Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus Aureus Bacteraemia: The EVOS Randomized Controlled Trial
Phase: PHASE3
Conditions: Staphylococcus Aureus Bacteremia
Sponsor: Clinical Research Centre, Malaysia

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
1                                                                      
 
 
 
 
 
Protocol number 
EVOS 1.3, dated 12-03-2024          (NMRR ID-23-02467-3JV) 
Principal 
Investigator 
Dr Steven Lim Chee Loon  
Infectious Disease Physician 
Department of Medicine, Hospital Raja Permaisuri Bainun 
Tel: 013-3620081  
Email: stevenlimcl@gmail.com 
 
Collaborators 
Clinical Research Centre (CRC) Hospital Raja Permaisuri Bainun  
CRC in respective study sites 
Site Principal 
Investigators 
1. Dr Steven Lim Chee Loon 
2. Dr Chuah Chuan Huan 
3. Dr Ng Tiang Koi 
4. Dr Sharifah Baizura Bt Syed Alwi 
5. Dr Ang Peng Peng 
6. Dr Noralfazita binti An 
 
7. Dr Lim Kah Chuan 
8. Dr Anuradha P. Radhakrisnan 
9. Dr Gan Wee Fu  
10. Dr Suraya Hanim Abdullah Hashim  
11. Dr Azureen Azmel 
12. Dr Tuang Wei Xuan 
Study Sites 
1. Hospital Raja Permaisuri Bainun 
2. Hospital Pulau Pinang 
3. Hospital Tuanku Ja’afar 
4. Hospital Sultanah Bahiyah 
5. Hospital Seberang Jaya 
6. Hospital Sultan Abdul Halim  
 
7. Hospital Sultan Idris Shah Serdang 
8. Hospital Selayang 
9. Hospital Melaka  
10. Hospital Ampang  
11. Hospital Tengku Ampuan Rahimah 
12. Hospital Sultanah Aminah 
 
Central CRC Team 
 
1. Dr Chow Lai Yeng                    pandorachow.crc@gmail.com       
2. Ms Nor Aizura Zulkifli             aizura.az@gmail.com  
3. Dr Josephine Paul Durai         joeyukijo.28@gmail.com      
(Corresponding person) 
       Tel: 05-208 5146 / 5148      
 
Sponsor 
Ministry of Health Malaysia (MOH) 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the written consent of principal investigator 
 
Early intravenous to oral antibiotic switch in 
uncomplicated Staphylococcus aureus bacteraemia:  
The EVOS randomized controlled trial  
STUDY PROTOCOL 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
2                                                                      
 
Information of study sites 
 
 
Site 
number 
Institution Address and Contact Number 
Site Principal Investigator 
01 
Hospital Raja Permaisuri Bainun 
Jalan Raja Ashman Shah, 30450 Ipoh, Perak 
Tel: 05-208 5000 
 
Dr Steven Lim Chee Loon 
Infectious Diseases Physician 
Email: stevenlimcl@gmail.com 
 
02 
Hospital Pulau Pinang 
Jalan Residensi, 10450 Georgetown, Pulau Pinang 
Tel: 04-217 5100 
Dr Chuah Chuan Huan 
Infectious Diseases Physician 
Email: chchuah7@yahoo.com 
 
03 
Hospital Tuanku Ja’afar 
Jalan Rasah, Bukit Rasah, 70300 Seremban, Negeri Sembilan 
Tel: 06-768 4000 
 
Dr Ng Tiang Koi 
Infectious Diseases Physician 
Email: tiangkoi79@yahoo.com 
 
04 
Hospital Sultanah Bahiyah 
Km 6, Jln Langgar, Bandar, 05460 Alor Setar, Kedah 
Tel: 04-740 6233 
 
Dr Sharifah Baizura Bt Syed Alwi 
Infectious Diseases Physician 
Email: baizura1973@hotmail.my 
 
05 
Hospital Seberang Jaya 
Jalan Tun Hussein Onn, Seberang Jaya, 13700 Perai, Penang 
Tel: 04-382 7333 
 
Dr Ang Peng Peng 
Infectious Diseases Physician 
Email: angpp2209@gmail.com 
 
06 
Hospital Sultan Abdul Halim 
Jalan Lencongan Timur 08000 Sungai Petani, Kedah 
Tel: 04-445 7333 
 
Dr Noralfazita binti An 
Infectious Diseases Physician 
Email: noralfazitaa@moh.gov.my 
 
07 
Hospital Sultan Idris Shah Serdang 
Jalan Puchong, 43000 Kajang, Selangor  
Tel: 03-8947 5555 
 
Dr Lim Kah Chuan 
Infectious Diseases Physician 
Email: ck7902@gmail.com 
 
08 
Hospital Selayang 
Lebuhraya Selayang - Kepong, 68100 Batu Caves, Selangor 
Tel: 03-6126 3333 
 
Dr Anuradha P. Radhakrisnan 
Infectious Diseases Physician 
Email: anurapr70@gmail.com 
 
09 
Hospital Melaka 
Jalan Mufti Haji Khalil, 75400 Melaka 
Tel: 06-289 2344 
 
Dr Gan Wee Fu 
Infectious Diseases Physician 
Email: ganweefu@gmail.com 
 
10 
Hospital Ampang 
Jalan Mewah Utara, Taman Pandan Mewah, 68000 Ampang, 
Selangor 
Tel: 03-4289 6000  
 
Dr Suraya Hanim Abdullah Hashim 
Infectious Diseases Physician 
Email: 
surayahanim.abdullahhashim@gmail.com 
 
11 
Hospital Tengku Ampuan Rahimah  
Jalan Langat, 41200 Klang, Selangor 
Tel: 03-3375 7000 
 
Dr Azureen Azmel 
Infectious Diseases Physician 
Email: aazmel@gmail.com 
 
12 
Hospital Sultanah Aminah 
Jalan Persiaran Abu Bakar Sultan, 80100 Johor Bahru, Johor 
Tel: 07-225 7000 
Dr Tuang Wei Xuan  
Infectious Diseases Physician 
Email: weixuan0706@gmail.com 
 
 
 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
3                                                                      
 
Protocol amendments 
 
No. 
Date of amendment 
(Protocol version) 
 
Protocol section(s) amended 
Reason of amendment(s) 
01 
 
18th September 2023 
 
(Version 1.1) 
 
 
• 
7.4.1 – Added case definition of 
uncomplicated SAB. 
• 
7.4.2 – Clarification of body 
temperature 37.5 ֯C or below as 
defervescence.  
• 
8.4.3 – Clarification on study drug 
accountability. 
• 
8.9 & 9.2 – Revised criteria for 
stopping study drug after 
development of clinically significant 
AE. 
Minor revisions based on comments 
and recommendation from JPP-NIH 
panel. 
02 
25th October 2023 
 
(Version 1.2) 
• 
9.3, 9.5 
• 
10.2 
• 
11.1, 11.4 
• 
13.4.3 
 
Minor revisions based on comments 
and 
requirements 
from 
MREC 
Secretariat. 
03 
12th March 2024 
 
(Version 1.3) 
 
• 
8.3 –Clarified that oxacillin-
susceptible staphylococci can be 
considered susceptible to cefazolin 
and cephalexin. 
 
• 
9.1.4, 14.4 – Revised the minimum 
adherence rate to ≥ 80% for 
patients to be deemed adherent to 
study antibiotics and completed 
study treatment as per protocol.  
• 
10.3 – Revised SAE reporting 
timeline 
 
 
• 
14.16 – Updated Gantt Chart 
 
 
For Staphylococcus aureus, oxacillin 
susceptibility predicts cefazolin and 
cephalexin susceptibility as per CLSI 
guidelines.    
 
Adherence rate of ≥ 80% is widely 
accepted as adherence threshold 
for study drugs in clinical trials. 
 
 
 
Revised SAE reporting timeline in 
accordance 
with 
MREC 
requirement. 
 
Revised study timeline after receipt 
of research grant in January 2024. 
 
 
 
 
 
 
 
 
 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
4                                                                      
 
TABLE OF CONTENTS 
 
 
  
  
 
1. STUDY SYNOPSIS 
7  
 
  
  
 
2. INVESTIGATOR’S AGREEMENT AND DECLARATION 
13  
 
  
  
 
3. LIST OF ABBREVIATIONS 
14  
 
  
  
 
4. GLOSSARY OF TERMS 
15  
 
  
  
 
5. INTRODUCTION & BACKGROUND 
16  
 
  
  
 
6. OBJECTIVES 
18  
 
6.1 Primary objective 
18  
 
6.2 Secondary objectives 
18  
 
6.3 Potential study benefit and risk 
18  
 
  
  
 
7. STUDY DESIGN 
19  
 
7.1 Overall study design 
19  
 
7.2 Schematic diagram of study design 
20  
 
7.3 Discussion of study design 
20  
 
7.4 Study population 
21  
 
7.4.1 Case definition of uncomplicated SAB 
21  
 
7.4.2 Inclusion criteria 
22  
 
7.4.3 Exclusion criteria 
22  
 
7.4.4 Study outcomes 
23  
 
7.4.5 Subject withdrawal & drop out 
25  
 
7.4.6 Procedures for handling withdrawal 
25  
 
7.4.7 Screening failures 
25  
 
  
  
 
8. TREATMENT AND STUDY PROCEDURES 
25  
 
8.1 Description of study intervention 
25  
 
8.2 Description of comparator intervention 
26  
 
8.3 Dosage and administration 
27  
 
8.4 Investigational product supply and handling 
29  
 
8.4.1 Supply, packaging, and labelling 
29  
 
8.4.2 Storage and dispensing 
29  
 
8.4.3 Accountability 
29  

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
5                                                                      
 
 
8.5 Treatment allocation and randomization 
29  
 
8.6 Baseline assessment and laboratory tests 
30  
 
8.7 Assessment of compliance 
30  
 
8.8 Concomitant therapy 
30  
 
8.9 Discontinuation and interruption of treatment 
30  
 
8.10 Assessment of efficacy and safety 
30  
 
  
  
 
9. STUDY CONDUCT 
31  
 
9.1 Study visits and procedures 
31  
 
9.1.1 Screening visit 
31  
 
9.1.2 Baseline visit 
31  
 
9.1.3 Eligibility verification and randomization 
32  
 
9.1.4 Study treatment and visits 
32  
 
9.2 Criteria for stopping subject treatment 
36  
 
9.3 Termination of study 
36  
 
9.4 Dropouts and withdrawals 
37  
 
9.5 Sample handling and analysis 
37  
 
  
  
 
10. ADVERSE EVENTS 
38  
 
10.1 Definitions 
38  
 10.1.1 Adverse event (AE) 
38  
 10.1.2 Unexpected adverse event 
38  
 10.1.3 Serious adverse event (SAE) 
38  
 
10.2 Detecting and documenting AE 
38  
 
10.3 Reporting SAE 
41  
 
10.4 Treatment and follow-up of AE 
41  
 
  
  
 
11. DATA MANAGEMENT 
41  
 
11.1 Data storage, data security and back-up 
41  
 
11.2 Data entry, checking and validation 
43  
 
11.3 Data quality assurance/quality control 
43  
 
11.4 Archiving and data destruction 
44  
 
  
  
 
12. STATISTICAL METHODS 
45  
 
12.1 Sample size and power considerations 
45  
 
12.2 Randomization 
45  
 
12.3 Statistical analysis plan 
46  
 12.3.1 Efficacy analysis 
46  
 12.3.2 Safety analysis 
46  
 12.3.3 Handling of missing, unused, and spurious data 
47  

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
6                                                                      
 
 12.3.4 Procedure for deviation from original statistical plan 
47  
 12.3.5 Planned interim analysis 
47  
 
12.4 Data and Safety Monitoring Board 
47  
 
  
  
 
13. ETHICS & REGULATORY CONSIDERATIONS 
48  
 
13.1 Independent Ethics Committee   
48  
 
13.2 Ethical conduct of the study  
48  
 
13.3 Informed consent and subject information  
48  
 
13.4 Patient protection procedures  
49  
 13.4.1 Procedures in the event of emergency  
49  
 13.4.2 Procedures in the event of pregnancy  
50  
 13.4.3 Patient data protection  
50  
 13.4.4 Insurance 
51  
 
  
  
 
14. ADMINISTRATIVE MATTERS 
51  
 
14.1 Notification of regulatory authority(ies) 
51  
 
14.2 Notification of primary care physician 
51  
 
14.3 Study initiation 
52  
 
14.4 Protocol deviation 
52  
 
14.5 Study documentation 
53  
 14.5.1 Essential documents 
53  
 14.5.2 Source document 
53  
 
14.6 Patient identification list/enrolment log 
54  
 
14.7 Curriculum vitae 
54  
 
14.8 Site signature/authorization log 
54  
 
14.9 Study monitoring 
54  
 
14.10 Audits and inspections 
55  
 
14.11 Retention of documents 
55  
 
14.12 Finance 
55  
 
14.13 Confidentiality 
55  
 
14.14 Publication policy 
55  
 
14.15 Anticipated subject accrual duration  
56  
 
14.16 Gantt Chart 
56  
 
  
  
 
15. REFERENCES 
57  
 
  
  
 
16. APPENDICES 
59  
 
  
  
 
 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
7                                                                      
 
1. STUDY SYNOPSIS 
Study title 
Early intravenous to oral antibiotic switch in uncomplicated Staphylococcus 
aureus bacteraemia: The EVOS randomized controlled trial  
Sponsor 
Ministry of Health Malaysia  
Clinical Phase 
Phase 3 
Investigators 
The principal investigators are infectious diseases (ID) physicians practicing in 
tertiary hospitals under the Ministry of Health Malaysia. 
Study sites 
12 government tertiary hospitals with ID physicians 
Study period 
12 months 
First subject enrolment: May 2024 
Last subject enrolment: January 2025 
Last subject to complete follow-up: April 2025 
 
Objectives 
Primary objective 
To demonstrate that early IV to oral antibiotic switch is as efficacious as 
standard 14-day IV antibiotic therapy for patients with uncomplicated SAB.  
 
Secondary objectives 
To evaluate the additional benefits of early IV to oral antibiotic switch for 
patients with uncomplicated SAB: 
• Duration of hospitalisation  
• All-cause mortality 
• Complications related to IV therapy 
• Safety of early IV to oral antibiotic switch in terms of adverse events and risk 
of Clostridium difficile diarrhoea. 
 
Methodology 
This is a multicentre, randomized, open-label, parallel group design trial to 
evaluate non-inferiority and safety of early IV to oral antibiotic switch versus 
standard 14-days IV antibiotic for patients with uncomplicated SAB. Eligible 
subjects will be randomized 1:1 into 2 groups (early oral antibiotic switch versus 
standard IV antibiotic therapy) following the inclusion and exclusion criteria.  
The study consists of 3 stages for each patient with a duration of approximately 
12 weeks: screening and enrolment, open-label treatment with 7 to 11 days of 
study antibiotics, and follow-up until day 90 post-randomization.  Phone call or 
inpatient follow up will be conducted at Day 7-11, Day 30, and Day 90 post-

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
8                                                                      
 
randomization to review patient’s condition. All data will be entered 
electronically into REDCap. 
 
