
5 
2 
6 
2.5 
7 
2.5 
8 
3 
9 
3.5 
10 
4 
11 
4 
12 
4.5 

 
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13 
5 
14 
5.5 
15 
5.5 
16 
6 
17 
6.5 
18 
7 
19 
7 
20 
7.5 
 
 
If the child can take iron tablets the recommendation is possible to prescribe a dose at increments of 
½ tablet (37.5mg) (Table 2).  
 
 
 
 
Table 2: Ferrous Fumarate/Folic acid - Elemental iron 65mg tablets Dosing 
 
Weight Range 
Tablets* 
10 to 14 kg 
1.0 
>15 to 20 kg 
1.5 
>20 to 30 kg 
2.0 
>30kg 
3.0 
*Dose to be split into BD 
 
Table 3: Ferrous sulphate - Elemental iron 55mg tablets Dosing 
 
Weight Range 
Dose 
20 to < 27 kg 
1 tab bd 
27 to < 37 kg 
2 tab am/1 tab pm 
37 kg and above 
2 tab bd 
 
 
Based on this the dose range when prescribing tablets for patient weight range 10 to 59 kg is 2.2 to 
6.5 mg-1kg-1day-1. The oral iron supplementation will be dispensed the same day as the outpatient 
clinic appointment, with clear verbal instructions on how to take the medication and potential side-
effects. The parent or legal guardian will also be given a patient information leaflet, with information 
on anaemia, how to take the medication, potential side-effects, and who to contact should they have 
any further questions or concerns (Appendix D). 
 
6.11 
Empiric treatment for worms 
 
If the patient has not been dewormed in the last 6 months, they will be administered deworming 
medication in the surgical out-patient clinic as per the Standard Treatment Guidelines and Essential 

 
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Medicines List for South Africa Primary Healthcare Level 2020 Edition for management of anaemia 
in children33. 
 
6.12 
 Research procedures, data collection and collation 
 
At recruitment phase 
 
Eligible patients will be screened for anaemia with a finger-prick bedside Hemacue test at outpatient 
clinic. If the patient meets the WHO criteria for anaemia EMLA cream will be applied to potential 
sites for venepuncture and the patient will then be sent to the pathology laboratory for venepuncture 
with a request form for tests that will include laboratory full blood count (FBC), ferritin, transferrin 
saturation (TSAT), C-reactive protein (CRP), and reticulocyte Hb content. Patients who have not 
been dewormed within the last 6 months will be treated with mebendazole or albendazole as per the 
South African guidelines33. 
 
The patients age, weight, height, co-morbidities, ASA physical status, planned surgical procedure, 
planned date of surgery, severity of surgery, and type of surgery will be recorded. They will also be 
informed that they will be contacted telephonically once a week by the research assistant to enquire 
about compliance with the medication and enquire about any side-effects with the medication. The 
telephonic contact details will be confirmed by the research nurse and documented on the paper 
Outpatient CRF. 
 
 
 
 
At home 
 
The laboratory blood test results will be reviewed within 48 hours to diagnose those patients who 
meet the criteria for IDA. Any patients who do not meet the criteria will be contacted via telephone 
by the research nurse to instruct them to stop taking the iron supplementation and to bring the 
remaining iron supplementation with them to their next hospital visit. These patient folders and results 
for those patients not meeting the criteria for IDA will be reviewed by the appropriate surgical team 
to decide on appropriate ongoing management and further investigations which will be individualised 
to the patient. 
 
For those patients meeting the criteria for IDA and continuing the oral iron supplementation, the 
parent or legal guardian will be contacted weekly to complete a short telephonic survey on compliance 
with the medication, side-effects, and to answer any questions or concerns they may have. 
 
At time of Surgery 
 
Repeat laboratory FBC at time of routine preoperative bloods if part of standard care. 
 
Repeat ferritin, CRP, TSAT ± FBC whilst under anaesthesia prior to start of surgery. 
 
Data collection 

 
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Each individual hospital will collect and record data on a paper case record form (CRF) for every 
patient recruited. These include an Outpatient Clinic CRF (Appendix E), Telephonic Survey CRF 
(Appendix F), and Surgical Admission CRF (Appendix G). The Outpatient Clinic CRF and the 
Surgical Admission CRF will be kept in a booklet in the patient folder and a sticker will be placed on 
the folder to identify that the patient has been recruited. All the CRFs, including the Telephonic 
Survey CRF will be kept in a secure study file in a locked cupboard. 
 
