Early Oral Step-down Antibiotic Therapy Versus Continuing Intravenous Therapy for Uncomplicated Gram-negative Bacteraemia (the INVEST Trial)
Phase: PHASE4
Conditions: Gram-negative Bacteraemia
Sponsor: Tan Tock Seng Hospital

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STUDY PROTOCOL 
 
PROTOCOL TITLE: 
Early oral step-down antibiotic therapy versus continuing intravenous therapy for uncomplicated 
Gram-negative bacteraemia (the INVEST trial) 
 
PROTOCOL VERSION: 10.0 
 
PROTOCOL DATE: 09-Sep-2024 
 
PROTOCOL NUMBER: DSRB 2021/00764 
 
PRINCIPAL INVESTIGATOR: 
Prof David Lye 
Senior Consultant, National Centre for Infectious Diseases (NCID), 
Tan Tock Seng Hospital, Singapore 
Email: David_Lye@ttsh.com.sg  
Tel: +65 6357 7457 
SITE PRINCIPAL INVESTIGATORS:  
A/Prof Sophia Archuleta 
Senior Consultant, Division of Infectious Diseases, 
National University Hospital, Singapore  
Email: sophia@nus.edu.sg 
Tel: +65 6772 6188 
Dr Candice Chan Yuen Yue  
Senior Consultant, Department of Infectious Diseases,  
Singapore General Hospital, Singapore  
Email: candice.chan.y.y@singhealth.com.sg  
Tel: +65 6321 3479 
 
Dr Humaira Shafi 
Senior Consultant, Department of Infectious 
Diseases, Changi General Hospital, Singapore  
Email: shafi.humaira@singhealth.com.sg  
Tel: +65 6936 6596 
 
Dr Jenna Chaung  
Consultant, Division of Infectious Diseases, 
Ng Teng Fong General Hospital, Singapore 
Email: jenna_chaung@nuhs.edu.sg       
Tel: +65 8118 6590 
 
Dr Zheng Shuwei 
Consultant, Department of Infectious Disease, 
Sengkang General Hospital, Singapore 
Email: zheng.shuwei@singhealth.com.sg  
Tel: +65 6930 2212 
 
 
 
STUDY SITES IN SINGAPORE: 
Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433 
National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074 
Singapore General Hospital, 20 College Road, Singapore 169856 
Changi General Hospital, 2 Simei Street 3, Singapore 529889 

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Ng Teng Fong General Hospital, 1 Jurong East Street 21, Singapore 609606 
Sengkang General Hospital, 110 Sengkang E Way, Singapore 544886 
 

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Investigator Protocol Agreement Page 
 
• 
I confirm agreement to conduct the study in compliance with the protocol, International 
Conference on Harmonisation Guideline for Good Clinical Practice (ICH-GCP) and applicable 
local regulations. 
• 
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or 
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. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
 
 
Principal Investigator Name:   
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 

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Key Information & Synopsis  
Key Information of the Study   
Study title 
Early oral step-down antibiotic therapy versus continuing intravenous 
therapy for uncomplicated Gram-negative bacteraemia (the INVEST 
trial) 
Domain Specific Review 
Board identifier 
2021/00764 
Health Sciences Authority 
identifier  
2218943B 
ClinicalTrials.gov identifier 
NCT05199324  
Funding source 
Singapore’s National Research Foundation Central Gap Fund: Clinical 
Trials Grant – Investigator Initiated Trial (Award ID: CTGIIT19nov-
0002) 
Study duration (patient 
recruitment and follow up) 
Oct 2021 – Mar 2026  
Overarching coordinating 
centre / Study sponsor  
Tan Tock Seng Hospital, Singapore  
Overarching coordinating 
network 
Singapore Infectious Disease Clinical Research Network 
Collaborating bodies 
Singapore Clinical Research Institute 
Global Project Manager 
Russel Lee PhD, Senior Research Fellow 
National Centre for Infectious Diseases, Tan Tock Seng Hospital 
Email: ivor_russel_mc_lee@ttsh.com.sg  
Tel: +65 6511 5060 
Chief Investigator  
Prof David Lye, National Centre for Infectious Diseases, Tan Tock Seng 
Hospital, Singapore 
Site Principal Investigators 
- 
Prof David Lye, National Centre for Infectious Diseases, Tan 
Tock Seng Hospital, Singapore 
- 
A/Prof Sophia Archuleta, National University Hospital, 
Singapore 
- 
Dr Candice Chan Yuen Yue, Singapore General Hospital, 
Singapore 
- 
Dr Humaira Shafi, Changi General Hospital, Singapore 
- 
Dr Jenna Chaung, Ng Teng Fong General Hospital, Singapore 
- 
Dr Zheng Shuwei, Sengkang General Hospital, Singapore 
- 
A/Prof Bridget Barber and Dr Hugh Wright, Royal Brisbane and 
Women’s Hospital, Australia 
- 
Dr Peter Simos and Dr Kylie Alcorn, Gold Coast University 
Hospital, Australia 
- 
Prof Joshua Davis, John Hunter Hospital, Australia 
- 
Prof Steven Tong, Royal Melbourne Hospital, Australia 
- 
Dr Burcu Isler, Princess Alexandra Hospital, Australia  
- 
Prof Graham Cooke, Imperial College Healthcare NHS Trust, 
London North West University Healthcare NHS Trust, Chelsea 
and Westminister NHS Foundation Trust Hospitals, United 
Kingdom 
- 
Dr Helmi bin Sulaiman, University Malaya Medical Centre, 
Malaysia 
- 
Dr Najma Kori and A/Prof Petrick Periyasamy, Hospital 

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Universiti Kebangsaan Malaysia 
- 
Dr Rasidah Binti Senian, Ampang Hospital, Malaysia 
- 
Dr Yasmin Mohamed Gani, Sungai Buloh Hospital, Malaysia  
- 
Dr Kyungmin Huh, Samsung Medical Center, South Korea 
- 
Prof Hong Bin Kim, Seoul National University Bundang 
Hospital, South Korea 
- 
Prof Dafna Yahav, Sheba Medical Centre, Israel 
- 
Prof Mical Paul, Rambam Hospital, Israel  
- 
Prof Mesut Yilmaz, Medipol Mega University Hospital, Turkey 
- 
Prof Souha Kanj, American University of Beirut Medical Centre, 
Lebanon 
- 
A/Prof Karolina Akinosoglou, University General Hospital of 
Patras, Greece 
- 
Prof Juan Pablo Horcajada and Dr Silvia Gomez-Zorrilla, 
Hospital del Mar, Spain 
- 
A/Prof Maddalena Giannella, IRCCS Policlinico di Sant’Orsola, 
University Alma Mater Studiorum, Italy 
- 
Prof Marco Falcone, University Hospital of Pisa, Italy 
- 
Dr Marco Ripa, IRCCS San Raffaele Hospital, Italy 
- 
Prof Emanuele Durante Mangoni, Monaldi Hospital, Italy 
- 
Prof Po-Yu Liu, Taichung Veterans General Hospital, Taiwan  
Trial Steering Committee 
Site Principal Investigators (PIs) are ex officio members of the Trial 
Steering Committee. Prof David Paterson, Director of ADVANCE-ID, is 
the independent Chairperson of the committee. 
Study Synopsis 
Background  
The incidence of Gram-negative bacteraemia is rising globally, and 
remains a major cause of morbidity and mortality for hospitalised 
patients. Although practice guidelines provide general recommendations 
for treatment duration for Gram-negative bacteraemia, the optimal route 
of administration is yet to be definitively defined. The majority of patients 
with Gram-negative bacteraemia initially receive intravenous (IV) 
antibiotic therapy. However, it remains unclear whether patients can step 
down to oral antibiotics after appropriate clinical response has been 
observed without compromising outcomes. Although the efficacy of early 
oral step-down therapy versus continuing IV therapy for uncomplicated 
Gram-negative bacteraemia is unknown, the advantages of oral therapy 
are evident. Compared with IV therapy, oral therapy eliminates the risk of 
catheter-associated adverse events, enhances patient quality of life, and 
reduces total healthcare costs. 
Purpose of study 
Current management of uncomplicated Gram-negative bacteraemia 
entails a duration of IV antibiotic therapy with limited evidence to guide 
oral conversion. We aim to evaluate the clinical efficacy and economic 
impact of early step-down to oral antibiotics (within 72 hours from index 
blood culture collection) versus continuing standard of care IV therapy 
(for at least another 24 hours post-randomisation) for clinically stable / 
non-critically ill inpatients with uncomplicated Gram-negative 
bacteraemia. 
Hypothesis   
- 
Early step-down to oral fluoroquinolones or trimethoprim-
sulfamethoxazole will be clinically non-inferior to continuing IV 