Study outcomes 
Primary outcome: 
Rate of SAB-relapse, defined as any new positive blood culture with S. aureus, 
and/or newly diagnosed metastatic S. aureus infection resulting from 
hematogenous dissemination. [Time Frame: 90 days] 
 
Secondary outcomes: 
1. Duration of hospitalisation in days [Time Frame: 90 days] 
• Number of calendar days of hospitalisation after the first positive blood 
culture for S. aureus. 
 
2. All-cause mortality [Time Frame: 90 days] 
• Rate of any death occurred within 90 days of randomization  
 
3. Complications related to IV therapy [Time Frame: 90 days] 
• Rate of complications related to insertion or usage of peripheral branula or 
central catheter, and administration of IV drugs 
 
4. Adverse events [Time Frame: 30 days] 
 
5. Clostridium difficile diarrhoea [Time Frame: 90 days] 
• A diagnosis of diarrhoea with ≥1 stool sample tested positive for C. difficile 
toxin or toxin gene. 
 
Sample size 
Sample size and power considerations 
We estimate a 4% event rate of primary outcome (SAB-relapse) among our 
study patients. A clinically acceptable non-inferiority margin of 8% was 
determined based on a consensus among infectious diseases physicians after 
considering the expected large gain of oral treatment (for examples, reduced 
hospital bed-days, saving inpatient costs, and lower risk of healthcare associated 
infections). 
Thus, a total of 256 patients are needed in this study to achieve 80% power with 
a one-sided 0.025 α-level. After adjustment for 10% potential dropout, the study 
will require 290 patients or 145 patients in each study arms. (Calculated using 
STATA/IC Version 13.1, Revision 16 Dec 2016). 
 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
9                                                                      
 
Study Population 
Hospitalized patients who fulfil the study criteria at the time of screening will be 
recruited and randomized. 
Inclusion criteria 
1. Age 18 years old and above. 
2. Blood culture positive for Staphylococcus aureus (S. aureus).  
3. Received 3 to 7 days of definitive IV antimicrobial therapy, defined as:  
• Cloxacillin or cefazolin for methicillin-sensitive staphylococcus aureus 
(MSSA); 
Vancomycin 
or 
ceftaroline 
for 
methicillin-resistant 
staphylococcus aureus (MRSA).  
• Proven in-vitro susceptibility and adequate dosing given (as determined 
by the principal investigator).  
4. Achieved clearance of bacteraemia, defined as at least one documented 
latest negative follow-up blood culture obtained within 72 hours after the 
initiation of definitive IV antimicrobial therapy. 
5. Achieved defervescence, defined as sustained body temperature ≤37.5°C 
within 48 hours before randomization. 
6. Able to provide written informed consent to participate trial. 
 
Exclusion criteria 
1. Evidence of metastatic infection of S. aureus: for example, infective 
endocarditis, intraabdominal abscess, lung empyema, and osteomyelitis. 
Radiological investigations such as chest X-ray, ultrasound, echocardiogram, 
and CT scan are not mandatory prior to enrolment, but should be done at 
the discretion of the treating physician if clinically indicated. 
2. Septic shock, defined as hypotension requiring vasopressors to maintain 
MAP ≥65 mmHg despite adequate volume resuscitation. 
3. Received more than 5 days of non-study antibiotics as empirical therapy 
prior to enrolment. 
4. Polymicrobial bloodstream infection, defined as isolation of pathogens 
other than S. aureus from a blood culture obtained prior to randomization. 
Common skin contaminants such as coagulase-negative staphylococci, 
Bacillus spp., and diphtheroid will not be considered to represent 
polymicrobial infection. 
5. Known history of S. aureus infection within the past 3 months. 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
10                                                                      
 
6. Inability to tolerate oral therapy or poor absorption of oral medications, or 
not suitable for ongoing IV therapy (for example, difficult intravenous 
access) 
7. No options of oral antibiotic available for patient due to: 
• In vitro resistance of S. aureus to all oral study drugs.  
• Known contraindications to receive the active oral study drugs. For 
example, 
hypersensitivity 
reaction 
to 
trimethoprim-
sulfamethoxazole, thrombocytopenia secondary to linezolid etc. 
• Non-availability of oral study drugs at the study sites. 
8. Patient is concomitantly receiving oral antibiotics which are active against S. 
aureus. For example, trimethoprim-sulfamethoxazole for Pneumocystis 
jirovecii pneumonia prophylaxis. 
9. Presence of a non-removable foreign body such as prosthetic heart valve, 
vascular 
graft, 
pacemaker, 
automated 
implantable 
cardioverter-
defibrillator, ventriculoperitoneal shunt, prosthetic joint, and fracture 
fixation implant 
10. Failure or inability to remove intravascular catheter that is present when 
first positive blood culture was drawn. 
11. Known comorbidity that increased the risk of complicated infections: 
• End-stage renal disease  
• Severe liver disease (Child-Pugh class C) 
• Severe immunodeficiency: 
o HIV-positive patients with CD4<200 cells/uL or AIDS 
o primary immunodeficiency disorders 
o high-dose steroid therapy (>1 mg/kg prednisone or equivalent 
doses given for > 4 weeks or planned during intervention) 
o immunosuppressive therapy  
o neutropenia (<500 neutrophils/μl) at randomization or 
neutropenia expected during intervention phase due to 
immunosuppressive treatment 
o solid organ or hematopoietic stem cell transplantation within the 
past 6 months or planned during treatment period 
 
13. Short life expectancy < 3 months 
14. Pregnancy (for women of childbearing potential) 
 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
11                                                                      
 
Test treatment, 
dose, and mode of 
administration 
Patients will receive either an oral or intravenous study drug, according to the 
treatment arm. The study drug will be selected by the site investigator from a 
list of study drugs as follows: 
Early Oral Switch (EOS) therapy: 
First choice for MSSA and MRSA: Tab. Trimethoprim-sulfamethoxazole 2-4 
tablets BD 
Alternative for MSSA: Tab. Clindamycin 600mg TDS, Tab. Cephalexin 1gm QID, 
Tab Linezolid 600mg BD 
Alternative for MRSA: Tab. Linezolid 600mg BD 
Standard IV (SIV) therapy: 
First choice for MSSA: IV Cloxacillin 2g QID 
Alternative for MSSA: IV Cefazolin 1-2g TDS 
First choice for MRSA: IV Vancomycin 15-20mg/kg BD 
Alternative for MRSA: IV Ceftaroline 600mg TDS 
The choice of study drug will depend on the susceptibility of the respective 
isolate, expected drug interactions, contraindications, and expected side 
effects. 
Investigators will assess whether the “first-choice” regimen can be given and 
then consider the alternative regimen. The study drug can be switched during 
therapy from first choice to the respective alternative antibiotics if clinically 
necessary. The route of administration must be maintained according to the 
randomized group. Doses should be adjusted in the setting of renal dysfunction. 
 
Duration of 
treatment with 
study medication 
Patients in both groups will receive 7 to 11 days of study drugs to achieve a total 
course of 14 days of definitive antimicrobial therapy for SAB. 
Statistical Analysis 
The primary analysis for this study will be performed on the intention-to-treat 
(ITT) population, which consists of all randomized patients analysed as assigned. 
Absolute between-group difference of SAB-relapse rate and its 95% confidence 
interval for the oral antibiotic stepdown and the standard IV antibiotic groups 
will be estimated using a one-tailed z-test. If the upper limit of the 95% 
confidence interval falls below the 8% non-inferiority margin, early oral 
antibiotic switch will be deemed non-inferior to standard IV antibiotics. 
 
A second supportive analysis on the primary endpoint will be derived from the 
per-protocol (PP) population, which includes patients who have been treated 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
12                                                                      
 
 
 
according to protocol and reached a defined relapse outcome in the trial. In this 
analysis, we will exclude patients who do not complete the study treatment as 
per protocol, lost to follow-up, withdraw during the study period, or meet the 
criteria for protocol deviation. 
 
Secondary outcome measures expressed as proportions will be compared 
between control arm (SIV) and intervention arms (EOS) using chi-squared test, 
and risk difference as well as relative risk of the outcome measures will be 
calculated together with its 95% confidence interval. Mean difference and its 
95% confidence interval will be provided for secondary outcome measures that 
are on numerical scale, and comparison between study arms will be done using 
independent t-test. P-value < 0.05 is considered statistically significant. 
Subgroup analysis of the primary endpoint may also be performed although the 
study power in subgroups may be low. 
 
An interim analysis will be performed on the efficacy and safety endpoints when 
50% of the targeted patients have been randomized and completed 30 days 
follow-up. The results will be presented to the Data and Safety Monitoring Board 
(DSMB) to determine whether the trial should proceed as planned or be stopped 
early due to overwhelming non-inferiority or safety concern or undergo sample 
size recalculation based on conditional power. 
 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
13                                                                      
 
2. INVESTIGATOR’S AGREEMENT AND DECLARATION 
 
I hereby agree to conduct the clinical trial in compliance with the protocol with the ethical 
principles outlined in the Declaration of Helsinki, Malaysian Good Clinical Practice 
Guideline (GCP), and applicable local regulations.  
 
I acknowledge that I am responsible for overall study conduct in my study site. I agree to 
personally conduct and supervise the described clinical study and maintain the 
appropriate records and documentation required. 
 
I agree to ensure that all site staff involved in the conduct of the study will be 
appropriately trained and informed of their responsibilities and obligations. 
 
I will ensure that all site investigators and I have no conflict of interest (COI) in this study. 
Any COI arises during the study shall be declared promptly. 
 
Site Principal Investigator 
 
Name: 
 
Site: 
 
Signature: 
 
Date: 
 
 
 
 
Principal Investigator 
 
Name: Dr Steven Lim Chee Loon 
 
Signature: 
 
Date:  
 
 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
14                                                                      
 
3. LIST OF ABBREVIATIONS  
 
AE 
Adverse events 
CRC  
Clinical Research Center  
CRF  
Case Report Form  
DG  
Director General of Health, Ministry of Health, Malaysia  
DSMB  
Data and Safety Monitoring Board  
EOS 
Early oral switch 
FDA  
Food and Drug Administration  
ICF  
Informed Consent Form  
ICU  
Intensive Care Unit  
ID Physician 
Infectious Diseases Physician 
IDSA 
Infectious Diseases Society of America 
IE 
Infective endocarditis 
ITT  
Intention-to-treat 
IV 
Intravenous 
MSSA  
Methicillin-Susceptible Staphylococcus aureus 
MRSA  
Methicillin-Resistant Staphylococcus aureus 
MOH  
Ministry of Health Malaysia 
MREC  
Medical Research Ethnics Committee  
NIH  
National Institute of Health  
OPAT  
Outpatient Parenteral Antimicrobial Therapy 
PI  
Principal Investigator  
RCT  
Randomized controlled trial  
REDCap  
Research Electronic Data Capture  
SAB  
Staphylococcus aureus Bacteraemia 
SAE  
Serious Adverse Event  
SIV 
Standard intravenous 
SOC  
Standard of Care  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
WHO  
World Health Organization  
 
 
 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
15                                                                      
 
4. GLOSSARY OF TERMS 
 
 
Arm 
A group or subgroup of participants in a clinical trial that receives a specific 
intervention/treatment, or no intervention, according to the trial’s protocol. 
Baseline 
characteristics 
Data collected at the beginning of a clinical study for all participants and for each arm or 
comparison group. These data include demographics, such as age, sex/gender, race and 
ethnicity, and study-specific measures 
Collaborator 
An organization other than the sponsor that provides support for a clinical study. This support 
may include activities related to funding, design, implementation, data analysis, or reporting. 
Data and Safety 
Monitoring Board 
A group of independent scientists who monitor the safety and scientific integrity of a clinical 
trial. They can recommend to the sponsor that the trial be stopped if it is not effective, is 
harming participants, or is unlikely to serve its scientific purpose. Members are chosen based 
on the scientific skills and knowledge needed to monitor the particular trial. 
Definitive therapy 
Targeted antibiotics administered based on the index culture and susceptibility results. 
Eligibility criteria 
The key requirements that people who want to participate in a clinical study must meet or the 
characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are 
required for a person to participate in the study) and exclusion criteria (which prevent a person 
from participating). 
Empirical therapy 
Antibiotics administered before the index culture and susceptibility results are known. 
Informed consent 
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial that are relevant to the 
subject’s decision to participate. Informed consent is documented by means of a written, 
signed and dated informed consent form. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by 
a team of individuals at a trial site, the investigator is the responsible leader of the team and 
may be called the principal investigator. 
Phase 3 
A phase of research to describe clinical trials that gather more information about a drug’s 
safety and effectiveness by studying different populations and different dosages and by using 
the drug in combination with other drugs. These studies typically involve more participants. 
Primary outcome 
In a clinical study’s protocol, the planned outcome measure that is the most important for 
evaluating the effect of an intervention/treatment.  
Protocol 
amendment 
A written description of a change(s) to or formal clarification of a protocol. 
Randomization 
The process of assigning trial subjects to treatment or control groups using an element of 
chance to determine the assignments in order to reduce bias. 
Secondary outcome 
In a clinical study’s protocol, a planned outcome measure that is not as important as the 
primary outcome measure for evaluating the effect of an intervention but is still of interest.  
Subject(s) 
An individual who participates in a clinical trial, either as a recipient of the investigational 
product(s) or as a control. 
 
 
 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
16                                                                      
 
5. INTRODUCTION & BACKGROUND 
Staphylococcus aureus is a common and serious cause of bloodstream infection worldwide with 
mortality rates ranging from 10% to 30% [1]. In the industrialized world, the population incidence 
of Staphylococcus aureus bacteraemia (SAB) varies from 10 to 30 per 100,000 person-years [2]. 
Based on a few reports from Asia on the prevalence of Staphylococcus aureus isolated from blood 
cultures, Malaysia showed a rate of 10.4%, Philippines 7.4%, Laos 19%, and India 18% [3-6]. 
 
SAB is well known for frequent relapse with distant metastatic foci such as infective endocarditis 
(IE), osteoarticular infection, pleuropulmonary and intrabdominal abscesses. In prospective 
cohort studies, 10% to 20% of SAB episodes are complicated by IE [7, 8]. To prevent these 
complications, most guidelines and experts recommend treating all SAB with at least 14 days of 
intravenous (IV) anti-staphylococcal antibiotics, albeit absence of high-quality evidence to 
support such practice [9, 10].  In fact, the current SAB guidelines do not cite any controlled clinical 
studies that established the superiority of IV-only therapy compared to oral therapy. Instead, the 
presumptive superiority of IV antibiotics stems from uncontrolled case series from the 1940s and 
1950s, and the limited bioavailability of the few oral antibiotics available at that time [11]. To 
date, there are several oral antibiotics with excellent bioavailability over 90%, such as linezolid, 
sulfamethoxazole-trimethoprim (TMX-SMX), and clindamycin [12], all of which have not been 
subjected to rigorous trials in SAB.  
 
The cornerstone in the management of SAB is the differentiation between a “complicated” and 
an “uncomplicated” infection. Fowler et al have ascertained 4 predictors of complicated SAB, 
namely community acquisition, persistent positive blood cultures at 48 to 96 hours, persistent 
fever at 72 hours, and skin findings suggestive of systemic infection. Patients with one of these 
characteristics were at approximately 35% probability for complicated SAB. In contrast, the 
probability of developing complications was about 16% in the absence of these risk factors [13]. 
The Infectious Diseases Society of America (IDSA) has published guidelines with the following 
criteria to define uncomplicated SAB: a) negative follow-up blood cultures obtained 2–4 days 
after the initial set; b) defervescence within 72 hours of initiating effective therapy; c) no 
prosthetic material; and d) no endocarditis and metastatic infection [14]. Patients at low risk for 
complications may thus benefit from an early switch to oral antibiotics through reduced length 
of hospital stay, fewer IV line-associated inflammation or infection, cost-saving, and improved 
general wellbeing. 
 