Data will be anonymised by generation of a unique study code and transcribed by local investigators 
onto a secure, password protected internet based electronic CRF in the REDCap platform. Each 
patient will only be identified on the electronic CRF by their numeric code; thus, the co-ordinating 
study team cannot trace data back to an individual patient without contact with the local team.  A 
participant (patient) list will be used in each hospital to match identifier codes in the database to 
individual patients to record clinical outcomes and supply any missing data points. Access to the data 
entry system will be protected by username and password delivered during the registration process 
for individual local investigators. All electronic data transfer between participating hospitals and the 
co-ordinating centre will be encrypted using a secure protocol (HTTPS/SSL 3.0 or better).  
 
Each hospital will maintain a secure study file including a protocol, local investigator delegation log, 
ethics approval documentation, the participant list, and other additional documentation such as study 
definitions. 
 
A final summary printout of included patients with major variables should be produced for each 
hospital together with final data submission to double check for completeness and accuracy. 
 
6.13 
 Dataset 
 
A realistic data set will be fundamental to the success of the investigation. This dataset will include 
the following: 
 
All patients: 
 
- 
Age (continuous, numerical) 
- 
Sex (categorical, nominal) 
- 
Weight (continuous, numerical) 
- 
Height (continuous, numerical) 
- 
Co-morbidities (categorical, nominal) 
- 
Chronic medication (categorical, nominal) 
- 
ASA Physical Status (categorical, ordinal) 
- 
Severity of surgery (categorical, nominal) 
- 
Type of surgery (categorical, nominal) 
- 
Hemacue Hb 
 
All anaemic patients 
 
- 
Pre-intervention Hb (continuous, numerical) 

 
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- 
Pre-intervention MCV (continuous, numerical) 
- 
Pre-intervention ferritin (continuous, numerical) 
- 
Pre-intervention TSAT (continuous, numerical) 
- 
Pre-intervention CRP (continuous, numerical) 
- 
Pre-intervention reticulocyte Hb content (continuous, numerical) 
- 
Syrup or tablet prescribed (categorical, nominal) 
- 
Actual dose of elemental iron prescribed (mg-1.kg-1.day-1) 
 
All patients with IDA 
 
- 
Post-intervention Hb (continuous, numerical) 
- 
Post-intervention MCV (continuous, numerical) 
- 
Post-intervention ferritin (continuous, numerical) 
- 
Post-intervention TSAT (continuous, numerical) 
- 
Post-intervention CRP (continuous, numerical) 
- 
Post-intervention reticulocyte Hb content (continuous, numerical) 
- 
Days of oral iron treatment (continuous, numerical) 
 
6.14 
 Case record forms 
 
Whole cohort (1110 patients) 
 
An Outpatient CRF will be completed for every enrolled patient (Appendix F). This will be completed 
by the research nurse at each site. 
 
IDA cohort 
 
A Telephonic Survey CRF will be completed on a weekly basis for up to 3 months for every patient 
(Appendix G). This will be completed by the research assistant. 
 
A Surgical Admission CRF will be completed on admission for surgery by the surgical team 
(Appendix H). 
 
6.15 
Collection and storage of blood samples 
 
EMLA will be applied by the research nurse at the outpatient clinic. These patients will then have 
venepuncture performed by the on-site hospital phlebotomist. These samples will include an EDTA 
tube for FBC, and reticulocyte Hb content, and a gold top tube (serum separator) for C-reactive 
protein, ferritin, and transferrin saturation content. These samples will be labelled and stored in 
accordance with standard operating procedure. 
 
6.16 
Monitoring medical adherence 
 
Few validated medical adherence surveys have been developed for the paediatric population and these 
are limited to asthma, HIV/AIDS, epilepsy, ADHD, and diabetes34. Therefore, medical adherence 
will be defined as the following: 

 
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Number of days the patient takes the iron supplement/number of days the patient is prescribed 
to take the iron supplement.  
 
This will be assessed on a weekly basis via the telephonic survey. 
 
The parent or legal guardian will also be asked to bring any unused iron supplements when their child 
is admitted for surgery. A pill count and a count of remaining iron syrup will be done to cross-
reference against the reported doses taken. 
 
6.17 
Safety reporting 
 
All study participants enrolled to take oral iron supplements will be monitored via a weekly 
telephonic survey for adverse events (AE). The parent or legal guardian will also be given contact 
details for the research nurse who will be available to be contacted with any concerns.  
 
Serious Adverse Events (SAE) including death, life-threatening, requiring inpatient hospitalisation 
or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, are 
extremely unlikely given the safety profile and well-established use of oral iron supplementation in 
the paediatric population. Should a SAE or Serious ADR occur this will be reported to the sponsor 
(University of Cape Town) within 24 hours, and within 7 days to the UCT HREC. SAE & Serious 
ADR will be collected on a specially designed form (Appendix H). 
 