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antibiotic therapy 
- 
Early oral step-down therapy will result in lower health resource 
and service utilisation costs compared with continuing IV therapy 
Primary outcome  
Compare the all-cause mortality at day 30 post-randomisation in patients 
from the standard arm versus intervention arm. 
Key secondary outcomes 
Compare between standard and intervention arms: 
- 
All-cause mortality at days 14 and 90 
- 
Number of days on IV therapy in the total index hospitalisation 
(including outpatient parenteral antibiotic therapy [OPAT]) for 
surviving participants from the time of randomisation until i. 
hospital discharge and ii. day 90   
- 
Adverse events by day 90, including Clostridioides difficile-associated 
diarrhoea, catheter-related complications, and liver function test 
abnormalities or acute kidney injury 
- 
Time to being discharged alive from the total index hospitalisation 
(including OPAT and hospital-in-the-home) by day 90 
- 
Health economic evaluation by day 90, including estimation of 
total healthcare cost as well as assessment of patient’s quality of 
life and number of quality adjusted life years saved 
Exploratory outcome  
Composite outcome for Desirability Of Outcome Ranking (DOOR)  
Study design  
This is an international, multicentre, randomised controlled, open-label, 
phase IV, non-inferiority trial with a non-inferiority margin of 6%. 
Eligible participants must be clinically stable / non-critically ill inpatients 
over the age of 18 (21 in Singapore) with uncomplicated Gram-negative 
bacteraemia. Randomisation into the intervention or standard arms will 
be performed with 1:1 allocation ratio according to a randomisation list 
prepared in advance using a secure online randomisation system. 
Randomisation will be stratified by country and random sequence will be 
generated using random permuted blocks of unequal length. Participants 
randomised to the intervention arm (within 72 hours from index blood 
culture collection) will be immediately converted to an oral 
fluoroquinolone (most commonly, ciprofloxacin) or trimethoprim-
sulfamethoxazole. In the event of microbiological or clinical failure of the 
oral antibiotic treatment, escalation to IV antibiotics may be initiated at 
any time point post-randomisation. Participants randomised to the 
standard arm should continue to receive IV therapy for at least another 
24 hours post-randomisation before clinical re-assessment and decision 
making by the treating doctor. All study drugs (and dosage) would be 
those routinely used in clinical practice and will be ordered/dispensed 
from the hospital pharmacy as per site institutional practice. The 
recommended treatment duration is 7 days of active antibiotics (including 
empiric therapy), although treatment regimen may be longer than 7 days 
if clinically indicated. Participants may be discharged home or to OPAT 
at any time post-randomisation. 
Inclusion criteria 
- 
1 set of blood cultures positive for GNB associated with 
evidence of infection 
- 
Able to be randomised within 72 hours of index blood culture 
collection 
- 
Age ≥18 years (≥21 in Singapore) 

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- 
Latest Pitt bacteraemia score <4  
- 
Patient or legal representative is able to provide informed consent 
Exclusion criteria 
- 
Established uncontrolled focus of infection (e.g. undrained 
abdominal abscess) 
- 
Complicated infections (e.g. necrotising fasciitis) 
- 
Septic shock 
- 
Polymicrobial bacteraemia 
- 
Bacteraemia due to vascular catheter or intravascular materials 
that cannot be removed 
- 
Specific Gram-negative pathogens that cannot be effectively 
treated with fluoroquinolones or trimethoprim-sulfamethoxazole 
(e.g. Burkholderia, Brucella) 
- 
Index GNB with resistance to fluoroquinolones AND 
trimethoprim-sulfamethoxazole 
- 
Hypersensitivity to fluoroquinolones AND sulpha drugs 
- 
Unable to consume or absorb oral medications for any reason or 
unsuitable for ongoing IV therapy (e.g. no intravenous access) 
- 
Severely immunocompromised 
- 
Women who are known to be pregnant or breast-feeding 
- 
Treatment is not with intent to cure the infection  
- 
Unable to collect patient’s follow-up data for at least 30 days post-
randomisation  
- 
Treating doctor deems enrolment into trial is not in the best 
interest of the patient 
- 
Previous enrolment in this trial 
Sample size  
Assuming a 30-day mortality of 8% in the standard and intervention arms, 
with 6% non-inferiority margin, a total of 720 patients are needed to 
achieve 80% power with a one-sided 0.025 -level after adjustment for 
5% drop-out. Recruitment will take place in numerous hospital sites from 
Singapore, Australia, United Kingdom, Malaysia, South Korea, Israel, 
Turkey, Lebanon, Greece, Spain, Italy and Taiwan. 
Statistical analyses 
Primary analysis will be performed on the modified intention-to-treat 
(mITT) population, which consists of all randomised patients excluding 
(i) those who did not have 30-day all-cause mortality data, (ii) intervention 
arm patients who did not receive any oral fluoroquinolones or oral 
trimethoprim-sulfamethoxazole post-randomisation, and (iii) standard 
arm patients who did not receive any IV antibiotics post-randomisation. 
Risk difference of 30-day all-cause mortality and its 95% confidence 
interval between intervention and standard arms will be estimated and 
compared using chi-squared test. If the upper limit of the 95% confidence 
interval falls below the 6% non-inferiority margin, clinical non-inferiority 
will be concluded. 
 