Furthermore, in this era of antimicrobial resistance, one of the key components of antimicrobial 
stewardship (ASP) is a continual “review every 48–72 hours” framework for inpatient 
administration of antibiotics. IDSA ASP guidelines strongly recommend the timely conversion 
from IV to oral antimicrobials in routine clinical practices [15]. Unwarranted long courses of IV 
antibiotics are resource heavy and lead to prolonged hospital stay, which exposes patients to 
nosocomial infections with multi-resistant organisms. 
  
There is growing evidence showing the safety and efficacy of IV to oral antibiotic switch in SAB. 
In a single-centre, observational study cohort of 492 patients with methicillin-resistant 
Staphylococcus aureus (MRSA) bloodstream infection (BSI), Jorgensen et al found no difference 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
17                                                                      
 
in 90-day failure between the oral-therapy group and the IV group [16]. Willekens et al compared 
an early switch to linezolid between Days 3 and 9 of standard IV therapy in a prospective study 
of 135 patients with low-risk SAB. There was no difference found in 90-day relapse between the 
two groups nor in 30-day all-cause mortality [17]. Recent randomized clinical trials, POET and 
OVIVA have shown that oral is safer than IV therapy with respect to treatment complications and 
has equivalent microbiological outcomes. Staphylococcus aureus has been well represented in 
these studies (23.4% and 36.2% in the oral treatment arms of the POET and OVIVA trials, 
respectively) [18, 19]. The findings of the SABATO randomized control trial were recently 
presented in a conference and showed that in the small group of patients at low risk of SAB 
complications, oral switch therapy after 5–7 days of IV treatment was not inferior compared to a 
complete 14-day IV course [20]. This latest evidence suggests that a more individualized 
treatment regimen involving oral antibiotics with good bioavailability is possible in selected 
patients with SAB.  
 
 
Table 1: Key published studies describing non-inferiority of oral antibiotic therapy for S. aureus 
bacteraemia 
 
Author/Year 
Study design 
Sample 
Oral therapy in 
the study arm 
Findings 
Willekens et 
al., 2018 
[17] 
Prospective matched 
cohort study comparing 
the efficacy, safety, and 
length of hospital stay of 
patients receiving standard 
parenteral therapy (SPT) 
and those where SPT was 
switched to oral linezolid 
between days 3 and 9 of 
treatment until 
completion. 
 
 
135 adult patients 
with low-risk SAB; 
45 oral linezolid 
vs 90 SPT cases 
Linezolid 
No difference in 90-day 
relapse between the 
linezolid group and the 
SPT group (2.2% vs 4.4% 
respectively; P = .87). 
Jorgensen et 
al., 2019 
[16] 
Single-centre, 
retrospective, cohort 
study comparing outcomes 
in adults completing MRSA 
BSI therapy with oral 
versus parenteral 
antibiotics in the 
outpatient setting. 
 
492 patients with 
SAB; 70 received 
oral therapy vs 422 
received IV 
therapy. 
 
  
Oral linezolid, 
TMP-SMX, 
clindamycin, or 
doxycycline 
+/- adjuvant 
rifampin 
Non-significant reduction 
in the rate of 90-day 
clinical failure in the oral 
therapy group compared 
with the IV therapy group 
[adjusted HR (aHR) 0.379, 
95% CI 0.131-1.101; P 
= .0747)] 
Iversen et 
al., 2019 
[18] 
Randomized, 
noninferiority, multicenter 
trial on patients with left-
sided endocarditis treated 
with at least 10 days of IV 
antibiotics, before being 
randomized to continue IV 
treatment or to switch to 
oral antibiotic treatment. 
400 adult patients 
with left-sided 
endocarditis; 199 
patients continued 
IV treatment vs 
201 switched to 
oral antibiotic 
treatment. 87 
patients with S. 
13 oral 
combinations for 
patients with S. 
aureus, 
of which the 
3 most common 
were dicloxacillin 
+ rifampicin, 
amoxicillin 
The primary composite 
outcome (all-cause 
mortality, unplanned 
cardiac surgery, embolic 
events, or relapse 
of bacteraemia with the 
primary pathogen) 
occurred in 24 patients 
(12.1%) in the 

 
 
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18                                                                      
 
aureus as the 
causative 
pathogen. 
+ rifampicin, and 
moxifloxacin + 
rifampicin. 
intravenously treated 
group and in 18 (9.0%) 
in the orally treated group 
(between-group 
difference, 3.1 percentage 
points; 95% confidence 
interval, −3.4 to 9.6; P 
= .40), which met 
noninferiority criteria. 
 
 
Overall, there is a dearth of high-quality evidence that informs appropriate management of SAB. 
Thus far there are no published well-designed and adequately powered RCT that evaluate the 
outcome of IV to oral stepdown therapy for uncomplicated SAB. The SABATO trial was completed 
in 2020 but has not been published in any peer-reviewed journal, for unknown reason. Robust 
clinical trials are needed to address this outstanding yet important clinical question in the 
management of SAB. We will therefore perform a national multicentre, open label, randomized 
clinical non-inferiority trial with the aim to assess the efficacy and safety of early IV to oral switch 
of antibiotics in SAB. Potentially, the study will be impactful locally and globally by providing the 
clinicians an essential evidence-based rationale for optimizing the treatment guidelines of SAB. 
 
 
6. OBJECTIVES 
 
6.1 
Primary objective 
To demonstrate that early IV to oral antibiotic switch is as efficacious as standard 14-day 
IV antibiotic therapy for patients with uncomplicated SAB.  
 
6.2 
Secondary objectives 
To evaluate the additional benefits of early IV to oral antibiotic switch for patients with 
uncomplicated SAB: 
• 
Duration of hospitalisation  
• 
All-cause mortality 
• 
Complications related to IV therapy 
• 
Safety of early IV to oral antibiotic switch in terms of adverse events and risk Clostridium 
difficile diarrhoea. 
 
6.3 
Potential study benefit and risk 
Patients who participate in this study may benefit from an early switch to oral antibiotics 
by shortening hospital stay, preventing nosocomial infections, and avoiding IV line-
associated complications, while not compromising the treatment outcome of SAB. 
Literatures have consistently showed that oral stepdown therapy leads to similar if not 
better treatment success compared to continuing standard IV therapy. For example, 
Jorgensen et al. reported a much lower clinical failure rate among patients who switched 

 
 
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19                                                                      
 
to oral therapy (7.1%) compared to patients who completed a standard course of IV 
therapy (14.9%) [16]. A similar trend was also observed among a selected cohort of low-
risk patient with SAB in Willekens et al., in which relapse was found only in 2.2% of 
patients receiving linezolid as oral stepdown therapy, as opposed to 4.4% who continued 
with standard parenteral therapy. The mortality rate was markedly lower in the oral group 
as well (2.2% versus 13.3%) [17]. In this study, patients will be recruited based on strict 
enrolment criteria for low-risk uncomplicated SAB, hence the event rate for SAB-relapse 
among study patients is estimated to be 4%.   
 
In terms of adverse events, approximately 3% of patients may experience sulfonamide 
allergy after taking trimethoprim-sulfamethoxazole [21]. The use of oral clindamycin, 
fluoroquinolones, and trimethoprim-sulfamethoxazole may also increase the incidence of 
Clostridium difficile-associated diarrhoea [22-24]. Nevertheless, these adverse events are 
well recognized and manageable by experienced treating physicians. Overall, the benefit 
of this study far outweighs the risk. 
 
 
7.   STUDY DESIGN 
 
7.1 
Overall study design 
The Early Intravenous to Oral Antibiotic Switch in Uncomplicated Staphylococcus aureus 
Bacteraemia (EVOS) study is a multicentre, randomized, open-label, parallel group, Phase 
3, non-inferiority trial of early intravenous to oral antibiotic switch in comparison with 
standard intravenous antibiotic regime among patients with uncomplicated 
Staphylococcus aureus bacteraemia. The study is based on the hypothesis that an early 
switch from IV to oral antimicrobial therapy is non-inferior and safe compared to 
conventional minimum 14-day course of IV therapy in patients with low-risk 
uncomplicated SAB.  
 
 
 
 

 
 
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7.2 
Schematic diagram of study design 
 
 
7.3 
Discussion of study design 
The EVOS Study is designed to evaluate non-inferiority and safety of early IV to oral 
antibiotic switch versus standard IV antibiotic therapy for patients with uncomplicated 
SAB. Considering the expected large gain of oral treatment (reduced hospital burden and 
improved patient wellbeing), and low incidence of SAB-related complications in selected 
low risk patients, a non-inferiority study design would be an appropriate initial approach 
to determine the benefit of oral antibiotics in the treatment of SAB with a clinically 
acceptable difference of 8% in efficacy compared to the standard IV therapy.  
 
Eligible subjects will be randomized 1:1 into either early oral antibiotic switch (EOS) or 
standard intravenous antibiotic (SIV) groups following the inclusion and exclusion criteria. 
All patients will have already received 3 to 7 days of definitive IV antibiotic therapy prior 
to enrolment and randomization. Definitive therapy is defined as the targeted antibiotics 
administered based on the index blood culture and susceptibility results. In the 
experimental EOS group, patients will switch from definitive IV therapy to oral antibiotics. 

 
 
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21                                                                      
 
Patients in the control SIV group will continue with IV therapy. Patients in both groups will 
receive 7 to 11 days of study drugs to achieve a total course of 14 (±2) days of definitive 
antimicrobial therapy. All patients will be followed up for 90 days from enrolment to 
evaluate efficacy and safety variables. Inpatient subjects will be reviewed by the site 
investigator clinical team in the hospital ward. Discharged patients are followed up by 
telephone interview with the patient or their nominated carer by designated site study 
investigators. Follow up assessment will be conducted at Day 7-11 (end of treatment), 
Day 30, and Day 90 post-randomization to review subjects’ condition. All data will be 
entered electronically into REDCap. 
 
7.4 
Study population 
Hospitalized adult patients with newly confirmed blood culture positive for S. aureus are 
identified by site study investigators through microbiology department. The patients are 
assessed for study eligibility and will be considered for enrolment when all inclusion 
criteria and none of the exclusion criteria are fulfilled. Strict inclusion and exclusion 
criteria are designed to select a group of patients with uncomplicated SAB and low risk 
for SAB-related complications.  
 
Ideally, patients should be enrolled in the study before receiving any non-study antibiotic 
therapy. In reality, this is unachievable as patients would have been given empirical 
antibiotics (many of which have anti-staphylococcal activity) while awaiting blood culture 
results. A positive blood culture with identification of isolates and antibiotic susceptibility 
is typically reported by laboratory 3 to 5 days after the sample is drawn. Therefore, 
patients who have received 5 day or less duration of non-study antibiotic therapy 
(empirical therapy) are allowed to enter this study. The duration and type of non-study 
antibiotics before enrolment will be considered for subgroup analysis if significant 
difference is noted between study groups. 
 
Patients entering the study will have already received 3 to 7 full days of definitive IV 
antibiotic therapy and have no evidence of complicated S. aureus infection prior to 
enrolment. Patients with a higher a priori risk for complicated infection are excluded (for 
example, severe immunodeficiency, end-stage renal disease, and presence of non-
removable foreign body). 
 
7.4.1   Case definition of uncomplicated SAB 
Hospitalized adult patients with confirmed SAB who have achieved the following criteria:  
• Clearance of bacteraemia, defined as negative follow-up blood culture obtained 
within 72 hours after the initiation of definitive IV antimicrobial therapy. 
• Defervescence, defined as sustained body temperature ≤37.5°C for 48 hours. 
• No evidence of metastatic infection of S. aureus. 
 
 
 

 
 
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22                                                                      
 
7.4.2   Inclusion criteria 
a) Age 18 years old and above. 
b) Blood culture positive for Staphylococcus aureus (S. aureus).  
c) Received 3 to 7 days of definitive IV antimicrobial therapy, defined as:  
• Cloxacillin or cefazolin for methicillin-sensitive staphylococcus aureus (MSSA); 
Vancomycin or ceftaroline for methicillin-resistant staphylococcus aureus (MRSA).  
• Proven in-vitro susceptibility and adequate dosing given (as determined by the 
principal investigator).  
d) Achieved clearance of bacteraemia, defined as at least one documented latest 
negative follow-up blood culture obtained within 72 hours after the initiation of 
definitive IV antimicrobial therapy. 
e) Achieved defervescence, defined as sustained body temperature 37.5°C or below 
within 48 hours before randomization.  
f) Able to provide written informed consent to participate trial. 
 
7.4.3   Exclusion criteria 
a) Evidence of metastatic infection of S. aureus: for example, infective endocarditis, 
intraabdominal 
abscess, 
lung 
empyema, 
and 
osteomyelitis. 
Radiological 
investigations such as chest X-ray, ultrasound, echocardiogram, and CT scan are not 
mandatory prior to enrolment, but should be done at the discretion of the treating 
physician if clinically indicated. 
b) Septic shock, defined as hypotension requiring vasopressors to maintain MAP ≥65 
mmHg despite adequate volume resuscitation. 
c) Received more than 5 days of non-study antibiotics as empirical therapy prior to 
enrolment. 
d) Polymicrobial bloodstream infection, defined as isolation of pathogens other than S. 
aureus from a blood culture obtained prior to randomization. Common skin 
contaminants such as coagulase-negative staphylococci, Bacillus spp., and diphtheroid 
will not be considered to represent polymicrobial infection. 
e) Known history of S. aureus infection within the past 3 months. 
f) Inability to tolerate oral therapy or poor absorption of oral medications, or not 
suitable for ongoing IV therapy (for example, difficult intravenous access) 
g) No options of oral antibiotic available for patient due to: 
• In vitro resistance of S. aureus to all oral study drugs.  
• Known contraindications to receive the active oral study drugs. For example, 
hypersensitivity reaction to trimethoprim-sulfamethoxazole, thrombocytopenia 
secondary to linezolid etc. 
• Non-availability of oral study drugs at the study sites.  
h) Patient is concomitantly receiving oral antibiotics which are active against S. aureus. 
For example, trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia 
prophylaxis. 
i) Presence of a non-removable foreign body such as prosthetic heart valve, vascular 
graft, 
pacemaker, 
automated 
implantable 
cardioverter-defibrillator, 
ventriculoperitoneal shunt, prosthetic joint, and fracture fixation implant 

 
 
EVOS Study Protocol V1.3, 12th March 2024 
 
23                                                                      
 
j) Failure or inability to remove intravascular catheter that is present when first positive 
blood culture was drawn. 
k) Known comorbidity that increased the risk of complicated infections: 
• End-stage renal disease  
• Severe liver disease (Child-Pugh class C) 
• Severe immunodeficiency: 
o HIV-positive patients with CD4<200 cells/uL or AIDS 
o primary immunodeficiency disorders 
o high-dose steroid therapy (>1 mg/kg prednisone or equivalent doses given for > 
4 weeks or planned during intervention) 
o immunosuppressive therapy  
o neutropenia (<500 neutrophils/μl) at randomization or neutropenia expected 
during intervention phase due to immunosuppressive treatment 
o solid organ or hematopoietic stem cell transplantation within the past 6 
months or planned during treatment period 
l) Short life expectancy < 3 months 
m) Pregnancy (for women of childbearing potential) 
 
7.4.4   Study outcomes  
The primary outcome of this trial is relapse of SAB, defined as any new positive blood 
culture with S. aureus, and/or newly diagnosed metastatic S. aureus infection resulting 
from hematogenous dissemination. The secondary outcomes are the all-cause mortality, 
length of stay in hospital after the first positive blood culture, complications related to IV 
therapy, Clostridium difficile diarrhoea, and adverse event (AE). All study outcomes are 
evaluated within 90 days of randomization, except for AE which is monitored within 30 
days from randomization and treatment initiation. Any events occurred beyond 30 days 
are unlikely related to study treatment.  
 