Non-serious adverse events (AE), will be documented clearly on the CRF for the telephonic surveys. 
Common side-effects will be asked about specifically, these include vomiting, nausea, stomach 
cramps or bloating, heartburn, constipation, and diarrhoea. Should the patient suffer from any of these 
side-effects they will be given telephonic advice on the management options as per the telephonic 
survey and referred to the research nurse or clinician investigators where appropriate. Any AE, 
illness, or clinically significant abnormal laboratory values, actions taken, and treatments provided 
will be clearly documented. It will also be recorded if the individual withdraws, and this will include 
the reason for withdrawal if the participant is willing to supply one. If the Hb <7.0g.dl-1 on the formal 
laboratory results, the parent or legal guardian must be contacted and referred for further medical 
investigation and treatment. 
 
5.10 
Expected benefits to individual participants and potential societal benefits 
 
As an individual the participant may benefit from the intervention by a direct increase in their 
haemoglobin levels. The impact of increased haemoglobin levels may translate to improved 
perioperative outcomes and reduced blood transfusion rates for the individual patient. Please note 
that the study is not designed to evaluate the impact of the intervention on these outcomes. The impact 
of treatment with iron may also have a positive impact on cognitive development, for the individual 
child, although again this study is not designed to assess this outcome. 
 
The potential benefit to the wider community of children undergoing surgery in South Africa is a 
greater understanding of the efficacy and feasibility of oral iron as treatment for preoperative anaemia 
in children, and further insight into the optimal oral iron regimen.  

 
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5.10 
Sample size calculation 
 
How many patients will need to have a screening finger-prick Hb for the pilot study to be a 
representative of children undergoing noncardiac surgery with preoperative anaemia? 
 
Secondary analysis of SAPSOS study found 46.2% patients were anaemic, using estimation for a 
single proportion with a specified precision and allowing for 10% drop out. 
 
n = [p(1-p)z2] / d2 
n:  sample size  
p: population proportion 
z: 1.96, level of confidence, normal distribution   
d: 0.05, acceptable margin of error 
 
n = 0.46.(0.538)3.8416 / 0.0025 = 381.98 
10% drop out rate: 38.2 
Sample size: 382 + 38 = 420 
 
Given a sample size of 420 patients allowing for 10% drop-out approximately how many 
anaemic patients will be enrolled? 
 
n = 420*0.90*0.462 ~ 176 
 
5.10 
Power analyses 
 
What effect size could we expect to find statistically significant for the whole cohort given an 
estimated sample size of 176 patients? 
 
Effect size for comparison between mean Hb pre and post intervention for whole cohort (matched 
pairs samples t-test) of 176 patients. Assuming data are normally distributed. 
Sample size = 176, power = 80%, two-tailed significance 0.05 
 
Effect size ~ 0.21 
 
 
 

 
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pwr.t.test(n = 176, d = NULL, sig.level = 0.05, power = 0.8,  
             type = "paired”, alternative = "two.sided") 
 
     Paired t test power calculation  
 
              n = 176 
              d = 0.2123609 
      sig.level = 0.05 
          power = 0.8 
    alternative = two.sided 
 
NOTE: n is number of *pairs* 
 
What effect size could we expect to find statistically significant for the cohort of patients with 
IDA** given an estimated sample size of 176 anaemic patients, if the incidence of IDA is 
unknown? 
 
IDA 
prevalence 
IDA  
Sample size 
Effect size (matched 
pairs samples t-test) 
Effect size (Wilcoxin signed-
rank test (matched pairs)) 
0,2 
35 
~0.5 
~0.5 
0,3 
53 
~0.4 
~0.4 
0,4 
70 
~0.34 
~0.35 
0,5 
88 
~0.3 
~0.31 
 
5.11 
Statistical analysis 
 
Categorical variables will be reported as number and percentage. All patient and surgical 
characteristics will be compared between children with and without anaemia and comparing children 
with IDA versus anaemia of other cause using Pearson's chi-squared or Fisher's exact tests as 
appropriate. These will include age groups, sex, type of surgery (general, orthopaedic, ENT, plastics, 
other), severity of surgery as per SAPSOS definitions (mild, moderate, severe), severity of anaemia 
as per WHO definitions (mild, moderate, severe).  
 
Normal distribution of continuous variables will be determined by Shapiro-Wilk testing and 
summarised appropriately as means ± standard deviation or as medians ± interquartile range (IQR). 
All patient and surgical characteristics will be assessed with parametric testing (Student’s t-test) for 
normally distributed data, and nonparametric testing (Mann-Whitney U test or Kruskal-Wallis test) 
for non-normally distributed data. These data will include pre-intervention Hb, post-intervention Hb, 
and duration of oral iron treatment (days). 
 
Pre- and post-intervention Hb for the patient with IDA will be assessed by a paired t-test if data are 
normally distributed, and if data are not normally distributed then the data will be analyse using 
Wilcoxon ranked sum test. 
 

 
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Is there a statistically significant difference in pre and post intervention Hb in the IDA patients 
after adjusting for baseline haemoglobin? 
 