Economic viability will be assessed through health economic evaluation 
according to ITT principle from healthcare system and patient 
perspectives. For base case analysis, private rate of each resource 
utilisation will be applied to calculate the average cost and savings. The 
health economic analysis will have two components: 
- 
If results confirm clinical non-inferiority, a cost saving analysis 

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will be conducted to estimate the economic impact of the new 
treatment regimen 
- 
If results fail to confirm clinical non-inferiority, a cost 
effectiveness analysis will be conducted to estimate the 
incremental cost effectiveness ratio (ICER) by comparing the 
difference in cost and clinical outcomes as well as quality-of-life 
between the two treatment arms (ICER=∆C/∆E) 
 

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Contents 
1. 
BACKGROUND AND RATIONALE ...................................................................................................................... 11 
1.1. 
GENERAL INTRODUCTION ...................................................................................................................................... 11 
1.2. 
RATIONALE AND JUSTIFICATION FOR THE STUDY .................................................................................................... 11 
A. 
RATIONALE FOR THE STUDY PURPOSE ................................................................................................................... 12 
B. 
RATIONALE FOR DOSES SELECTED ......................................................................................................................... 12 
C. 
RATIONALE FOR STUDY POPULATION ..................................................................................................................... 13 
D. 
RATIONALE FOR STUDY DESIGN ............................................................................................................................ 13 
2. 
HYPOTHESIS AND OBJECTVES ......................................................................................................................... 14 
2.1. 
HYPOTHESIS ......................................................................................................................................................... 14 
2.2. 
PRIMARY OBJECTIVES ........................................................................................................................................... 14 
2.3. 
SECONDARY OBJECTIVES ....................................................................................................................................... 14 
2.4. 
POTENTIAL RISKS AND BENEFITS: ......................................................................................................................... 16 
A. 
END POINTS - EFFICACY ....................................................................................................................................... 16 
B. 
END POINTS – SAFETY .......................................................................................................................................... 17 
3. 
STUDY POPULATION ............................................................................................................................................ 17 
3.1. 
LIST THE NUMBER OF SUBJECTS TO BE ENROLLED ................................................................................................... 17 
3.2. 
CRITERIA FOR RECRUITMENT ................................................................................................................................ 17 
3.3. 
INCLUSION CRITERIA ............................................................................................................................................ 18 
3.4. 
EXCLUSION CRITERIA ............................................................................................................................................ 18 
3.5. 
WITHDRAWAL CRITERIA ........................................................................................................................................ 19 
3.6. 
SUBJECT REPLACEMENT ......................................................................................................................................... 19 
4. 
TRIAL SCHEDULE ................................................................................................................................................... 19 
5. 
STUDY DESIGN ....................................................................................................................................................... 20 
5.1. 
SUMMARY OF STUDY DESIGN ................................................................................................................................ 20 
6. 
METHODS AND ASSESSMENTS ......................................................................................................................... 21 
6.1. 
RANDOMISATION AND BLINDING ........................................................................................................................... 21 
6.2. 
CONTRACEPTION AND PREGNANCY TESTING .......................................................................................................... 21 
6.3. 
STUDY VISITS AND PROCEDURES ........................................................................................................................... 21 
A. 
SCREENING VISITS AND PROCEDURES .................................................................................................................... 21 
B. 
STUDY VISITS AND PROCEDURES ........................................................................................................................... 22 
C. 
FINAL STUDY VISIT: ............................................................................................................................................. 23 
D. 
POST STUDY FOLLOW UP AND PROCEDURES .......................................................................................................... 23 
E. 
DISCONTINUATION VISIT AND PROCEDURES .......................................................................................................... 23 
F. 
LABORATORY STUDIES ........................................................................................................................................... 23 
7. 
TRIAL MATERIALS ................................................................................................................................................. 24 
7.1. 
TRIAL PRODUCT (S) .............................................................................................................................................. 24 
7.2. 
STORAGE AND DRUG ACCOUNTABILITY .................................................................................................................. 24 
8. 
TREATMENT ............................................................................................................................................................. 24 
8.1. 
RATIONALE FOR SELECTION OF DOSE .................................................................................................................... 24 
8.2. 
STUDY DRUG FORMULATIONS ................................................................................................................................ 26 
8.3. 
STUDY DRUG ADMINISTRATION ............................................................................................................................. 26 
8.4. 
SPECIFIC RESTRICTIONS / REQUIREMENTS ............................................................................................................ 26 
8.5. 
BLINDING ............................................................................................................................................................. 26 
8.6. 
CONCOMITANT THERAPY........................................................................................................................................ 26 

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8.7. 
SAFETY MONITORING PLAN ................................................................................................................................... 26 
8.8. 
COMPLAINT HANDLING .......................................................................................................................................... 26 
9. 
DATA ANALYSIS ..................................................................................................................................................... 27 
9.1. 
DATA QUALITY ASSURANCE ................................................................................................................................... 27 
9.2. 
DATA ENTRY AND STORAGE .................................................................................................................................. 27 
10. SAMPLE SIZE AND STATISTICAL METHODS ................................................................................................ 27 
10.1. 
DETERMINATION OF SAMPLE SIZE ......................................................................................................................... 27 
10.2. 
STATISTICAL AND ANALYTICAL PLANS .................................................................................................................... 28 
11. ETHICAL CONSIDERATIONS .............................................................................................................................. 29 
11.1. 
INFORMED CONSENT ............................................................................................................................................. 29 
12. SAFETY MEASUREMENTS .................................................................................................................................... 30 
12.1. 
DEFINITIONS ........................................................................................................................................................ 30 
12.2. 
COLLECTING, RECORDING AND REPORTING OF “UNANTICIPATED PROBLEMS INVOLVING RISK TO SUBJECTS OR 
OTHERS” – UPIRTSO EVENTS TO THE NHG DOMAIN SPECIFIC REVIEW BOARDS (DSRB) ................................................... 31 
12.3. 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO THE HEALTH SCIENCE 
AUTHORITY (HSA) ............................................................................................................................................................. 32 
12.4. 
IRB REVIEW ......................................................................................................................................................... 32 
12.5. 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS .............................................................................................. 33 
13. PUBLICATIONS ....................................................................................................................................................... 33 
14. RETENTION OF TRIAL DOCUMENTS ............................................................................................................... 33 
15. REFERENCES ........................................................................................................................................................... 33 
 
 
 

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1.        BACKGROUND AND RATIONALE 
 
1.1. 
General Introduction 
 
The incidence of Gram-negative bacteraemia is rising globally, and remains a major cause of 
morbidity and mortality for hospitalised patients. Enterobacterales, particularly Escherichia coli and 
Klebsiella pneumoniae, are currently the predominant pathogens isolated from blood, overtaking the 
Gram-positive Staphylococcus aureus as the major cause of bacteraemia.1,2 Although practice 
guidelines provide general recommendations for antibiotic treatment duration for Gram-negative 
bacteraemia, the optimal route of administration is yet to be definitively defined.3 The majority 
of patients with Gram-negative bacteraemia initially receive intravenous (IV) antibiotic therapy. 
However, it remains unclear whether patients can step down to oral therapy after appropriate 
clinical response has been observed without compromising outcomes. Doctors must exercise 
judgement based on multiple factors such as severity of disease, host immune status, anticipated 
adherence, and predicted adequacy of drug absorption and infection-site penetration. Limited 
data suggesting conversion to oral therapy is effective and safe are generally restricted to Gram-
negative bacteraemia secondary to urinary tract infection (UTI).4–7 Although the efficacy of early 
oral step-down therapy versus continuing IV therapy for uncomplicated Gram-negative 
bacteraemia (not limited to urinary tract sources) is unknown, the advantages of oral therapy are 
evident. Compared with IV therapy, oral therapy eliminates the risk of catheter-associated 
adverse events such as venous thrombosis, phlebitis, line breakage and catheter-associated 
bloodstream infections.8,9 Oral therapy enhances patient quality of life by eliminating discomfort 
associated with IV catheters, enabling mobility and reducing length of stay (LOS) in hospital.8,9 
The healthcare cost of oral therapy is lower compared with IV therapy as there are no charges 
associated with placement/maintenance of central lines or drug preparation and 
administration.8,10  
 