These individual outcomes will be derived from clinical evaluation, patient interviews, 
laboratory results, and radiological reports. The detailed definitions of each outcome 
measures are described in Table 2. 
 
Adverse events (AE) and serious adverse events (SAE) are evaluated and graded according 
to Common Terminology Criteria for Adverse Events Version (CTCAE) version 5.0 [25].  
 
 
 
 
 
 
 
 
 
 
 

 
 
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24                                                                      
 
Table 2: Definition of study outcomes 
 
Outcomes 
Definition 
Relapse of SAB  
[Time Frame: 90 days] 
Any new positive blood culture with S. aureus  
AND/OR 
Any newly diagnosed metastatic S. aureus infection resulting 
from hematogenous dissemination, such as infective 
endocarditis, liver/splenic abscess, lung empyema, 
osteomyelitis, or septic arthritis. Diagnosis of metastatic 
infection requires either imaging studies or diagnostic 
procedures (eg. arthroscopy) showing the presumed focus, or 
an isolation of S. aureus from culture samples taken from the 
respective site of metastatic infection.  
The S. aureus isolate needs to exhibit the same 
characteristics as the original infecting isolate based on 
antimicrobial susceptibility, and not to be considered by the 
site investigator to represent a contaminant. 
Catheter-related infections (from new catheter inserted 
during study period), superficial skin-and soft tissue, and 
wound infections are not regarded as metastatic infection. 
All-cause mortality 
[Time Frame: 90 days] 
Any death occurred. 
Length of hospital stay 
[Time Frame: 90 days] 
Total number of calendar days in hospital after the first 
positive blood culture with S. aureus. The duration includes 
readmission due to SAB relapse, complications related to IV 
therapy, adverse events, and any acute illnesses. Elective 
admission for procedure is excluded. 
Complications related to IV 
therapy 
[Time Frame: 90 days] 
Any complications related to insertion or usage of peripheral 
branula or central catheter, and administration of IV drugs. 
For examples, chemical or septic thrombophlebitis, 
extravasation of IV drugs, hematoma, and cellulitis.  
Clostridium difficile diarrhoea 
[Time Frame: 90 days] 
A diagnosis of diarrhoea with ≥1 stool sample tested positive 
for C. difficile toxin or toxin gene. 
Adverse event (AE)   
[Time Frame: 30 days] 
Any untoward medical occurrence in a patient after receiving 
study drugs and which does not necessarily have a causal 
relationship with treatment. All AE should be described in 
accordance with the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. 
 

 
 
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7.4.5   Subject withdrawal & dropout 
Subjects are free to withdraw from the study at any time for any reason. Subjects may 
also be withdrawn from the study at any time at the discretion of the investigator due to 
AE or safety reasons. Reasons for withdrawn will be documented. Subjects withdrawn will 
not be replaced. 
 
7.4.6   Procedures for handling withdrawal 
Subjects who withdraw or are withdrawn from the study should: 
• Have their reason(s) for withdrawal recorded in CRF. 
• Be asked about the presence of any AEs and if so should be followed up by regular 
scheduled visits or telephone contact until satisfactory clinical resolution of AEs is 
achieved. Frequency of visits is at the discretion of the investigator. 
• Be assessed by an investigator (physical visit or telephone call) and all final 
assessments will be performed and recorded in the CRF. 
• Have at least one follow-up contact (scheduled visit or telephone contact) for 
safety evaluation during the 30 days following the last dose of study treatment. 
• Be encouraged to participate in end of study telephone call follow up at Day 90 
post-randomization. 
 
7.4.7   Screening failures 
All hospitalised adult patients with newly confirmed blood culture positive for S. aureus 
identified by site study investigators through microbiology department will be screened 
for eligibility. Patients who fail to meet the inclusion and exclusion criteria are defined as 
screening failures. The investigator will maintain a Screening and Enrolment Log which 
includes screen failures. The log will document the patient screening number, patient 
initials, and the reason(s) for excluding the patient from the study. This log will be kept in 
the Investigator Site File. 
 
 
8.   TREATMENT AND STUDY PROCEDURES 
 
8.1 
Description of study intervention 
The study intervention involves switching to oral antibiotics after completion of at least 3 
to 7 days of definitive IV antibiotics for the treatment of uncomplicated SAB. All antibiotics 
used this study are commercially available and commonly used in hospitals under the 
Ministry of Health Malaysia. Although there may be some variation in generic products 
used between hospitals, all individual study drugs contain the same active compounds 
and are approved by the National Pharmaceutical Regulatory Agency (NPRA).  
 

 
 
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26                                                                      
 
The information of oral antibiotics for intervention arm is presented in Table 3. Details 
about individual drug’s action, pharmacokinetics, adverse reactions, contraindications, 
and drug-drug interactions can be found in the Appendix. 
 
Table 3: Description of oral antibiotics for intervention arm (Early Oral Switch therapy) 
Study Drug 
Route of 
administration 
Formulation 
 
Composition/ 
Strength 
Manufacturer 
 
Trimethoprim-
sulfamethoxazole 
Oral 
Tablet 
Each tablet contains 
Trimethoprim 80mg and 
Sulphamethoxazole 
400mg 
 
Pharmaniaga 
Manufacturing Berhad 
Clindamycin 
Oral 
Capsule 
Each capsule contains 
Clindamycin 
Hydrochloride 300mg 
 
Y.S.P. Industries (M) 
Sdn. Bhd 
 
Cephalexin 
Oral 
Capsule 
Each capsule contains 
250mg or 500mg of 
Cephalexin anhydrous 
 
Pharmaniaga 
Manufacturing Berhad 
 
Linezolid 
Oral 
Film-coated 
Tablet 
Each tablet contains 
600mg of linezolid 
 
Pfizer Pharmaceutical  
 
 
8.2 
Description of study comparator  
The study comparator involves continuation of the ongoing definitive IV antibiotics for a 
total of 14-day duration, as per current standard of care. The information of IV antibiotics 
in comparator arm is presented in Table 4. Details about individual drug’s action, 
pharmacokinetics, adverse reactions, contraindications, and drug-drug interactions can 
be found in the Appendix. 
 
Table 4: Description of IV drugs for comparator arm (Standard IV therapy) 
Comparator 
Drug 
Route of 
administration 
Pharmaceutical 
form 
 
Composition 
Manufacturer 
 
Cloxacillin 
Intravenous 
White crystalline 
powder in glass 
vial 
 
Each vial contains 
Cloxacillin sodium BP 
250mg or 500mg 
 
Karnataka Antibiotics 
& Pharmaceuticals 
Limited 
 
Cefazolin 
Intravenous 
Dry substance in 
glass vial 
Each vial contains 
Cefazolin as sodium salt 
1000mg 
 
Sandoz GmbH  
Vancomycin 
Intravenous 
White 
lyophilized 
powder in glass 
vial 
Each vial contains 
Vancomycin Hydrochloride 
USP equivalent to 
Vancomycin 500mg 
Gland Pharma 
Limited 
 

 
 
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Ceftaroline 
Intravenous 
Pale yellowish 
white to light 
yellow powder in 
glass vial 
 
Each vial contains 
ceftaroline fosamil acetic 
acid solvate monohydrate 
equivalent to 600mg of 
ceftaroline fosamil 
 
ACS Dobfar S.p.A. 
 
 
 
8.3 
Dosage and administration 
Intervention arm (Early Oral Switch therapy): 
Patients will switch to an oral antibiotic, selected by the site investigator from the 
following list of drugs: 
• First choice for MSSA and MRSA: Tab. Trimethoprim-sulfamethoxazole  
• Alternative for MSSA: Tab. Clindamycin, Tab. Cephalexin, Tab Linezolid 
• Alternative for MRSA: Tab. Linezolid  
 
Comparator arm (Standard IV therapy): 
Patients will continue to receive IV antibiotics from the following list of drugs: 
• First choice for MSSA: IV Cloxacillin  
• Alternative for MSSA: IV Cefazolin  
• First choice for MRSA: IV Vancomycin  
• Alternative for MRSA: IV Ceftaroline 
 
The choice of study drug will depend on the susceptibility of the respective isolate, 
expected drug interactions, contraindications, and expected side effects. Oxacillin-
susceptible staphylococci can be considered susceptible to cefazolin and cephalexin [26]. 
Investigators will assess whether the “first-choice” regimen can be given and then 
consider the alternative regimen. The antibiotics can be switched from first choice to the 
respective alternative medication during the intervention period if clinically necessary (for 
example, switching to oral linezolid due to allergic reaction to sulfamethoxazole-
trimethoprim). The route of administration must be maintained according to the 
randomized group. 
 
Treatment of patients in this trial follows a pragmatic approach. Study medication is 
prescribed and administered according to local hospital practice. The recommended 
doses and frequency of study antibiotics in Table 5 are determined based on the National 
Antimicrobial Guideline 2019 [27], hospital site’s clinical practice, and consideration to 
maximize the bioavailability of oral antibiotics for SAB. Doses should be adjusted in the 
setting of renal dysfunction according to the recommendations.   
 
Study drugs will be prescribed, supplied, and dispensed to patients, whether in ward or 
upon discharge, in a sufficient number of doses or tablets to complete the predetermined 
number of treatment days from randomization Day 1 (Table 6). For example, patient who 
is planned to receive 8 days of Tab Linezolid 600mg bd should be supplied full 16 tablets 
upon discharge.   

 
 
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Table 5: Study drugs and dosage   
Isolates 
Route of 
administration 
Drugs  
(Definitive therapy for SAB) 
Dose in normal renal 
function 
 
Renal dose 
adjustment* 
 
 
IV 
Cloxacillin 
2gm 4 hourly or 6 hourly 
 
No 
 
 
Cefazolin 
2gm tds 
 
Yes 
 
MSSA 
 
 
 
Trimethoprim-
sulfamethoxazole 
TMP 10mg/kg/day 
 
Yes 
 
Oral 
Clindamycin 
600mg tds 
 
No 
 
 
Cephalexin 
1gm qid 
 
Yes 
 
 
Linezolid 
600mg bd 
 
No 
 
 
 
 
 
 
MRSA 
 
 
 
 
IV 
Vancomycin 
15-20mg/kg bd  
Loading dose 25-30mg is 
acceptable. 
 
TDM is mandatory. Aim for 
trough level of 15-20 ug/mL 
Based on 
TDM 
 
 
Ceftaroline 
600mg tds 
 
Yes 
 
 
 
Oral 
Trimethoprim-
sulfamethoxazole 
TMP 10mg/kg/day 
 
Yes 
 
 
Linezolid 
600mg bd 
 
No 
 
*Renal dose adjustment should be based on current antibiotic guidelines. Pharmacist consultation is encouraged. 
Abbreviations: MSSA, methicillin-sensitive staphylococcus aureus; MRSA, methicillin-resistant staphylococcus aureus; TDM, therapeutic drug 
monitoring; TMP, Trimethoprim  
 
 
Table 6: Determining the number of days of study treatment   
 
 
Days of treatment 
Number of days receiving definitive IV therapy before randomization 
(Date of last dose – Date of first dose) 
3 
4 
5 
6 
7 
Number of days for study treatment (IV/oral) from randomization Day 1 
11 
10 
9 
8 
7 
Total number of days of definitive therapy 
14 
14 
14 
14 
14 
 

 
 
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8.4 
Investigational product supply and handling 
 
8.4.1   Supply, packaging, and labelling 
All study medications are commercially available, commonly prescribed in hospitals, and 
approved by the NPRA. They will be supplied by, but not limited to, the respective 
manufacturers as stated in Table 3 and 4. The oral antibiotics in the intervention arm will 
be in blister packing of 10’s x 10 while comparator IV drugs will be packaged in 
appropriately labelled carton box containing 10 vials each. They are labelled 
with the following information: 
• Product identification   
• Caution statement  
• Direction for use 
• Storage conditions 
• Manufacturer's identification  
• Manufacturing details (Batch Number, manufacturing date and expiry date) 
 
8.4.2   Storage and dispensing 
All the study drugs will be stored, dispensed, and administered by pharmacists and ward 
nurses in accordance with standard pharmacy procedures at respective study sites. 
Storage conditions, temperature monitoring and accountability of the study drugs will be 
as per hospital pharmacy policy and manufacturers' instructions. 
 
8.4.3   Accountability 
All the IV and oral study drugs are antibiotics commonly used in MOH hospitals for the 
treatment of Staphylococcus aureus infections. The investigators will ensure the study 
drugs are used in accordance with the protocol and dispensed to patients enrolled in the 
study. All study drug prescription, dispensing and administration must be accurately 
recorded and signed off in the patient medication charts. If there is any dispensing error 
or discrepancy, the PI must be notified immediately. Patient medication charts must be 
available for inspection by the study monitor at any time.  
 
8.5 
Treatment allocation and randomization 
Patients are randomized in a 1:1 ratio to either the early oral antibiotic switch (EOS) group 
and standard intravenous antibiotic (SIV) group. The randomization is based on an 
investigator-blinded randomization list uploaded to REDCap, which allocates the patients 
via a central, computer-generated randomization scheme across all study sites during 
enrolment. The randomization list is generated independently using random permuted 
block sizes 2 to 6. The randomization is not stratified by site. When a patient meets the 
enrolment criteria, the authorized site personnel will login to the secure website to 
randomize the patient and receive all the relevant details on the allocated treatment. The 
corresponding medication will be dispensed and/or reconstituted by the designated 
personnel. 

 
 
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8.6 
Baseline assessment and laboratory tests 
• Social demographics, weight, and height 
• Co-morbidity 
• Antibiotic history 
• Laboratory data 
• Urine pregnancy test for women with childbearing potential 
 
8.7 
Assessment of compliance 
Study drug compliance will be assessed through medication chart for inpatient and 
telephone interview for outpatient. The designated personnel who administered the 
study drugs in ward are required to fill up and sign the medication administration chart at 
every dose. If a subject is significantly non-compliant with the study medication, the 
investigators may consider withdrawing the subject from the study. 
 
8.8 
Concomitant therapy 
There is no restriction of concomitant medications, except for non-study antibiotics. 
Protocol deviation may be considered if non-study antibiotics are given during the study 
period (please refer to section 14.4). Only concomitant medications taken by the patients 
during index admission will be documented in the CRF. 
 