The proposal is to use a mixed effect regression model. The final model will depend on the 
distribution of the outcome variable (post-intervention Hb). If the outcome is normally distributed, a 
linear mixed effect model will be used. If the outcome is not normally distributed, different 
approaches can be used depending on how skewed the outcome is e.g. Generalised Linear Mixed 
Effect Model 
 
7. Study organisation and management  
 
7.1 Study steering committee  
 
The Steering Committee will be chaired by HM. The study management team will be appointed by 
the Steering Committee and led by HM. The duties of this team will include administration of all 
project tasks, communication between project partners (including funders, Steering Committee 
members, local coordinators, etc.), data collation and management and preparation of reports for 
individual study sites. The Steering Committee is responsible for the scientific conduct and 
consistency of the project. The Steering Committee will ensure communication between the 
funder(s), study management team and co-ordinators as necessary. 
 
 
 
 
7.2 Patient advocate 
 
Patient advocate(s) will be appointed who will advise the Steering Committee on possible protocol 
amendments if required, based on patient concerns regarding delivery of the study or communication 
of the study. 
  
7.3 Local co-ordinators 
 
Local co-ordinators in individual institutions will have the following responsibilities: 
 
- 
Provide leadership for the study in their institution 
- 
Ensure all relevant regulatory and ethics approvals are in place for their institution 
- 
Ensure adequate training of all relevant staff prior to data collection 
- 
Supervise daily data collection and site recruitment and follow up management 
- 
Act as guarantor for the integrity and quality of data collected 
- 
Ensure timely completion of electronic CRFs 
- 
Communicate with the relevant national co-ordinator 
 
7.4 Training of investigators 
 
Training will be done via online virtual training sessions. Each study site will be required to complete 
an online questionnaire as part of the site initiation, prior to starting data collection. 

 
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8 Data management and ownership 
 
On behalf of the Steering Committee, the Department of Anaesthesia and Perioperative Medicine, 
Groote Schuur Hospital and University of Cape Town will act as custodian of the data. The Steering 
committee will retain the right to use all pooled data for scientific and other purposes. Members of 
the SAPSOS-2 study group will have the right to access the pooled data for research purposes 
provided the research proposal has been reviewed and deemed appropriate by the Steering 
Committee. The primary consideration for such decisions will be the quality and validity of any 
proposed analysis. Only summary data will be presented publicly, and all institutions will be 
anonymised except in the individualised report provided to each institution at the end of the study. 
Individual patient data provided by participating sites remain the property of the respective 
institutions. 
 
 
9 Publication plan 
 
Data will be presented and disseminated in a timely manner. The Steering Committee will appoint a 
writing committee to draft the scientific report(s) of this investigation. The group will be known as 
‘The SAPSOS-2 Investigators’. Participation and authorship opportunities will be based on 
contribution to the primary study. On request, hospitals will be provided with an individual report 
allowing comparison of their individual hospital’s summary data to that of their national cohort. In 
line with the principles of data preservation and sharing, the Steering Committee will, after 
publication of the overall dataset, consider all reasonable requests to make the dataset available in 
whole or part for secondary analyses and scientific publication. The Steering Committee will consider 
the scientific validity and the possible effect on the anonymity of participating hospitals prior to 
granting any such requests. Where appropriate, a prior written agreement will set out the terms of 
such collaborations. The Steering Committee will consider proposals for secondary analyses on the 
basis of the scientific quality of the proposal. The Steering Committee must approve the final version 
of all manuscripts prior to submission, whether they relate to part or all of the SAPSOS-2 dataset.  
 
 
10 Management of premature termination of the trial 
 
Once the decision is taken to terminate or suspend a study, all relevant bodies should be notified as 
soon as possible, stating the reasons for the suspension or termination. This will include informing 
all participants promptly by phone, assessing treatment requirements and develop a follow-up 
schedule for all participants where necessary and informing the institution, sponsor (University of 
Cape Town), IEC/IRB and other relevant bodies involved and providing a detailed written report, as 
appropriate. 
 
 
 
 
 

 
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10.  Appendices 
 
Appendix A – SAPSOS2 Parent or legal guardian informed consent form V2.0 
 
Appendix B – SAPSOS2 Patient assent form V1.0 
 
Appendix C – SAPSOS2 Patient information leaflet V2.0 
 
Appendix D - SAPSOS2 Patient broadcasting poster V1.0 
 
Appendix E – SAPSOS2 Outpatient Clinic Case Record Form V1.0 
 
Appendix F – SAPSOS2 Telephonic Survey Case Record Form V1.0 
 
Appendix G – SAPSOS2 Surgical Admission Case Record Form V1.0 
 
Appendix H – Serious Adverse Event Reporting Form V1.0 
 
Appendix I  – Oral iron supplement leaflets