1.2. 
Rationale and justification for the Study 
 
Tamma et al recently compared patient outcomes from early oral step-down therapy (within the 
first 5 days of treatment) versus continued IV therapy for monomicrobial Enterobacterales 
bacteraemia.7 This retrospective multicentre study involved a 1:1 propensity score-matched 
cohort of 4,967 unique cases. Key eligibility criteria included: effective antibiotics administered 
from day 1 until treatment discontinuation, appropriate source control and clinical response by 
day 5. The authors found that 30-day all-cause mortality was not significantly different between 
739 patients who received oral step-down therapy versus 739 on continued IV therapy (HR 1.03, 
95% CI 0.82–1.30). This suggested conversion to oral therapy may be an efficacious option for 
patients who received appropriate source control and demonstrated favourable clinical response 
to the initial IV therapy. Additionally, patients who stepped down to oral therapy were 
discharged from hospital an average of 2 days earlier than those who continued IV therapy (5 
[IQR 3–8] days vs. 7 [IQR 4–14] days; p < 0.001). 
 
In an earlier retrospective single-centre study of Enterobacterales bacteraemia from the urinary 
tract, Rieger et al compared outcomes between 135 patients who transitioned early to oral 
therapy (median 4 days of IV therapy) versus 106 patients who continued to receive IV therapy.4 
The composite outcome consisted of treatment failure defined by escalation to IV antibiotic 
from oral antibiotic, change in antibiotic due to worsening clinical status, and readmission due to 
the same UTI and/or bacteraemia within 30 days of discharge. The key eligibility criterion was 
positive urine and blood cultures collected within 24 hours with the same Enterobacterales 

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pathogen. Treatment failure was not significantly different between patients who received only 
IV antibiotics versus those who received IV-oral antibiotics (3.8% [95% CI 1.0–9.4%] vs. 8.2% 
[95% CI 4.1–14.1%]; p = 0.19). Similar to Tamma et al,7 the authors reported that patients who 
transitioned early to oral therapy were discharged from hospital approximately 2 days earlier than 
patients who continued to receive IV therapy (4.6 [IQR 3.1–7.8] days vs. 7.1 [IQR 4.0–17.5] 
days; p < 0.001). 
 
a. 
Rationale for the Study Purpose 
 
No randomised controlled trial (RCT) has been conducted to assess the efficacy of early oral 
step-down therapy for uncomplicated Gram-negative bacteraemia that are not limited to urinary 
tract sources. High-bioavailability oral antibiotics such as fluoroquinolones or trimethoprim-
sulfamethoxazole have been utilised for Gram-negative bacteraemia based on clinical and 
pharmacokinetics/pharmacodynamics (PK/PD) data.11–13 However, the use of fluoroquinolones 
and trimethoprim-sulfamethoxazole increases the risk of potential adverse effects including 
Clostridioides difficile-associated diarrhoea.13–15 As a result, interest has been spurred in the role of 
oral -lactams that have low-to-moderate bioavailability. The question of whether oral -lactams 
can be used as an efficacious alternative to oral fluoroquinolones or trimethoprim-
sulfamethoxazole for Gram-negative bacteraemia is controversial. 
 
Many doctors assume that patients who switch to oral fluoroquinolones or trimethoprim-
sulfamethoxazole are less likely to experience treatment failure compared with patients who 
switch to oral -lactams. This is due to the higher bioavailability and more favourable PK/PD 
profile of fluoroquinolones and trimethoprim-sulfamethoxazole compared with -lactams. This 
assumption is supported by the retrospective study of Kutob et al, which investigated whether 
varying bioavailabilities of different oral antibiotics affected outcomes for Gram-negative 
bacteraemia predominantly from the urinary tract.16 The authors found the risk of treatment 
failure was higher in patients who received antibiotics with low-to-moderate bioavailability 
compared to those who received antibiotics with high bioavailability.  
 
However, in another retrospective study by Mercuro et al, clinical success was similar between 
patients who received oral fluoroquinolones and those who received oral -lactams as step-down 
therapy for Enterobacterales bacteraemia.17 Likewise, in the earlier described study by Tamma et al, 
the authors found no difference in 30-day mortality between patients who switched to high-
bioavailability agents versus those who switched to low-bioavailability agents.7 It is noteworthy 
the studies by Kutob et al, Mercuro et al and Tamma et al were underpowered to determine 
whether bioavailability of oral antibiotics is crucial for successful treatment of Gram-negative 
bacteraemia.7,16,17  
 
b. 
Rationale for Doses Selected 
 
In view of the uncertainty associated with high-bioavailability versus low-bioavailability agents 
for Gram-negative bacteraemia, our team decided the oral step-down arm of this RCT will 
consist only of fluoroquinolones or trimethoprim-sulfamethoxazole. This conservative decision 
(in not testing oral -lactams) is supported by a recent review article highlighting many oral -
lactams have short half-life requiring frequent dosing that may negatively impact patient 
adherence.18 Furthermore, the dose of oral -lactams (unlike IV -lactams) required to attain 
specific PD targets is still unclear and the determination of minimum inhibitory concentration of 

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Page 13 of 34 
oral -lactams is not routinely performed in many hospitals.18 This conundrum is further 
complicated in clinical scenarios when dose adjustments are needed for patients with renal 
impairment.18 A recent systematic review and meta-analysis revealed infection recurrence 
occurred more frequently in Gram-negative bacteraemic patients transitioned to oral -lactams 
compared with oral fluoroquinolones, although all-cause mortality was not significantly different 
between the -lactams group versus fluoroquinolones or trimethoprim-sulfamethoxazole 
group.19  
 
In this RCT, the recommended doses of oral antibiotics to be used in the intervention arm for 
patients with normal renal function would be ciprofloxacin 750 mg twice daily (if body weight 
≥70 kg) or ciprofloxacin 500 mg twice daily (if body weight <70 kg) or trimethoprim-
sulfamethoxazole 5 mg/kg (for trimethoprim component) every 12 hours up to a maximum 
trimethoprim-sulfamethoxazole (160 mg / 800 mg; double strength) two tablets twice daily. 
Ciprofloxacin is the most common fluoroquinolone class of antibiotics for treatment of Gram-
negative bacteraemia. For patients in the standard arm, the IV antibiotic dose will be determined 
by the patient’s treating doctor (e.g. ceftriaxone 2 g daily, cefazolin 2 g three times daily). The 
recommended treatment duration is 7 days of active antibiotics (including empiric therapy), 
although treatment regimen may be longer than 7 days due to regimen extension or requirement 
for prolonged regimen as clinically indicated. Treatment duration is not the focus/subject of this 
trial as there is one ongoing RCT (BALANCE, NCT02261506) investigating optimal duration of 
antibiotic therapy for Gram-negative bacteraemia. The study drugs are routinely used in clinical 
practice and will be ordered/dispensed from the hospital pharmacy as per site institutional 
practice. 
 