8.9 
Discontinuation and interruption of treatment 
The study drugs will be initiated within the same calendar day after randomization. Study 
drug will be discontinued after 7 to 11 days (depending on the duration of definitive 
antimicrobial therapy received before randomization). Patients will receive an overall 
course of 14 days of definitive antimicrobial therapy.  
 
The study drug will also be terminated in case of any of the following occur: 
➢ any relevant contraindication to study drug arises. 
➢ eligibility criteria violation was noted after subject started study drug, when 
continuation of study drug would place the subject at risk.  
➢ occurrence of clinically significant AE that renders patient unfit to continue with 
the study drug. 
➢ subject requests withdrawal from the study. 
➢ the investigator believes it is in the best interest of the subject. 
➢ Death occurs. 
 
8.10 Assessment of efficacy and safety 
The aim of the trial is to demonstrate non-inferiority of early IV to oral antibiotic switch 
versus standard 14-day IV antibiotic therapy for patients with uncomplicated SAB. This 
will be achieved by comparing the rate of SAB relapse, defined as any new positive blood 
culture for S. aureus, and/or newly diagnosed metastatic S. aureus infection resulting 
from hematogenous dissemination within 90 days of randomization. Additional effects on 

 
 
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31                                                                      
 
all-cause mortality, duration of hospital stay, complications related to IV therapy, and 
safety outcomes Clostridium difficile diarrhoea and adverse events will also be evaluated. 
 
Assessment of efficacy and safety will be derived from patient interviews, clinical notes, 
laboratory reports, and clinical evaluation during intervention and follow-up schedule 
presented in Table 7. In addition, patients are given phone numbers to contact the 
designated site study investigators if they are admitted to hospital or experience adverse 
events during the study period. 
 
 
9.   STUDY CONDUCT 
 
9.1 
Study visits and procedures 
 
9.1.1   Screening visit 
➢ Patient with SAB from all disciplines in the hospital will be referred or notified by the 
primary team clinicians to the site investigator as soon as S. aureus is identified in the 
blood culture (reported from the microbiological department). An infographic poster 
(see appendix) about the trial will be disseminated among clinicians at respective 
study sites to help them to identify potential trial patients. 
➢ Informed consent will be obtained from patients prior to study enrolment, and before 
any protocol-directed procedures are performed.  
➢ The patient will be screened for eligibility to enter study according to the inclusion 
and exclusion criteria.  
➢ A unique subject identification number (subject ID) will be assigned to each subject; 
this subject number will be used throughout the study. 
➢ Women of childbearing potential should have a pregnancy test done. Study 
medication should not be initiated until a report of a negative pregnancy test has been 
obtained. 
➢ Baseline evaluation and randomization can be performed during the screening visit or 
another visit. 
➢ All patients screened for enrolment in the study will be recorded in Screening & 
Enrolment Log and Subject Identification Log. 
 
9.1.2   Baseline visit 
The following data will be collected at baseline:  
➢ Subject's demography: date of birth/age, gender, ethnicity, height (cm) and weight 
(kg).  
➢ Background and medical history which includes any diagnosed medical conditions 
within the previous 12 months, history of medication which includes list of antibiotics 
commenced by the primary team prior to enrolment and medical procedures within 
the previous 30 days of entry into the study.  

 
 
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32                                                                      
 
➢ Physical examination performed by an attending physician or investigator within 24 
hours before enrolment. The examination should include examination of the heart, 
lungs, abdomen, skin & soft tissues, joints, and spine, which aim to look for signs of 
complicated S. aureus infections. 
➢ Latest vital signs recorded during screening and baseline assessment: 
• Pulse in beats/min 
• Blood pressure in mmHg  
• Temperature in ֯C 
➢ Latest laboratory tests done within 72 hours prior to enrolment and randomization:  
• WBC, Creatinine, ALT, CRP (optional) 
➢ Imaging or diagnostic procedures done within 1 week before enrolment. 
 
9.1.3   Eligibility verification and randomization 
➢ Patients will be assessed for eligibility before study enrolment based on the inclusion 
and exclusion criteria. 
➢ Women of childbearing potential should have a negative test (based on the pregnancy 
test kit used in the study site) prior to enrolment.  
➢ All patients who are screened for eligibility will be recorded in the Screening & 
Enrolment Log regardless of whether the patients have been enrolled into the study 
or not. 
➢ If eligible, designated personnel will enter all required data into online randomization 
platform where randomization result (intervention or control group) will be generated. 
Subject ID and randomization group will be recorded in the Patient Screening & 
Enrolment Log and Patient Identification List. 
➢ If not eligible, the patient is considered as screen failure. Reasons for screen failure 
will be recorded in the Screening & Enrolment Log. 
➢ As this is an open label trial, both the investigators and patient are aware of the 
drug/treatment given. 
➢ The patients have equal chances to be in either intervention or control arm. 
➢ The following information will be recorded during randomization:  
• Study ID (assigned during study initiation)  
• Site Number/ID (assigned during study initiation)  
• Patient's screening status  
• Date of informed consent signed by subject  
 
9.1.4   Study treatment and visits 
Patients randomized to intervention arm (EOS group) may either remain as inpatient or 
be discharged to home at the discretion of the attending physician. If they remain in 
hospital, the oral antibiotics will be administered to them by the ward nursing staff. If they 
are discharged home, they will be given a supply of oral antibiotics sufficient to complete 
the planned duration of therapy.   
 

 
 
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33                                                                      
 
If the patient is randomized to control arm (SIV group), administration of the IV antibiotics 
will be continued in the ward to complete the total 14-day duration of therapy as per 
standard of care. Patients in SIV group can only be discharged when an outpatient 
antimicrobial therapy (OPAT) service is available at the local study site to administer the 
IV antibiotics. Alternatively, patients in SIV group can be transferred district hospital for 
continuation of IV therapy and will be followed by telephone interview.  
 
All patients will be followed for 90 days from enrolment to evaluate efficacy and safety 
variables based on the study visit/follow-up schedule and procedures summarised in table 
7. Patients in the hospital will be visited by the site investigator clinical team. Discharged 
patients are followed by telephone interview with the patient or their nominated carer 
by designated site study investigators.  
 
At the end of therapy follow-up (Day 7 – 11), the study investigator will check for study 
drug adherence. For patients who are discharged home, their drug adherence will be 
determined by self-reported pill count during telephone interview. For patients in ward, 
drug adherence is determined by documentation of IV or oral study antibiotics 
administered in medical chart. 
 
Patients will be assessed for study outcomes during each follow-up visits or telephone 
interviews: end of therapy day 7-11, mid-study day 30 (±5), and end of study day 90 (±5). 
All patients will be given phone numbers to contact the designated site study investigators 
if they are admitted to hospital or experience adverse events. If indicated, patient will be 
advised by investigator to visit the study site or nearest hospital for further assessment. 
The decisions to do investigations such as chest X-ray, ultrasound, CT scan, 
echocardiogram, or repeat blood culture during the study period depends on the clinical 
judgement of the primary treating physician in accordance with the standard of care.  
 
Key information to be collected during follow-up assessment: 
➢ Adherence to study antibiotics  
▪ Review of medication chart for inpatient or self-reported pill count during 
telephone interview:  
➢ SIV: Number of doses administered / Number of doses prescribed   X 100% 
➢ EOS: Number of tablets taken / Number of tablets supplied   X 100%  
▪ Patients are deemed adherent to study antibiotics and completed study 
treatment as per protocol only if ≥ 80% of prescribed drugs are taken. 
▪ Taking less than 80% of study drugs may warrant protocol deviation reporting 
(please refer to section 14.4). 
➢ New positive blood culture for S. aureus  
▪ Date of sample(s) 
➢ New diagnosis of metastatic S. aureus infection resulting from hematogenous 
dissemination 
▪ Date of diagnosis 
▪ Examples of metastatic infection include infective endocarditis, liver/splenic 
abscess, lung empyema, osteomyelitis, septic arthritis etc.  

 
 
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34                                                                      
 
▪ Diagnosis of metastatic infection requires either imaging studies or diagnostic 
procedures (eg. arthroscopy) showing the presumed focus, or an isolation of 
S. aureus from culture samples taken from the respective site of metastatic 
infection. 
➢ Duration of hospital stay  
▪ Total number of calendar days in hospital after the first positive blood culture 
(date of first positive blood culture & date of discharge)  
▪ The duration includes readmission due to SAB relapse, complications related 
to IV therapy, Clostridium difficile diarrhoea, or adverse events. 
➢ Mortality  
▪ Date and cause of death.  
➢ Clostridium difficile-associated diarrhoea 
▪ A diagnosis of diarrhoea with ≥1 stool sample tested positive for C.  
▪ Date of first stool sample tested positive for C. difficile toxin or toxin gene. 
➢ Complications related to IV therapy 
▪ Any complications related to insertion or usage of peripheral branula or 
central catheter, and administration of IV drugs.  
▪ For examples, chemical or septic thrombophlebitis, extravasation of IV drugs, 
hematoma, and cellulitis.  
➢ Adverse events and serious adverse events  
▪ Date and progress of AE or SAE 
▪ Classification based on the Common Terminology Criteria for Adverse Events 
Version (CTCAE) version 5.0. 
 
Discharged patients are followed by telephone interview by designated site study 
investigators based on a structured questionnaire: 
➢ To ascertain completion of study oral antibiotics for patients randomized in EOS group.  
➢ To elicit symptoms suggestive of SAB relapse or adverse event, for example fever, rash, 
chest pain, abdominal pain, joint pain or swelling, etc.  
➢ To document any readmission to hospital, visit to emergency department or clinic, 
receipt of non-study antibiotics etc. Investigator should obtain and verify key 
information from attending physician or hospital/clinic records. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table 7: Study schedule of visits, follow-up, and data collection 
 
 
Screening for 
eligibility & 
baseline 
assessment 
Randomization 
& study 
treatment 
initiation 
End of 
therapy 
Mid-study 
End of 
study 
Visit/Follow-upa 
1 
2 
3 
4 
5 
Procedures / Timeline 
Within 24 hours 
before 
randomization 
D1 
D7-11 
 
D30 (±5) 
D90 (±5) 
Check eligibility through 
inclusion & exclusion criteria 
x 
 
 
 
 
Informed consent 
x 
 
 
 
 
Demographic data & medical 
history 
x 
 
 
 
 
Baseline characteristics 
x 
 
 
 
 
Vital signs & physical 
examination 
x 
 
 
 
 
Routine laboratory testsb 
(WBC, Creatinine, ALT, ± CRP) 
X 
 
 
 
 
Imaging/diagnostic 
procedures donec 
X 
 
 
 
 
Urine pregnancy test for 
women with childbearing 
potential 
X 
 
 
 
 
Randomization 
 
x 
 
 
 
Dispense study treatment  
 
x 
 
 
 
Drug adherence checkd 
 
 
x 
 
 
Efficacy assessmentd 
 
x 
x 
x 
x 
Report AE and SAE 
 
x 
x 
x 
 
 
aDischarged patients are followed by telephone interview by designated site study investigators. 
bLatest laboratory tests done within 72 hours prior to enrolment and randomization.  
cAny imaging or diagnostic procedures done within 1 week before enrolment 
dDetails of assessment can be found in section 9.1.4. Study treatment and visits  
 
 
 
 
 
 
 

 
 
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36                                                                      
 
9.2 
Criteria for stopping subject treatment 
The study treatment will be discontinued prior to the protocol planned completion of 
study drug administration under the following circumstances: 
➢ any relevant contraindication to study drug arises. 
➢ any situation in which continued study participation might result in a safety risk to 
the patient. 
➢ occurrence of clinically significant AE that renders patient unfit to continue with 
the study drug. 
➢ patient’s decision. 
➢ the investigator believes it is in the best interest of the subject. 
 
If discontinuation from study treatment occurs, the investigator should make reasonable 
effort to understand the primary reason for the patient’s discontinuation and record this 
information. 
 
9.3 
Termination of study 
The coordinating PI may choose to terminate this study prematurely after consultation 
with DSMB. Criteria for termination of the trial include: 
• New evidence indicating early oral stepdown therapy in SAB is unsafe. 
• Overwhelming non-inferiority or efficacy of oral therapy proven during interim 
analysis. 
• Futility of study when there is statistically little or no chance of demonstrating 
non-inferiority of oral therapy compared to IV therapy during interim analysis. 
• Unacceptable high incidence of SAB-relapse of >16% considering the study 
population are deemed to be low-risk with uncomplicated SAB prior to 
randomization.  
• Increased number of unexpected serious adverse events or death due to study 
intervention. 
• Substantial missing data that would unacceptably undermine trial conclusions. 
 
The coordinating PI also reserves the right to terminate the trial at a study site for reasons 
below: 
• Unsatisfactory or poor patient enrolment. 
• Data recording is consistently inaccurate and/or incomplete. 
• Poor supervision of study conducts by site PI.  
• Lack of cooperation between local site investigators and study monitoring team. 
• Deliberate violation of the approved study protocol. 
• Deliberate violation of the ethical principles outlined in the Declaration of Helsinki 
and Malaysian Good Clinical Practice Guideline (GCP). 
 
Should the coordinating PI decide to close the study site, all study materials including CRFs 
must be returned to the study central team in Hospital Raja Permaisuri Bainun. The site 
investigators may be informed of any additional procedures to be followed to ensure 

 
 
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adequate consideration is given to protect the subject’s interests. The PI will be 
responsible for informing MREC of the early termination of the trial. 
 
9.4 
Dropouts and withdrawals 
Subject may discontinue participation in the trial at any time. If a subject wishes to 
withdraw consent, we will use the following strategies to minimize the impact on the trial, 
while respecting autonomy. We will seek a better understanding of the subject’s wishes 
and offer the following alternatives:  
• Discontinue study drug but allow data collection via in-person follow-up, 
telephone follow-up and access to medical records 
• Discontinue study drug, in-person follow-up but allow telephone follow-up and 
access to medical records 
• Discontinue study drug, in-person and telephone follow-up, but allow access to 
medical records 
• Discontinue study drug, all follow-up and no access to medical records (Complete 
withdrawal) 
 
Subject will be considered lost to follow up if they failed to be contacted without  
stating to withdraw consent. The site must attempt to contact the subject (3 phone  
calls per day for 3 consecutive days. These contact attempts should be documented in the 
subject file. Subjects who withdrawn or lost to follow up will not be replaced.  
 
9.5 
Sample handling and analysis 
All blood or urine specimens will be collected following acceptable laboratory procedures 
at the time points specified in the study schedule. The standard labels should be used to 
label each sample.  
 
All biospecimens in this study will be collected, stored, and processed by designated 
personnel in accordance with the standard clinical practice in patient management and 
local laboratory procedures. There will be no additional biospecimen collected from 
patients solely for research purpose. This study does not involve any stored specimen 
used for future research. All biospecimens collected in this study is as per requirement of 
standard clinical management of SAB. 
 
Laboratory tests are required at baseline before enrolment: 
• White blood cell count 
• Serum creatinine 
• Alanine aminotransferase (ALT) 
• C-reactive protein (CRP) (to be done at the discretion of the treating physician) 
• Urine pregnancy test (only for female subjects of childbearing potential) 
 
 

 
 
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38                                                                      
 
10.  ADVERSE EVENTS 
 
10.1 Definitions 
 
10.1.1   Adverse event (AE) 
Any untoward medical occurrence in a subject administered a medicinal product and 
which does not necessarily have a causal relationship with treatment.  
 
The following should be reported as AE: 
➢ Treatment emergent symptoms which include: 
• Medical conditions or signs or symptoms that was absent before starting study 
treatment. 
• Medical conditions or signs or symptoms present before starting study 
treatment and worsen (increase severity or frequency) after starting study 
treatment. 
➢ Abnormal laboratory values or tests that induce clinical signs or symptoms or require 
therapy. 
➢ For studies involving a marketed drug in an established indication, AE includes 
significant failure of expected pharmacological or biological action. 
➢ Any doubtful event should be treated as an AE. 
➢ Lack of efficacy, aggravation, relapse of current infection, or new infection are not an 
AE in the study and therefore also not an SAE (except death). 
 
10.1.2   Unexpected adverse event 
Any adverse event not reported in the safety section of the Investigator's Brochure or if 
the event is of greater frequency, specificity, or severity. 
 
10.1.3   Serious adverse event (SAE) 
An adverse event that: 
• results in death 
• is life threatening (places the participant at immediate risk of death) 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
 
A hospitalisation or prolongation of a hospitalisation for reasons other than an adverse 
event would not be considered an SAE. 
 
10.2 Detecting and documenting AE 
As our trial intervention involves only a short course of study drugs (7 to 11 days), all study 
patients will be monitored for occurrence of AEs within 30 days from randomization and 

 
 
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39                                                                      
 
treatment initiation. Any events occurred beyond 30 days are unlikely related to study 
treatment. 
 
AEs that begin or worsen after treatment initiation should be recorded in the “Adverse 
Event” section of the CRF. Conditions that were already present or any intercurrent 
illnesses at the time of informed consent should be recorded in the “Co-morbidities” 
section of the CRF. The occurrence of AEs will be sought by non-directive questioning of 
the patient after study drug initiation, at the end of antibiotic therapy (between Day 7-
11), and at Day 30 of randomization. AEs may also be detected via patient’s self-reporting 
to the study team at any time point between the scheduled follow-ups. 
 
The investigator shall maintain and keep detailed records of all AEs in the patient files. All 
information about AEs, whether volunteered by the patient, discovered by the 
investigator during interview, or detected through physical examination, laboratory test 
or by other means, will be recorded on the “Adverse Event” page of the CRF and followed 
up as appropriate. 
 
When eliciting experiences of AE from a subject, a standard non-leading question will be 
asked, for example, "Do you feel different in any way since starting the new treatment/the 
last visit?" This question will be put to the subject in his/her own language at each study 
visit or telephone interview. 
 
Each AE should be described by:  
 
a) Nature of AE  
The investigator should describe the AE using terminology in the Common 
Terminology Criteria for Adverse Events Version (CTCAE) version 5.0 [25]. When this 
is not possible, the AE should be documented in terms of signs and/or symptoms 
observed by the investigator or reported by the subject.  
 
b) Duration  
Start date and end dates (if the patient has recovered from the AE).   
 
c) Assessment of causality  
The investigator should attempt to explain each AE and assess its relationship, if any, 
to the study treatment. Causality should be assessed and reported using the 
description in Table 8.  
 
The degree of certainty with which an AE is attributed to study treatment or 
alternative cause like natural history of disease or concomitant treatment should be 
guided by the following considerations:  
▪ Time relationship between treatment and occurrence of AE  
▪ De-challenge and re-challenge information, if applicable  
▪ Known pharmacology of the drug  
▪ Dose response relationships  

 
 
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40                                                                      
 
▪ Lack of alternative explanations i.e. no concomitant drug used and no other 
inter-current disease  
▪ Reaction of similar nature being previously observed with this drug or class of 
drug  
▪ Reaction having often been reported in literature for similar drug  
 
d) Severity of AE  
The severity of events will be assessed and graded based on CTCAE, Version 5.0 [25] 
in Table 9. Grade 4 and 5 AE should be considered as SAE and need to be reported and 
notified to MREC. 
 
Table 8: Causality assessment of adverse events 
Causality 
Description 
Very likely 
The AE follows a reasonable temporal sequence from study treatment administration.  
Abates upon discontinuation of study treatment.  
Reappears on repeated exposure (re-challenge).  
Probable 
The AE follows a reasonable temporal sequence from study treatment administration.  
Abates upon discontinuation of study treatment.  
Cannot reasonably be explained by known characteristics of the subject's clinical state. 
Possible 
The AE follows a reasonable temporal sequence from study treatment administration but 
could have been produced by the subject's clinical state or other mode of therapy 
administered to the subject. 
Doubtful 
The temporal association between study treatment and AE is such that the study treatment 
is not likely to have any reasonable association with the observed event. 
Very unlikely 
The AE is caused by the subject's clinical state or other mode of therapy administered to 
the subject. 
 
 
Table 9: Grading of severity of adverse event 
 
Severity 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL.  
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.  
Grade 4 
Life-threatening consequences; urgent intervention indicated.  
Grade 5 
Death related to AE. 
Adopted from CTCAE version 5.0 
 

 
 
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41                                                                      
 
10.3 Reporting SAE 
Information about all SAEs will be recorded on the Serious Adverse Event Report Form. 
The investigators must assess the relationship of each SAE to the study drug and submit 
the completed SAE Report form to coordinating PI and MREC. For non-fatal/life-
threatening SAE, initial report should be submitted within 15 calendar days from 
awareness of the event. For fatal/life-threatening SAE, initial report is to be submitted 
within 7 calendar days, followed by a follow-up report within the next 8 calendar days. 
Detailed instructions regarding the submission process are in the Investigator Site File 
provided at each site.  
 
Follow-up information is submitted as instructed in the Investigator Site File. Each 
recurrence, complication or progression of the original event must be reported as a 
follow-up to that event, regardless of when it occurs. The follow-up information should 
describe whether the patient continued or withdrew from study participation. All SAEs 
should be followed up until resolution or permanent outcome of the event.  
 
Where applicable, information from relevant medical records and autopsy reports should 
be obtained. Any death or congenital abnormality, if brought to the attention of the 
investigator within 6 months after cessation of study treatment, whether considered 
treatment related or not, should be reported. 
 
10.4 Treatment and follow-up of AE 
Treatment of any AE is at the sole discretion of the investigator who should follow up 
subjects with AE until the event has resolved or until the condition has stabilised. Non 
serious AEs considered related to the trial medication as judged by a medically qualified 
investigator will be followed up either until resolution, or the event is considered stable.  
 
It will be left to the Investigator’s clinical judgment to decide whether an AE is of sufficient 
severity to require the participant’s removal from treatment. A participant may also 
voluntarily withdraw from treatment due to what he or she perceives as an intolerable 
AE. If either of these occurs, the participant must undergo an end of trial assessment and 
be given appropriate care under medical supervision until symptoms cease, or the 
condition becomes stable.  
 
Abnormal tests should be repeated until they return to baseline levels, or an adequate 
explanation of the abnormality has been found.  
 
 
11.  DATA MANAGEMENT 
 
11.1 Data storage, data security and back up 
This study uses the REDCap, an Electronic Data Capture (EDC) System for study data 
collection. The designated site clinical trial staff will enter the data into the REDCap using 

 
 
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42                                                                      
 
electronic Case Report Forms (eCRFs), under the supervision of site-PI. The EDC system 
can only be accessed by designated personnel from each study site. Study personnel are 
only allowed access to data entry and data viewing of their own study site. Only 
coordinating PI and central study team members have access to view data from all sites, 
insert manual queries and export data from the EDC system.  
 
Personal information about study subjects will be kept confidential and managed under 
the applicable laws and regulations. Those regulations require a signed informed consent 
that informs the subject of the following:  
• What protected health information (study data) will be collected from subjects in 
this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to withdraw their consent or authorization for use 
of their personal information 
 
(Please refer to the Patient Information Sheet and Informed Consent Form for more 
information) 
 
If a subject withdraws consent to collect or use their personal information, the 
investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of subject authorization. Attempts will be made to obtain permission to collect 
follow-up safety information (e.g. has the subject experienced any new or worsened AEs) 
at the end of their scheduled study period. 
 
The data collection system for this study uses built-in security features to encrypt all data 
for transmission in both directions, preventing unauthorized access to confidential 
subject information. Access to the system will be controlled by a sequence of individually 
assigned user identification codes and passwords, made available only to authorized 
personnel who have completed prerequisite training. 
 
Backup data from REDCap will be downloaded as both Excel file and XML File format every 
week. All the electronic research files will be stored within the study file in CRC HRPB 
server which has been located and password protected. The access is limited to 
designated study personnel only. The server is backed up to hard-drive every month. The 
hard-drive is password-locked and store in a locked cabinet which is only accessible by 
designated personnel only. Date format of ddmmyyyy will be used at the end of each file 
stored in the server for version management. At all times there will only be one current 
version of any document. 
  
Paper copies of all study-related documents including subject study files and logs will be 
stored in locked filing cabinets in a locked office at each site. Identified data will be stored 
separately from de-identified data. Before archiving of data, study personnel will review 
existing and newer formats regarding longevity of data storage and ensure archival quality. 
Format changes will be approved by the PI. Should there be a sufficient risk of 

 
 
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43                                                                      
 
obsolescence for the period in which data is to be kept, the study personnel will upgrade 
the format. Previous formats of the same data will be preserved with their identifiers. 
Newer file or data set formats will be assigned new identifiers but will link back to prior 
formats/ identifiers. For example, files may have the same name with the new format 
data having a suffix “-updated”. 
 
11.2 Data entry, checking and validation 
Data entry will be done by designated personnel within the timeline based on the source 
documentation maintained at the clinical site. A guide for data entry will be available for 
all sites. REDCap used in this study has multiple automated edit checks including 
univariate and multivariate. In univariate alerts for multiple-choice field, REDCap provide 
valid-value edit check where the user is required to choose at least one checkbox from a 
series of different data choices. For field with “yes” and “no” options, user is required to 
choose only “yes” or only “no”. Multivariate alerts in REDCap include user to compulsory 
to fill in “other, specify” when “others” is chosen. User are required to answer the queries 
in the REDCap. There are EDC generated queries and manual queries. EDC-generated 
queries are resulted from automated edit checks. Manual queries are used in cases where 
data is impractical to program an automatic check. Manual queries are also used during 
audit eCRF with source documents. Logic checks are conducted as data is entered into the 
EDC.  
 
Data cleaning will be conducted monthly. Frequency tables will be created to check for 
invalid character values for all items, based on expected ranges and values of scales. 
Frequency tables will also be used to check for any missing values. 
 
Before database lock, several checks will need to be carried out: 
• All queries are answered by all sites.  
• All the eCRFs are checked to ensure all expected data have been entered. 
• The status of each subject in the eCRF are completed.  
• Data are determined to be clean. 
• Ensure absence of value formatting problems in the database. 
• Ensure all expected site signed-off have been done. 
 
11.3 Data quality assurance/quality control 
A risk-based approach is used for trial quality management. It is initiated by the 
assessment of critical data and processes for trial subject protection and reliability of the 
results as well as identification and assessment of associated risks. An integrated Quality 
and Risk Management Plan documents the rationale and strategies for risk management 
during trial conduct including monitoring approaches, vendor management and other 
processes focusing on areas of greatest risk. Continuous risk review and assessment may 
lead to adjustments in trial conduct, trial design and monitoring approaches. 
 

 
 
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Steps to be taken to ensure the accuracy and reliability of data include the selection of 
qualified study site-investigators and appropriate study sites, review of protocol 
procedures with the study site-investigators and personnel before the study, periodic 
monitoring visits by Principal Coordinating Investigator or designee, and direct 
transmission of clinical data into the central database. Guidelines for eCRF completion will 
be provided and reviewed with study site personnel before the start of the study. 
 
Independent personnel designated by the Principal Investigator will conduct the 
monitoring visits to ensure the completeness, consistency, and accuracy of the data. 
Periodical data monitoring visits will be initiated once first subject being enrolled into the 
study for each site. The designee will review eCRF for accuracy and completeness during 
on-site monitoring visits and after transmission to the Principal Investigator; any 
discrepancies will be resolved with the site-investigator or designee, as appropriate. After 
upload of the data into the study database they will be verified for accuracy and 
consistency with the data sources. 
 
At the close of study, all data will be checked against the source document. Errors found 
during the monitoring visits will be corrected in the database before data lock. 
 
A quality assurance audit/inspection of this trial may be conducted by independent 
personnel or by IRB/IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial. 
 
11.4 Archiving and data destruction 
Within 6 months of the completion of the research study and final publication of data, the 
electronic data will be stored at CRC HRPB. The paper documents will be stored at each 
site. Paper data will be boxed and labelled. The boxes will be transferred to the designated 
archival centre for archiving. Details of all archived data, including location, will be 
documented.  
 
The investigator should maintain the trial documents and data as specified in Essential 
Documents for the conduct of the study as per regulations and guidelines. These 
documents will be retained for a period of not less than fifteen (15) years from the 
completion of the clinical trial. The investigator should take measures to prevent 
accidental or premature destruction of these documents. 
 
After 15 years from the completion and publication of the study, the PI may declare that 
the trial documents and data are of no continuing value and will be recommended for 
destruction. Paper documents will be shredded, and mulched, digital data will be 
reformatted. 
 
 
 

 
 
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12. STATISTICAL METHODS 
 
12.1 Sample size and power considerations 
The main aim of this study is to demonstrate non-inferiority of early IV to oral switch of 
antibiotic therapy in preventing relapse among a selected group of low-risk patients with 
uncomplicated SAB.  
 
A large prospective cohort study by Fowler et al found that low-risk patients with 
intravascular catheter–associated SAB with neither haemodialysis nor a permanent 
foreign body had a rate of 2.4% for hematogenous complications such as septic arthritis, 
vertebral osteomyelitis, or endocarditis [13]. Willekens et al, in a prospective cohort study 
of adult patients with uncomplicated SAB reported 90-day relapse rate of 4.4% for 
patients receiving standard IV therapy, and 2.2% for those who switched to oral linezolid 
[17].  
 
In our study, the choice of oral antibiotics for the intervention arm consists of 
trimethoprim-sulfamethoxazole, clindamycin, cephalexin, and linezolid. Given the 
heterogeneity of treatment effects with each oral antibiotics, and the strict enrolment 
criteria for low-risk uncomplicated SAB, we estimate a 4% event rate of primary outcome 
(SAB-relapse) among our study patients. 
 
A clinically acceptable non-inferiority margin of 8% was determined based on a consensus 
among infectious diseases physicians after considering the expected large gain of oral 
treatment (for examples, reduced hospital bed-days, saving inpatient costs, and lower risk 
of healthcare associated infections), as well as practical aspects of realistic recruitment of 
patients and completion of the trial. 
 
Thus, a total of 256 patients are needed in this study to achieve 80% power with a one-
sided 0.025 α-level. After adjustment for 10% potential dropout, the study will require 
290 patients or 145 patients in each study arms (calculated using STATA/IC Version 13.1, 
Revision 16 Dec 2016). 
 