c. 
Rationale for Study Population 
 
Current management of uncomplicated Gram-negative bacteraemia typically entails a duration of 
IV antibiotic therapy with limited evidence from prospective studies to guide oral conversion. In 
this RCT, we aim to evaluate the clinical efficacy and economic impact of early step-down to 
oral antibiotics (within 72 hours from the time of index blood culture collection) versus 
continuing IV therapy (for at least another 24 hours post-randomisation) for clinically stable / 
non-critically ill inpatients with uncomplicated Gram-negative bacteraemia. As these infections 
can be seen in a large range of clinical situations spanning all hospital departments and patient 
populations, the study logically requires recruitment of patients from all areas of the hospital 
system. Gram-negative bacteraemias are usually treated in admitted patients and therefore 
inclusion of outpatients is not applicable. 
 
d. 
Rationale for Study Design 
 
Recent data from a multicentre, propensity score-matched, retrospective study suggested 7 days 
of antibiotics may be sufficient for treatment of uncomplicated Enterobacterales bacteraemia.20 
Consistent with this, recently completed RCTs demonstrated non-inferiority of 7 days versus 14 
days of antibiotic treatment for uncomplicated Gram-negative bacteraemia.21,22 Therefore, 
switching to oral therapy on day 7 or later will not be meaningful as it is likely that sufficient IV 
antibiotics would have already been administered. In this study, we propose 3 days (72 hours 
from the time of index blood culture collection) as the cut-off time frame for switching to oral 
therapy for patients randomised to the intervention arm. This proposed randomisation window 
of 72 hours from index blood culture collection is supported by the observational analyses of 

INVEST Master Protocol, Version 10.0, Dated 09-Sep-2024 
Page 14 of 34 
Rieger et al, Kutob et al and Mercuro et al, where patients typically received 3–5 days of IV 
therapy prior to oral step-down therapy.4,16,17 The options for oral therapy in this study are 
fluoroquinolones or trimethoprim-sulfamethoxazole – selected due to their extensive use in 
clinical practice with well-established safety and efficacy across a plethora of infections. For 
example, in one of the aforementioned RCTs studying treatment duration for uncomplicated 
Gram-negative bacteraemia, >70% (across both study arms) received oral fluoroquinolones 
among the subjects who transitioned to step-down therapy.21 For patients randomised to the 
standard arm, the continuing IV antibiotic therapy should be maintained for at least 24 hours 
post-randomisation before clinical re-assessment and decision making by the treating doctor. At 
the doctor’s discretion, patients in the standard arm may be converted to oral antibiotic therapy 
(after continuing the IV therapy for at least 24 hours post-randomisation). This data on oral 
antibiotic switch for patients in the standard arm will be recorded in the case report form (CRF). 
This study will help inform local and international practice guidelines on optimal antibiotic 
management for uncomplicated Gram-negative bacteraemia. A finding of non-inferiority in 
clinical efficacy of oral fluoroquinolones or trimethoprim-sulfamethoxazole versus IV antibiotics 
may translate to wider adoption of a more cost-effective treatment strategy that reduces hospital 
LOS as well as better patient-centred outcomes and satisfaction. 
 
2. 
HYPOTHESIS AND OBJECTVES 
 
2.1. 
Hypothesis 
 
We hypothesise in clinically stable / non-critically ill patients with uncomplicated Gram-negative 
bacteraemia that: 
1. Early step-down to oral fluoroquinolones or trimethoprim-sulfamethoxazole will be non-
inferior to continuing IV antibiotic therapy in the primary outcome of 30-day all-cause 
mortality, and 
2. Early oral step-down therapy will result in significantly lower health resource/service 
utilisation and associated costs compared with continuing IV therapy. 
 
2.2. 
Primary Objectives 
 
Compare the all-cause mortality at day 30 post-randomisation in patients from the standard arm 
versus intervention arm. 
 
2.3. 
Secondary Objectives 
 
              Compare between standard and intervention arms: 
1. All-cause mortality at days 14 and 90 from the time of randomisation  
2. Duration of survival from the time of randomisation until day 90 
3. Number of days on IV antibiotic therapy in the total index hospitalisation (including 
outpatient parenteral antibiotic therapy [OPAT]) for surviving participants from the time of 
randomisation until i. hospital discharge and ii. day 90  
4. Number of days alive and free of antibiotics (i. for all antibiotics and ii. for IV antibiotics) 
between the time of randomisation and day 90  
5. Adverse events from the time of randomisation until day 90 including:  
- 
C. difficile-associated diarrhoea  
- 
Peripherally inserted central catheter and other central venous catheter complications 
(such as catheter-related bloodstream infection, catheter-related superficial or deep 

INVEST Master Protocol, Version 10.0, Dated 09-Sep-2024 
Page 15 of 34 
venous thrombosis/thrombophlebitis, catheter blockage, and exit site infection) 
requiring line removal during index hospitalisation (including OPAT) from the time of 
randomisation 
- 
Liver function test abnormalities or acute kidney injury (defined in section 12.1) 
6. Change in treatment strategy (e.g. switch to IV antibiotics from allocated oral antibiotics or 
vice versa) between the time of randomisation and day 30 due to: 
- 
An adverse event deemed by the treating doctor to be of sufficient severity to change 
treatment strategy 
- 
Presumed lack of efficacy of treatment strategy according to the judgement of treating 
doctor 
7. Time to being discharged alive from the total index hospitalisation (including OPAT and 
hospital in the home) between the time of randomisation and day 90 (note: any death 
occurrence within 90 days will be considered ‘90 days’) 
8. Number of days alive and not in hospital (including OPAT) between the time of 
randomisation and day 90 
9. Readmission or extended hospitalisation by day 90. Readmission is defined as a new 
hospitalisation for any cause or a return to ambulatory hospital services occurring after 
discharge from the index hospitalisation. Extended hospitalisation is defined as >14 days of 
hospital LOS starting from the day of randomisation. 
10. Health economic evaluation, including estimation of total healthcare cost (from healthcare 
system and patient perspective)* and assessment of patient’s quality of life via EQ-5D by day 
90 
*Cost savings/effectiveness analyses will be performed in selected hospital sites 
 
Exploratory outcome 
Composite Desirability Of Outcome Ranking (DOOR) outcome comprising: 
- 
All-cause mortality at day 30 from the time of randomisation 
- 
Clinical failure as defined by one or more of the following related to the index infection:  
➢ Extended duration of active antibiotics beyond 7–14 days, depending on planned 
duration of original regimen 
➢ Addition of a rescue antibiotic including switching to an alternate, non-study 
antibiotic 
➢ Additional unplanned therapeutic interventions 
- 
Infectious complications as defined by one or more of the following related to the index 
infection: 
➢ Bloodstream relapse due to the same index Gram-negative bacteria (GNB) 
occurring any time between the completion of study drug intervention period 
and day 30 
➢ Distant seeding (i.e. growth of index GNB in a distant sterile site different from 
the original source of infection) occurring any time between completion of study 
drug intervention period and day 30 
➢ Local suppurative complication (e.g. renal abscess in pyelonephritis, empyema in 
pneumonia) that was not present at the time of randomisation and occurring any 
time between completion of study drug intervention period and day 30 
- 
Presence of adverse events or serious adverse events (SAEs) that lead to study drug 
discontinuation 
- 
Quality-of-life by functional status, calculated as change from baseline functional 
bacteraemia outcome score (measured on the day of randomisation) to functional 
bacteraemia outcome score measured on the last day of study drug treatment  