12.2 Randomization 
Patients who meet all criteria for enrolment is recruited and will undergo randomization 
at Day 1. Patients will be randomized into either one of the two treatment arms which is 
the investigational arm (Early Oral Switch therapy) or the control arm (Standard IV therapy) 
in a 1:1 ratio according to a site-specific randomization schedule. The randomization is 
based on an investigator-blinded randomization list uploaded to REDCap, which allocates 
the patients via a central, computer-generated randomization scheme across all study 
sites during enrolment. The randomization list is generated independently using random 
permuted block sizes 2 to 6. The randomization is not stratified by site. When consent is 
obtained and a patient meets the enrolment criteria, the authorized site personnel will 
login to the secure website to randomize the patient into the study arm according to the 

 
 
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46                                                                      
 
randomization sequence and receive all the relevant details on the allocated treatment. 
The corresponding medication will be dispensed and/or reconstituted by the designated 
personnel. The schedule will be prepared and provided by biostatistician. 
 
12.3 Statistical analysis plan 
Baseline characteristics and therapy adherence will be summarised using counts and 
percentages. A one-tailed z-test will be used to compare the two observed proportions 
for the IV to oral antibiotic switch and the standard IV antibiotic groups based on the 8% 
non-inferiority margin defined in the study design. Data management and all statistical 
analyses will be performed using IBM Statistical Package for Social Sciences (SPSS) for 
Windows, version 22.0 (IBM Corp).  
 
12.3.1   Efficacy analysis 
The primary analysis for this study will be performed on the intention-to-treat (ITT) 
population, which consists of all randomized patients analysed as assigned. Absolute 
between-group difference of SAB-relapse rate and its 95% confidence interval for the oral 
antibiotic stepdown and the standard IV antibiotic groups will be estimated using a one-
tailed z-test. If the upper limit of the 95% confidence interval falls below the 8% non-
inferiority margin, early oral antibiotic switch will be deemed non-inferior to standard IV 
antibiotics. 
 
A second supportive analysis on the primary endpoint will be derived from the per-
protocol (PP) population, which includes patients who have been treated according to 
protocol and reached a defined outcome in the trial. In this analysis, we will exclude 
patients who do not complete the study treatment as per protocol, lost to follow-up, 
withdraw during the study period, or meet the criteria for protocol deviation. 
 
Secondary outcome measures expressed as proportions will be compared between 
control arm (SIV) and intervention arms (EOS) using chi-squared test, and risk difference 
as well as relative risk of the outcome measures will be calculated together with its 95% 
confidence interval. Mean difference and its 95% confidence interval will be provided for 
secondary outcome measures that are on numerical scale, and comparison between 
study arms will be done using independent t-test. P-value < 0.05 is considered statistically 
significant. Subgroup analysis of the primary endpoint may also be performed although 
the study power in subgroups may be low. 
 
12.3.2   Safety analysis 
All treated patients will be included in the safety analysis. Patients will be classified 
according to actual treatment received. In general, safety analyses will be descriptive in 
nature and no hypothesis testing is planned.  
 
Adverse events will be classified using the Common Terminology Criteria for Adverse 
Events (CTCAE), Version 5.0 [25]. For each category, we will report both the total number 

 
 
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47                                                                      
 
of events and the proportion of participants with at least one event. Frequency, severity, 
and causal relationship of all AE will be tabulated by system organ class and preferred 
term after classification according to the CTCAE at database lock.  
 
12.3.3   Handling of missing, unused, and spurious data 
The study team will manage the data and will conduct quality control of the data following 
their own standard operating procedures. Missing data or suspected errors will be raised 
as data queries by the lead study coordinator and monitor. The missing, unused, and 
spurious data will be resolved prior to database lock and analysis. An audit trail will be 
maintained for tracking purposes.  
 
In ITT analysis, the missing outcome data of patients who drop out from follow-up during 
study period will be handled based on the Last Observation Carried Forward (LOCF) 
imputation method. For example, if a patient was well during the end of treatment but 
lost to subsequent follow-up, he/she will be considered not to have met the primary 
outcome of 90-day SAB-relapse. 
 
12.3.4   Procedure for deviation from original statistical plan 
Any changes or deviation from the original statistical analysis plan must be approved by 
coordinating PI before the interim analysis and final analysis of the study. 
 
12.3.5   Planned interim analysis 
An interim analysis will be performed on the efficacy and safety endpoints when 50% of 
the targeted patients have been randomized and completed 30 days follow-up. The 
results will be presented to the Data and Safety Monitoring Board (DSMB) to determine 
whether the trial should proceed as planned or be stopped early due to overwhelming 
non-inferiority or safety concern or undergo sample size recalculation based on 
conditional power. 
 
12.4 Data and Safety Monitoring Board 
The members of the Data and Safety Monitoring Board (DSMB) of this trial will consist of 
at least 3 independent experts, namely an infectious diseases physician, an academician, 
and a statistician. They will be formally invited and appointed to the DSMB in their 
individual capacity. They will be required to periodically review and evaluate the 
accumulated study data for participant safety, study conduct and progress, treatment 
efficacy, and when appropriate, make recommendations concerning the continuation, 
modification, or termination of the trial. 
 
 
 
 

 
 
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13.  ETHICS & REGULATORY CONSIDERATIONS 
 
13.1 Independent Ethics Committee 
The study protocol, case report form (CRF), Patient Information Sheet (PIS), Informed 
Consent Form (ICF), subject requirement procedures, and information on payments and 
compensation available to subjects, will be submitted to the Medical Research & Ethics 
Committee (MREC) of the Ministry of Health (MOH), Malaysia. Unconditional approval 
must be received from the MREC before commencement of this study. Approval from the 
MREC must be documented in a letter to the investigator specifying the study title, 
protocol number, the documents reviewed, the date on which the committee met and 
granted the approval, the name, occupation and institutional affiliation of the chairman 
and members of the MREC, and provisions for periodic review if any. Any amendments to 
the protocol, other than administrative ones, must also be approved by this committee. 
 
The principal investigator will inform the MREC of: 
➢ Any amendment to the protocol, informed consent changes or revisions of other 
documents originally submitted for review. 
➢ Any serious and/or unexpected events occurring during the study, where required. 
➢ Any new information that may adversely affect the safety of the subjects or the 
conduct of the study. 
➢ An annual update on the progress of the study and/or request for reapproval, 
where required. 
➢ Final study report when the study has been completed, where required. 
 
All correspondence with the MREC will be filed by the principal investigator in 
the Master Study File. 
 
13.2 Ethical conduct of the study 
The study will be conducted after obtaining approval from the Medical Research & Ethics 
Committee (MREC) of the Ministry of Health (MOH), Malaysia via the National Medical 
Research Register (NMRR). The study will be conducted in compliance with the protocol 
and CRC standard operating procedures. Investigators will adhere to the ethical principles 
that have their origin in the "World Medical Association Declaration of Helsinki", the 
"Malaysian Guidelines for Good Clinical Practice" and applicable regulatory Requirements. 
 
13.3 Informed consent and subject information 
Freely given informed consent will be obtained from every subject prior to participation 
in this study. The investigator will inform every subject in detail about the nature of the 
study, its purpose, the treatments and the probability of random assignment to treatment 
groups, those aspects of the study that are experimental, the procedures involved 
including all invasive procedures and the discomfort they may entail, the possible risks 
including to an embryo, foetus or nursing infant where applicable, the reasonably 

 
 
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49                                                                      
 
expected benefits the expected duration and the approximate number of subjects 
involved and the subject's responsibilities. 
 
Study subjects will also be informed that: 
➢ Participation in this study is voluntary and that he/she may withdraw from this 
study at any time for any reason and that withdrawal of consent will not affect 
his/her subsequent medical treatment or relationship with the treating physician. 
➢ They will be notified in a timely manner if information becomes available that may 
be relevant to their willingness to continue participation in the study. 
➢ Alternative procedures or treatments that may be available and the important 
potential benefits and risks of these available alternative procedures or 
treatments. 
➢ Any compensation for additional costs and/or injury caused to a subject 
attributable to participation in the study. 
➢ Financial expenses, if any, to the subject for participating in the study as well as 
prorated payment, if any, to the subject for participating in the study. 
➢ Any foreseeable circumstances and/or reasons under which the subject's 
participation in the study may be terminated. 
➢ The person(s) to contact for further information regarding the study and whom to 
contact in the event of study related injury. 
 
Written consent will be obtained from each subject involved in the study. If written 
consent is not possible, oral consent can be obtained if witnessed by a signed statement 
from one or more persons not involved in the study, stating why the patient was unable 
to sign the consent form. The informed consent form used to document written or oral 
consent in the study must be received prior to approval from the MREC. If the subject and 
his/her parent/guardian are unable to read, the investigator or designee will explain to 
the subject the content of the Patient Information Sheet and Consent Form point by point 
in the presence of an impartial witness. The witness should personally sign and date the 
consent form. The potential study subject and/or his/her parent/guardian will be given 
the opportunity to ask questions and time for consideration. 
 
A copy of the Patient Information Sheet and signed Consent Form will be given to the 
subject. The original will be filed by the PI in the Investigator Site File.  
 
13.4 Patient protection procedures 
 
13.4.1   Procedures in the event of emergency 
The investigators are responsible for ensuring that procedures and expertise are available 
to cope with medical emergencies during the study. An emergency may constitute an SAE 
(please refer to SAE section). 
 
 

 
 
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13.4.2   Procedures in the event of pregnancy 
Patients with childbearing potential will be instructed upon enrolment to inform the 
investigator if she becomes pregnant during the study treatment period. Investigator will 
decide on continuation or change of study treatment based on the pregnancy risk defined 
by the FDA pregnancy categories: 
 
Category B: Cloxacillin, cefazolin, clindamycin, cephalexin, ceftaroline 
Category C: Vancomycin, Linezolid 
Category D: Trimethoprim-sulfamethoxazole 
 
None of the study drugs is absolutely contraindicated in pregnancy. Study antibiotics in 
Category B and C are generally safe to be used in pregnancy. Trimethoprim-
sulfamethoxazole, which is in Category D (evidence of human foetal risk based on adverse 
reaction data from investigational or marketing experience or studies in humans, but 
potential benefits of the drug may outweigh the risks) may be switched to alternative drug 
in Category B or C if the patient becomes pregnant. In a rare case scenario, if a patient in 
EOS group taking oral trimethoprim-sulfamethoxazole becomes pregnant, investigator 
may consider switching her trimethoprim-sulfamethoxazole to oral linezolid while 
maintaining her with oral study drug as per protocol. The investigators should explain to 
patient regarding the risk and benefit involved.  
 
Foetal complications are not expected since the study drugs are given over a short course. 
However, any study drug exposure during pregnancy must be notified to the principal 
investigator. If the exposure is deemed significant, the outcome of the pregnancy must 
be followed up and reported on the Pregnancy Monitoring Form for Clinical Studies. 
 
13.4.3   Patient data protection 
The investigator will assure that the subjects' anonymity will be maintained and that the 
confidentiality of records and documents that could identify subjects will be protected, 
respecting the privacy and confidentiality rules in accordance with applicable regulatory 
requirements. 
 
Subjects will be identified only by their assigned identification number and initial on all 
CRFs and other study-related records and documents. The investigator will keep a Patient 
Identification List with complete identification information (name, address, contact 
number, IC#) on each subject. This list will be kept by Principal Investigator on site in a 
locked cabinet. Subject's written informed consent form will be maintained by the 
investigator in strict confidence by keeping them in a locked cabinet, which can only be 
accessed by investigators on site. 
 
Study monitors, auditors and representatives of MREC will be granted direct access to 
subject medical records and other study documents for verification of study procedures 
and data without violating the confidentiality of the subject. The subject will be informed 
that by signing a written informed consent form, he/she is authorizing such access. The 

 
 
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51                                                                      
 
subjects and their next of kin will not be given direct access to their personal study data. 
The subjects may be informed about study findings upon request, but only after the 
completion and publication of the study. 
 
All data will be entered into an electronic database (REDCap), which only allows assigned 
investigators with username and password to enter and view data from respective site. 
Only coordinating PI and assigned personnel for data management will be granted 
permission to view data from all sites and export data. The electronic data will be 
identified by patient numbers only, thereby ensuring that patients' identity remains 
unknown. 
 
13.4.4   Insurance 
This clinical trial is sponsored by the Ministry of Health (MOH) Malaysia. All the 
investigators in this trial will conduct the trial according to the policies and guidelines set 
out by the MOH. The investigators will follow strict scientific standards to protect all trial 
participants. Investigators involved in this trial are encouraged to have professional 
indemnity to cover liabilities concerning clinical/professional conduct. However, all 
doctors in MOH are provided coverage under Section 5, Act 359. The trial investigators 
are responsible for managing all medical treatments for trial-related injury, directly or 
through referrals to related specialty departments, within the MOH facilities without any 
MOH hospital charges being subjected to the affected trial participants [PENGECUALIAN 
CAJ HOSPITAL BAGI PARA SUBJEK KAJIAN YANG TERLIBAT DALAM PENYELIDIKAN 
INVESTIGATOR INITIATED TRIALS; (101) DLM.KKM-58/900/69.JLD5 30 MAC 2011]. 
Coverage of the said treatment for trial-related injury, however, does not include 
monetary compensation, or treatment charges outside of MOH facilities. The trial sponsor 
and investigators are not liable for events unrelated to the trial procedures or the 
investigational product or, events due to a disease's natural progression. 
 
 
14.  ADMINISTRATIVE MATTERS 
 
14.1 Notification of regulatory authority(ies) 
All necessary arrangements for the registration and approval of this study with the 
responsible authorities and the disposition of the required data and document will be 
undertaken by the Principal Investigator. 
 
14.2 Notification of primary care physician 
Investigators should ask patients if they wish for their general practitioner or primary care 
physician to be notified about their involvement in this study. This is so that if the patients 
need to see their own physician for any reason, the physician will be aware that they are 
taking a study drug. 
 

 
 
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14.3 Study initiation 
Investigators involved in this study must not enrol any patient prior to completion of a 
formal meeting conducted by the coordinating PI and Site Coordinator. This meeting will 
include an inventory of study supplies, a detailed review of the protocol and eCRF, training 
on study procedures and other procedures required of GCP. Investigators who are not 
GCP certified will undergo GCP training during the study. 
 
14.4 Protocol deviation 
Protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the approved protocol. For example, a patient is enrolled into trial 
despite having persistent SAB (non-compliance with the inclusion and exclusion criteria). 
 
In addition, patients under the following situations during study treatment period are 
considered to have failed to complete study treatment as per protocol, and may warrant 
protocol deviation reporting: 
• Any change of route of antibiotic administration 
• Switching or addition of antibiotics other than those study drugs in Table 4  
• Earlier discontinuation of study drugs before the study treatment duration defined 
in Table 6. (±2 days difference is acceptable) 
• Extension of study drugs beyond the study treatment duration defined in Table 6. 
(±2 days difference is acceptable)  
• Use of combination antibiotic therapy for SAB 
• Less than 80% of study drugs are taken by patient 
 
However, the above scenarios will not be considered protocol deviation if the following 
occurs during the study treatment, which may necessitate a change or escalation of 
antibiotic regimen and duration. This clinical decision is at the discretion of the primary 
treating physician: 
• SAB relapse  
• New infections (other than S. aureus)  
• Adverse events due to study drugs  
• Difficult IV access (for SIV group)  
• Difficult oral administration of medications (for EOS group)  
• Patient’s non-adherence to study drugs (in the absence of medication dispensing 
or administration error) 
• Clinical deterioration or failure  
• Death  
 
Any protocol deviation will be documented by the study monitor with rectification as soon 
as possible. The investigator should be notified immediately. Except for emergencies, no 
changes, or deviations in the conduct of this protocol will be permitted without prior 
approval from MREC. In the event of any emergency, the investigators will institute any 

 
 
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53                                                                      
 
medical procedures deemed appropriate. All such procedures must be promptly reported 
to PI and MREC. 
 
14.5 Study documentation 
The investigator must maintain adequate and accurate records to document the conduct 
of the study and substantiate the study data. These documents are Essential Documents 
and Source Documents. 
 
14.5.1   Essential documents 
These are documents that permit evaluation of the study and the quality of the data 
produced.  
The Essential Documents are:  
• Signed protocol amendments  
• Sample CRFs  
• MREC approval letter 
• Informed consent form  
• CV of investigator and co-investigator  
• Correspondences with MREC, sponsor and CRC  
• Interim reports to MREC 
• Investigational product accountability and shipping records  
• Site signature log  
• Monitor visit log  
• Other appropriate documents in accordance with GCP guidelines. 
 
The coordinating PI will maintain a Master Study File. The investigator at each site will 
maintain an Investigator Site File (ISF). This file shall be used to facilitate and ensure filing 
of all relevant and Essential Documents during and after the study. The site investigator 
will be responsible for keeping the Investigators Site File updated and ensuring that all 
required documents are filed. The file will be inspected during monitoring visits. 
 
14.5.2   Source documents 
These are original documents, data and records including hospital records, clinical and 
office charts, laboratory reports, memoranda, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as 
being accurate, radiological films, subjects' files, and records kept at the pharmacy, at the 
laboratories and at medico-legal departments involved in the study. The investigator must 
maintain source documents for each patient in the study.  
 
All information on CRFs must be traceable to these source documents:  
• Patient identification list  
• Curriculum vitae  
• Site signature/authorization log 

 
 
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14.6 Patient identification list/enrolment log 
The investigator must maintain a Subject Identification Log to record subjects’ personal 
details including full name, date of birth, contact number and house address. The list has 
to show an equivocal study identification number. The investigator is also required to 
maintain Subject Screening and Enrolment Log to document the relevant information 
during screening and enrolment including the date of enrolment and randomization 
number. The logs will be filed in the Investigator Site File on site. 
14.7 Curriculum vitae 
The investigator will provide curriculum vitae showing his/her experience in the area of 
the proposed study. These should be filed at Master Study File as well as in the 
Investigator Site File at study site. 
 
14.8 Site signature/authorization log 
The investigator must maintain a Signature Log to document signatures and initials of all 
staff authorized to make entries and/or corrections on study related records or 
documents. The log will be filed in the Investigator Site File. 
 
14.9 Study monitoring  
Study monitoring and data management service will be outsourced to an independent 
certified, and reputable clinical research company. The scope of responsibility and 
activities are as follows: 
 
Study Monitoring 
• Protocol training for study sites (treatment and study procedures, safety reporting, 
eCRF completion guideline etc.)   
• Onsite and remote monitoring of study conduct in each study sites at planned 
intervals during study period.  
• Inspection of eCRF to verify adherence to the protocol and the completeness, 
consistency, and accuracy of the data in accordance with source documents. 
• Maintenance of Investigator Site File (ISF) at each study sites and ensuring completion 
of all essential documents. 
 
Data Management 
• eCRF design start-up using REDCap or any EDC platform recommended by the clinical 
research company. 
• Development of data management and validation plan 
• Data review and quality control 
• Data query resolution 
 
The site investigators must cooperate with the study monitor to ensure that any problems 
detected during these monitoring visits are resolved. 
 

 
 
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55                                                                      
 
14.10 Audits and inspections 
The investigators should make available the various records of the trial to qualified 
personnel from health authority inspectors after appropriate notification. The verification 
of eCRFs data will be made by direct inspection of source documents. 
 
 
14.11 Retention of documents 
Upon study completion or study site closure, the coordinating PI shall arrange for the 
retention of all study documents and records for at least 15 years after completion or 
discontinuation of the study. The paper documents will be transferred to the designated 
archival centre for archiving. Details of all archived data, including location, will be 
documented. If the PI moves or retires, he/she must nominate someone in writing to be 
responsible for archiving. Archived data may be held in electronic record, provided a 
backup exists and a hard copy can be obtained from it if required. Where source 
documents are required for the continued care of the subject, appropriate copies should 
be made for storage outside of the site. 
 
14.12 Finance 
This study is funded by the Ministry of Health Malaysia. 
 
14.13 Confidentiality 
The investigator agrees that all information communicated to him/her is the exclusive 
property of the research team and ensure that the same will be kept strictly confidential 
by the investigator or any person connected with the work and shall not be disclosed to 
any third party without the prior written consent of the Principal Investigator. 
 
14.14 Publication policy 
All investigators are responsible for writing and reviewing the final study report and 
preparing the manuscript for journal submission. The first publication must be based on 
data from all centres, analysed as stipulated in the protocol.  
 
Investigators in this study agree not to present data gathered from one centre or a small 
group of centres before the full initial publication, unless formally agreed to by all other 
investigators and PI.  
 
Authorship will be determined by mutual agreement prior to the start of the study and 
will include lead authors for the primary presentation and publication of this  
study. Criteria for selection of additional authors will be agreed prior to the start of this 
study, based on International Committee of Medical Journal Editors (ICMJE) guideline. As 
it will not be possible for all investigators to be named as authors in the primary 
publication, other investigators who have enrolled patients and involved in data collection 
phase will be acknowledged as being part of the study team.  

 
 
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56                                                                      
 
 
Director General (DG) of Health Malaysia’s approval will be required before publishing or 
presenting data. Only summarized data will be presented in reports or publications. 
Patients’ identities will not be disclosed in any publication or presentation. 
 
14.15 Anticipated subject accrual duration 
This study is expected to start in May 2024. The projected timeline for subject accrual is 
as follows: 
▪ First patient enrolled is expected in May 2024 
▪ Last patient enrolled is expected in January 2025 
▪ Last patient expected to complete follow-up in April 2025 
 
These accrual rates are based on reasonable planning expectations. The investigator 
should however continually compare the actual and expected accrual rates and make 
every effort to ensure that they are as closely matched as possible. If the investigator 
anticipates major problems with recruitment, or delay in the expected completion date, 
he/she should discuss this with the coordinating PI as early as possible. 
 
14.16 Gantt Chart 
The study duration is planned for 12 months, from 1st May 2024 till 30th April 2025.  The 
study timeline is as follows: 
 
 
 
 
2023 
2024 
2025 
 
Mac - Jun 
Jul - Dec 
Jan - Mac 
April - Jun 
Jul - Sep 
Oct - Dec 
Jan - 
Feb 
Mac - 
Apr 
May 
- Jun 
Literature review, protocol 
development 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethical review, research, 
and fund approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study enrolment and 
follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Compilation of data, 
analysis, and 
interpretation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presentation and 
publication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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57                                                                      
 
15. REFERENCES 
1. van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of mortality in 
Staphylococcus aureus Bacteremia. Clin Microbiol Rev. 2012 Apr;25(2):362-86. doi: 10.1128/CMR.05022-
11. PMID: 22491776; PMCID: PMC3346297 
 
2. Laupland KB, Lyytikainen O, Sogaard M, Kennedy KJ, Knudsen JD, Ostergaard C, Galbraith JC, Valiquette L, 
Jacobsson G, Collignon P, Schonheyder HC, International Bacteremia Surveillance Collaborative. 2013. The 
changing epidemiology of Staphylococcus aureus bloodstream infection: a multinational population-based 
surveillance study. Clin Microbiol Infect 19:465–471. 
 
3. Karunakaran R, Raja NS, Ng KP, Navaratnam P. Etiology of blood culture isolates among patients in a 
multidisciplinary teaching hospital in Kuala Lumpur. J Microbiol Immunol Infect 2007;40:432–7. 
 
4. Pasumbal E, Pen˜a A. Epidemiology and outcome of bacteremia at St Luke’s Medical Center: a one-year 
prospective study. Phil J Microbiol Infect Dis 2004;33: 53–67. 
 
5. Phetsouvanh R, Phongmany S, Soukaloun D, Rasachak B, Soukhaseum V, Soukhaseum S, et al. Causes of 
community-acquired bacteremia and patterns of antimicrobial resistance in Vientiane, Laos. Am J Trop 
Med Hyg 2006;75: 978–85. 
 
6. Eshwara VK, Munim F, Tellapragada C, et al. Staphylococcus aureus bacteremia in an Indian tertiary care 
hospital: observational study on clinical epidemiology, resistance characteristics, and carriage of the 
Panton-Valentine 
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2013;17(11):e1051-e1055. 
doi:10.1016/j.ijid.2013.06.002 
 
7. Fowler VG Jr, Li J, Corey GR, et al. Role of echocardiography in evaluation of patients with Staphylococcus 
aureus bacteremia: experience in 103 patients. J Am Coll Cardiol 1997; 30:1072–8. 
 
8. Rasmussen RV, Høst U, Arpi M, et al. Prevalence of infective endocarditis in patients with Staphylococcus 
aureus bacteraemia: the value of screening with echocardiography. Eur J Echocardiogr 2011; 12:414–20 
 
9. Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG Jr. Staphylococcus aureus infections: epidemiology, 
pathophysiology, clinical manifestations, and management. Clin Microbiol Rev. 2015 Jul;28(3):603-61. doi: 
10.1128/CMR.00134-14. PMID: 26016486; PMCID: PMC4451395. 
 
10. Holland TL, Arnold C, Fowler VG Jr. Clinical management of Staphylococcus aureus bacteremia: a review. 
JAMA. 2014;312(13):1330-1341. doi:10.1001/jama.2014.9743. 
 
11. Spellberg B, Chambers HF, Musher DM, Walsh TL, Bayer AS. Evaluation of a Paradigm Shift From 
Intravenous Antibiotics to Oral Step-Down Therapy for the Treatment of Infective Endocarditis: A Narrative 
Review. JAMA internal medicine. 2020. 
 
12. The Role of Oral Antibiotics in Bacterial Bloodstream Infections. US Pharm. 2021;46(4):17-20. 
https://www.uspharmacist.com/article/the-role-of-oral-antibiotics-in-bacterial-bloodstream-infections 
 
13. Fowler VG Jr, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus 
bacteremia. Arch Intern Med. 2003;163(17):2066-2072. doi:10.1001/archinte.163.17.2066. 
 

 
 
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14. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray 
BE, Ryback MJ, Talan DA, Chambers HF. Clinical practice guidelines by the Infectious Diseases Society of 
America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: 
executive summary. Clin Infect Dis. 2011;52:285–292. 
 
15. Barlam TF, Cosgrove SE, Abbo LM, et al. Executive Summary: Implementing an Antibiotic Stewardship 
Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare 
Epidemiology of America. Clin Infect Dis. 2016;62(10):1197-1202. doi:10.1093/cid/ciw217 
 
16. Jorgensen SCJ, Lagnf AM, Bhatia S, Shamim MD, Rybak MJ. Sequential intravenous-to-oral outpatient 
antibiotic therapy for MRSA bacteraemia: one step closer. J Antimicrob Chemother. 2019 Feb 1;74(2):489-
498. doi: 10.1093/jac/dky452. PMID: 30418557. 
 
17. Willekens R, Puig-Asensio M, Ruiz-Camps I, Larrosa MN, González-López JJ, Rodríguez-Pardo D, Fernández-
Hidalgo N, Pigrau C, Almirante B. Early Oral Switch to Linezolid for Low-risk Patients With Staphylococcus 
aureus Bloodstream Infections: A Propensity-matched Cohort Study. Clin Infect Dis. 2019 Jul 18;69(3):381-
387. doi: 10.1093/cid/ciy916. PMID: 30351401. 
 
18. Iversen K, Ihlemann N, Gill SU, Madsen T, Elming H, Jensen KT, Bruun NE, Høfsten DE, Fursted K, Christensen 
JJ, Schultz M, Klein CF, Fosbøll EL, Rosenvinge F, Schønheyder HC, Køber L, Torp-Pedersen C, Helweg-Larsen 
J, Tønder N, Moser C, Bundgaard H. 2019. Partial oral versus intravenous antibiotic treatment of 
endocarditis. N Engl J Med 380:415–424. 10.1056/NEJMoa1808312. 
 
19. Li H-K, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL, Lipsky BA, Hughes HC, Bose D, Kümin 
M, Scarborough C, Matthews PC, Brent AJ, Lomas J, Gundle R, Rogers M, Taylor A, Angus B, Byren I, Berendt 
AR, Warren S, Fitzgerald FE, Mack DJF, Hopkins S, Folb J, Reynolds HE, Moore E, Marshall J, Jenkins N, 
Moran CE, Woodhouse AF, Stafford S, Seaton RA, Vallance C, Hemsley CJ, Bisnauthsing K, Sandoe JAT, 
Aggarwal I, Ellis SC, Bunn DJ, Sutherland RK, Barlow G, Cooper C, Geue C, McMeekin N, Briggs AH, Sendi P, 
Khatamzas E, Wangrangsimakul T, Wong THN, Barrett LK, Alvand A, Old CF, Bostock J, Paul J, Cooke G, 
Thwaites GE, Bejon P, Scarborough M. 2019. Oral versus intravenous antibiotics for bone and joint infection. 
N Engl J Med 380:425–436. 10.1056/NEJMoa1710926. 
 
20. Kaasch A.J. Early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection (SABATO): a 
randomised open-label, phase III, non-inferiority trial. ECCMID; April 25th, 2022; Lisbon 2022.  
 
21. Giles A, Foushee J, Lantz E, Gumina G. Sulfonamide Allergies. Pharmacy (Basel). 2019 Sep 11;7(3):132. doi: 
10.3390/pharmacy7030132. PMID: 31514363; PMCID: PMC6789825. 
 
22. Dale N. Gerding, Clindamycin, Cephalosporins, Fluoroquinolones, and Clostridium difficile–Associated 
Diarrhea: This Is an Antimicrobial Resistance Problem, Clinical Infectious Diseases, Volume 38, Issue 5, 1 
March 2004, Pages 646–648, https://doi.org/10.1086/382084 
 
23. Tandan, M., Cormican, M. & Vellinga, A. Adverse events of fluoroquinolones vs. other antimicrobials 
prescribed in primary care: A systematic review and meta-analysis of randomized controlled trials. Int. J. 
Antimicrob. Agents 52, 529–540 (2018). 
 
24. Ho, J. M.-W. & Juurlink, D. N. Considerations when prescribing trimethoprim-sulfamethoxazole. Can. Med. 
Assoc. J. 183, 1851–1858 (2011). 
 

 
 
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25. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. US 
Department of Health and Human Services; 2017. 
 
26. CLSI M100 Performance Standards for Antimicrobial Susceptibility Testing, 34th Edition, Feb 28, 2024 
 
27. National 
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edition.html 
 
 
16.  APPENDICES 
• EVOS Case Report Form (CRF) Version 1.1, dated 12th March 2024 
• EVOS Patient Information Sheet & Informed Consent Form (English and Bahasa Malaysia) 
Version 1.2, dated 12th March 2024 
• EVOS Infographic Poster Version 1, dated 26th May 2023 
• Investigational product labels 
• Study investigators’ curriculum vitae