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Table 1. Functional bacteraemia outcome scoring system. 
7 
Out of hospital; basically healthy; able to complete daily activities and has no healthcare 
interaction* since discharge from the index hospitalisation in the last 7 days 
6 
Out of hospital; moderate signs or symptoms of disease; unable to complete daily activities OR 
has required 1-2 healthcare interactions* since discharge from the index hospitalisation over the 
last 7 days  
5 
Out of hospital; significant disability; requires a high level of care and assistance daily OR has 
required more than two healthcare interactions* since discharge from the index hospitalisation 
over the last 7 days 
4 
Hospitalised but not requiring ICU 
3 
Hospitalised in ICU 
2 
Accommodated in a long-term ventilator unit 
1 
On palliative care in terminal phases of life (in hospital or at home) 
0 
Dead 
*Healthcare interactions include home nursing visits, telehealth calls, emergency room visits and office 
visits 
 
Table 2. Composite DOOR scoring system. 
Rank 
Alive 
How many of: 
1) Clinical failure 
2) Infectious complications 
3) AEs or SAEs leading to study drug 
discontinuation  
Quality-of-life 
1 
Yes 
0 of 3 
Tiebreaker based on QoL 
functional bacteremia 
outcome score 
2 
Yes 
1 of 3 
3 
Yes 
2 of 3 
4 
Yes 
3 of 3 
5 
No 
Any 
Rank 1 – Alive without any of the following binary (yes/no) components: (1) evidence of clinical failure, 
(2) an infectious complication, or (3) any SAE or an AE leading to study drug discontinuation 
Rank 2 – Alive with one of the following binary (yes/no) components: (1) evidence of clinical failure, (2) 
an infectious complication, or (3) any SAE or an AE leading to study drug discontinuation 
Rank 3 – Alive with two of the following binary (yes/no) components: (1) evidence of clinical failure, (2) 
an infectious complication, or (3) any SAE or an AE leading to study drug discontinuation 
Rank 4 – Alive with all of the following binary (yes/no) components: (1) evidence of clinical failure, (2) an 
infectious complication, or (3) any SAE or an AE leading to study drug discontinuation 
Rank 5 – Death 
 
2.4. 
Potential Risks and Benefits:  
 
a. 
End Points - Efficacy 
Early switch to oral antibiotics (within 72 hours from the time of index blood culture collection) 
may be clinically non-inferior to continuing IV antibiotic therapy (for at least another 24 hours 
post-randomisation). The recommended treatment duration for both study arms is 7 days of 
active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 
days due to regimen extension or requirement for prolonged regimen as clinically indicated. The 
benefits of oral therapy over IV therapy include elimination of risk of catheter-associated 
adverse events, enhancement of patient’s quality of life, and reduction of healthcare associated 
costs. 
 

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b. 
End Points – Safety 
All the study drugs would be commonly used in clinical practice for Gram-negative pathogens. 
We will not be exposing participants to excess risk by study inclusion beyond the risks involved 
in standard therapeutic decisions and clinical management. The main risk for patients 
randomised to the intervention arm is that oral antibiotics may not be as efficacious compared 
with IV antibiotics for treatment of Gram-negative bacteraemia. In the event of microbiological 
or clinical failure of the oral antibiotic treatment, escalation to IV antibiotics may be initiated at 
the discretion of the treating doctor at any time point post-randomisation. Antibiotic escalation 
will not be considered a protocol deviation. 
 
3. 
STUDY POPULATION 
 
3.1. 
List the number of subjects to be enrolled  
A total of 720 participants will be enrolled in this study. Recruitment in Singapore will be carried 
out in Tan Tock Seng Hospital, National University Hospital, Singapore General Hospital, 
Changi General Hospital, Ng Teng Fong General Hospital and Sengkang General Hospital. 
Recruitment will also be carried out in several overseas sites in Australia (Royal Brisbane and 
Women’s Hospital, Gold Coast University Hospital, John Hunter Hospital, Royal Melbourne 
Hospital, Princess Alexandra Hospital), Malaysia (University Malaya Medical Centre, Hospital 
Universiti Kebangsaan Malaysia, Ampang Hospital, Sungai Buloh Hospital), South Korea 
(Samsung Medical Center, Seoul National University Bundang Hospital), United Kingdom 
(Imperial College Healthcare NHS Trust, London North West University Healthcare NHS 
Trust, Chelsea and Westminister NHS Foundation Trust Hospitals), Israel (Sheba Medical 
Centre, Rambam Hospital), Turkey (Medipol Mega University Hospital), Lebanon (American 
University of Beirut Medical Centre), Greece (University General Hospital of Patras), Spain 
(Hospital del Mar), Italy (IRCCS Policlinico di Sant’Orsola, University Alma Mater Studiorum, 
University Hospital of Pisa, IRCCS San Raffaele Hospital, Monaldi Hospital) and Taiwan 
(Taichung Veterans General Hospital).  
 
3.2. 
Criteria for Recruitment 
 
Potential study participants will be identified on the basis of positive blood cultures by liaison 
between the investigators and the clinical microbiologists. The following information will be 
transcribed into the screening log by a study team member at the time of referral: date and time 
the blood culture was collected, hospital record number, participant’s name and date of birth, 
and the date and time referral was received. No “cold-calling” will be performed. The 
investigator will only approach the patient or his/her legal representative on invitation by the 
treating team (who will also have been notified of the blood culture results by the clinical 
microbiologist). The treating team will have the rationale of the study explained to them by the 
study investigator(s) before any patient contact occurs. On invitation by the treating team, the 
patient will be approached by a study team member to evaluate suitability for inclusion (by 
review of medical records and discussion with treating team) and have the study explained to 
him/her and be offered an opportunity to be enrolled. This will only occur after written material 
has been provided, and the patient has had time to consider and ask questions to the study team 
or the treating team. Informed consent will be obtained prior to performing any research-related 
procedures. 
 

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3.3. 
Inclusion Criteria 
 
Inclusion criteria will be non-restrictive allowing a representative and generalisable cohort of 
eligible participants including elderly patients: 
1. 1 set of blood cultures positive for GNB associated with evidence of infection 
2. Able to be randomised within 72 hours of index blood culture collection 
3. Age ≥18 years (≥21 in Singapore) 
4. Latest Pitt bacteraemia score <4  
5. Patient or legal representative is able to provide informed consent 
 
3.4. 
Exclusion Criteria 
 
              Exclusion criteria include: 
1. Established uncontrolled focus of infection, including but not limited to:  
- 
Undrained abdominal abscess, deep seated intra-abdominal infection and other 
unresolved abdominal sources requiring surgical intervention  
- 
Central nervous system abscess (patients with focal neurology should have cranial CT 
prior to enrolment)  
- 
Undrained moderate-to-severe hydronephrosis 
2. Complicated infections, including but not limited to:  
- 
Necrotising fasciitis 
- 
Empyema 
- 
Central nervous system infections and meningitis  
- 
Endocarditis / endovascular infections 
3. Septic shock as defined by systolic blood pressure <90 or mean arterial pressure <70 mmHg 
despite adequate fluid resuscitation or need for inotropic/vasopressor support  
4. Polymicrobial bacteraemia involving Gram-positive pathogens or anaerobes (defined as 
either growth of 2 different microorganism species in the same blood culture, or growth of 
different species in 2 separate blood cultures within the same episode [<48 hours] and with 
clinical or microbiological evidence of the same source) 
5. Bacteraemia is due to a vascular catheter or intravascular materials (e.g. pacing wire, vascular 
graft) that cannot be removed 
6. Specific Gram-negative pathogens that cannot be effectively treated with fluoroquinolones 
or trimethoprim-sulfamethoxazole, including but not limited to, Burkholderia spp. and Brucella 
spp. 
7. Index GNB with resistance to fluoroquinolones AND trimethoprim-sulfamethoxazole 
8. Hypersensitivity to fluoroquinolones AND sulphur drugs as defined by history of rash, 
urticaria, angioedema, bronchospasm, circulatory collapse or significant adverse reaction 
following prior administration  
9. Unable to consume or absorb oral medications for any reason or unsuitable for ongoing IV 
therapy (e.g. no intravenous access)   
10. Severely immunocompromised in the opinion of the treating doctor, including but not 
limited to, medical conditions such as:  
- 
Active leukaemia or lymphoma  
- 
Aplastic anaemia  
- 
Bone marrow transplant within two years of transplantation or transplants of longer 
duration still on immunosuppressive drugs or with graft-versus-host disease 
- 
Congenital immunodeficiency  
- 
HIV/AIDS with CD4 lymphocyte count <200  

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- 
Neutropenia or expected post-chemotherapy neutropenia within 14 days from the time 
of screening, defined as absolute neutrophil count < 500 cells/μL 
11. Women who are known to be pregnant or breast-feeding 
12. Treatment is not with intent to cure the infection (i.e. palliative care) 
13. Unable to collect patient’s follow-up data for at least 30 days post-randomisation for any 
reason  
14. Treating doctor deems enrolment into the trial is not in the best interest of the patient  
15. Previous enrolment in this trial 
a. Withdrawal Criteria  
 
Subjects may voluntarily withdraw their consent from study participation at any time and for any 
reason without penalty. A subject may also be withdrawn from participation in the study for the 
following reasons: 
- 
Termination of study 
- 
Any new information becomes available that makes continuing participation unsafe  
 
Handling of withdrawals 
An early termination occurs when an enrolled subject withdraws consent to participate in the 
study, regardless of circumstances, prior to the primary outcome assessment at day 30. The 
reason(s) for early termination should be reflected in the source documentation and on the 
applicable CRF. In all cases, the reasons why a participant is withdrawn must be recorded in 
detail and entered into the CRF.  
  
b. Subject Replacement 
Patients who withdraw from the study will not be replaced. Patients whose randomised 
treatment is changed due to an adverse event or treatment failure or an unintentionally fulfilled 
exclusion criterion will remain in the study to assess outcomes and for safety analysis regardless 
of study arm allocation. 
 
4. 
TRIAL SCHEDULE 
 
Table 3. Trial schedule of study activities. 
Study activity 
Screening 
Antibiotic intervention 
Follow up 
As 
necessaryb 
-72 hours 
to Day 1 
Day 
1–7a  
Before 
hospital 
discharge 
End of 
treatment 
(window 
period: 3 
days) 
Day 
14  
(±3 
days) 
Day 
30  
(±3 
days) 
Day 
90  
(±3 
days) 
Check eligibility 
x 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
Charlson comorbidity 
index 
x 
 
 
 
 
 
 
 
Physical examination, 
complication screening (if 
suspected) 
x 
 
x 
 
 
 
 
x 
Randomisation 
 
x 
 
 
 
 
 
 
Study druga  
 
x 
 
 
 
 
 
 
Antibiotic historyc 
x 
 
 
xd 
 
xd 
xd 
 
Blood culturese 
 
 
 
 
 
 
 
x 
Full blood countf 
x 
 
x 
 
 
 
 
x 

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C-reactive protein 
x 
 
x 
 
 
 
 
x 
Renal & liver panelg 
x 
 
x 
 
 
 
 
x 
Adherence checkh  
 
 
 
xd 
 
 
 
 
Adverse event monitoringi 
 
x 
x 
xd 
xd,j 
xd,j 
xd,j 
 
Review mortality status  
 
 
 
 
xd 
xd 
xd 
 
Review for development 
of complications, relapse 
and distant seeding 
 
 
 
 
 
xd 
 
 
Review hospital admission 
and discharge summaries 
 
 
 
 
xd 
xd 
xd 
 
Review health service/ 
resource utilisation costk 
 
 
 
 
 
 
xd 
 
Quality-of-life survey 
x 
 
 
xd 
 
 
xd 
 
a – Recommended duration of active antibiotic treatment (including empiric therapy) is 7 days. Final day of study 
treatment may be as early as day 4 considering the 72 hours randomisation window, but will typically be between 
days 5 and 7. Regimen may be extended beyond 7 days if clinically indicated or treating doctor may prescribe a 
prolonged original regimen of >7 days according to his/her discretion.   
b – According to the discretion of clinician if participant is still an inpatient  
c – Document all antibiotics taken during this bacteraemia episode including empiric treatment, study drug and any 
additional antibiotics administered 
d – Via telephone interview or home visit by the study team if participant has been discharged and information 
cannot be obtained via medical records or administrative sources 
e – Blood cultures usually ordered if patient is febrile >38°C in the last 24 hours during bacteraemia episode or if 
previous blood cultures remain positive or if any secondary infection is suspected 
f – Full blood count includes white blood cells, neutrophils, platelets and haemoglobin 
g – Renal panel includes sodium, potassium and creatinine; liver panel include alanine transaminase, aspartate 
transaminase, alkaline phosphatase and total bilirubin 
h – Pill count for participants on oral therapy and documentation of IV antibiotics administered for participants on 
IV therapy; participant deemed compliant if 90% of prescribed study antibiotics taken 
i – Only adverse events deemed by the treating and/or study doctor to be related or possibly related to the study 
drug (from standard arm or intervention arm) will be documented in the CRF 
j  – Only targeted adverse events will be monitored during the follow-up time points, such as C. difficile-associated 
diarrhoea, catheter-related complications, and liver and kidney function test abnormalities  
k – Cost savings/effectiveness analyses will be performed in selected hospital sites  
 
5. 
STUDY DESIGN 
 
5.1. 
Summary of Study Design 
 
This study is designed as an international, multicentre, randomised controlled, open-label, phase 
IV, non-inferiority trial with a non-inferiority margin of 6%. Eligible participants must be 
clinically stable / non-critically ill inpatients over the age of 18 (21 in Singapore) with 
uncomplicated Gram-negative bacteraemia. Randomisation into the intervention or standard 
arms will be performed with a 1:1 allocation ratio. Participants randomised to the intervention 
arm (within 72 hours from the time of index blood culture collection) will be immediately 
converted to oral therapy. Participants randomised to the standard arm should continue to 
receive IV therapy for at least 24 hours post-randomisation before clinical re-assessment and 
decision making by the treating doctor. At the doctor’s discretion, patients in the standard arm 
may be converted to oral antibiotic therapy (after continuing the IV therapy for at least 24 hours 
post-randomisation). This data on oral antibiotic switch for patients in the standard arm will be 
recorded in the CRF. All study drugs (and dosage) would be those routinely used in clinical 
practice and will be ordered/dispensed from the hospital pharmacy as per site institutional 
practice. The recommended treatment duration is 7 days of active antibiotics (including empiric 
therapy), although treatment regimen may be longer than 7 days due to regimen extension or 

INVEST Master Protocol, Version 10.0, Dated 09-Sep-2024 
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requirement for prolonged regimen as clinically indicated. Participants may be discharged home 
or to OPAT at any time post-randomisation according to the discretion of the treating doctor. 
At day 30 post-randomisation, participants will be assessed for the primary outcome of all-cause 
mortality. The key secondary outcome is health economic evaluation including estimation of 
total healthcare cost (from healthcare system and patient perspective) to determine the economic 
impact of early oral step-down therapy. Health services/resource utilisation and related cost data 
over the entire duration of the study will be collected from medical records or administrative 
sources whenever possible. A health outcome analysis will be conducted to assess patients’ 
quality of life and the number of quality adjusted life years saved.  
 
6. 
METHODS AND ASSESSMENTS 
 
6.1. 
Randomisation and Blinding 
 
Randomisation may occur if eligibility criteria have been met and informed consent has been 
obtained. Participants will be randomly assigned to either standard or intervention arms in a 1:1 
ratio according to a randomisation list prepared in advance using a secure online randomisation 
system hosted by Singapore Clinical Research Institute. Randomisation will be stratified by 
country (Singapore, Australia, Malaysia, South Korea, United Kingdom, Israel, Turkey, Lebanon, 
Greece, Spain, Italy and Taiwan) to ensure balance between study arms across countries. 
Random sequence will be generated using random permuted blocks of unequal length. The day 
of randomisation is considered day 1 of treatment and the last dose of study drug to be given for 
the day is the dose next due prior to 23:59 hr (i.e. the last scheduled dose prior to midnight). As 
the drugs in the standard and intervention arms have different routes of administration, this will 
be an open-label study. 
  
6.2. 
Contraception and Pregnancy Testing 
 
Women who are known to pregnant will not be enrolled into the study. As the intervention 
period is short (typically 4–7 days) and occurring during a hospital admission, it is not anticipated 
that contraceptive advice is relevant. 
 
6.3. 
Study Visits and Procedures 
 
a. 
Screening Visits and Procedures 
 
The screening visit will include:  
- 
Eligibility assessment (including a urine pregnancy test if applicable) 
- 
Written informed consent  
- 
Documentation of demographics  
- 
Documentation of Charlson comorbidity index and antibiotic history since admission  
- 
Vital signs measurement and physical examination, such as measurement of blood pressure 
and heart rate as well as cardiovascular, respiratory and abdominal examination  
- 
Radiographic findings (if any) 
- 
Baseline blood tests including full blood count (FBC; white blood cells, neutrophils, 
platelets, haemoglobin), C-reactive protein (CRP), renal panel (sodium, potassium, 
creatinine) and liver panel (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], total bilirubin [TBL])  
- 
Blood culture results and antibiotic sensitivities of bacteraemia isolate 

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- 
EQ-5D quality-of-life survey  
 
Screening for metastatic complications will be undertaken if symptoms or examination findings 
are suggestive. Randomisation must be achieved within 72 hours of the positive blood culture 
collection.  
 
b. 
Study Visits and Procedures 
 
If participant is randomised to intervention arm, the first dose of the oral antibiotic will be 
administered by the ward nursing staff, and the participant may either remain as inpatient or be 
discharged to home. If participant is randomised to standard arm, administration of the IV ‘best 
available treatment’ antibiotic should continue for at least 24 hours post-randomisation, which 
may be done as inpatient or in OPAT. The recommended treatment duration for both study 
arms is 7 days of active antibiotics (including empiric therapy), although treatment regimen may 
be longer than 7 days due to regimen extension or requirement for prolonged regimen as 
clinically indicated. Participants will be monitored by the clinical team in the hospital as per 
institutional practice until discharged, which typically entails standardised clinical assessments 
such as adverse event monitoring, physical examination, and complication screening (if 
suspected). Blood cultures may be repeated on any day during the study period according to the 
discretion of the treating doctor to ensure clearance of bacteraemia especially if there is 
persistent fever or if previous blood cultures remain positive or if any secondary infection is 
suspected.  
 
Before a participant is discharged from hospital, the standardised clinical assessments (physical 
examination, review of adverse events, complication screening [at treating doctor’s discretion]) 
and blood tests (FBC, CRP, renal and liver panels) should be performed again. 
 
At the end of study drug treatment (window period: 3 days), the study team will: 
- 
Check for adherence to treatment regimen (pill count for participants in intervention arm 
and documentation of IV antibiotics administered for participants in standard arm)  
- 
Review and document all antibiotics taken as well as adverse events experienced since 
randomisation  
- 
Request for completion of the quality-of-life survey  
 
The above study procedures may be conducted via telephone interview or home visit by the 
study team if participant has been discharged from hospital and information cannot be obtained 
from medical records or administrative sources.  
 
On day 14 (±3 days) and/or day 30 (±3 days), the study team will review and document: 
- 
Mortality status of the participant (days 14 and 30) 
- 
Specific adverse event occurrence, if any, since the last study review (days 14 and 30) 
- 
Development of complications, relapse and distant seeding (day 30) 
- 
Hospital admission and discharge summaries (days 14 and 30) 
- 
Any antibiotics taken since the end of the study drug treatment regimen (day 30) 
 
The above procedures may be conducted via telephone interview or home visit by the study 
team if participant has been discharged from hospital and information cannot be obtained from 
medical records or administrative sources. 
 

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c. 
Final Study Visit: 
 
On day 90 (±3 days), the study team will review and document: 
- 
Mortality status of the participant 
- 
Specific adverse event occurrence, if any, since the last study review 
- 
Any antibiotics taken since the last study review 
- 
Hospital admission and discharge summaries since the last study review   
- 
Health services/resource utilisation and related cost data for the entire study duration 
(applicable only to selected hospital sites) 
 
On day 90 (±3 days), the study team will also request for completion of the quality-of-life survey 
by the participant. The above procedures may be conducted via telephone interview or home 
visit by the study team if participant has been discharged from hospital and information cannot 
be obtained from medical records or administrative sources. 
 
d. 
Post Study Follow up and Procedures 
 
There is no requirement for post study follow-up or procedures. 
 
e. 
Discontinuation Visit and Procedures 
 
Participants or legal representatives have the right to choose to withdraw from the study at any 
time. The investigator may also discontinue a participant from the study or from treatment if 
deemed appropriate. The decision to withdraw a participant from the study must be discussed 
with the coordinating investigators. If a participant withdraws consent from study participation 
and withdraws consent for collection of future information, no further evaluations will be 
performed and no additional data will be collected. The study team may retain and continue to 
use any data or samples collected before such withdrawal of consent. Participants who abscond 
will continue to be followed, if possible, until the end of the trial to avoid missing data. 
Participants withdrawn from the treatment by the treating or study doctors will continue to be 
followed up to the end of the trial to avoid missing data and will be used in the analysis if they 
satisfy the analysis population definitions. Withdrawn participants will not be replaced. If a 
participant is withdrawn, the reason will be recorded in the database and source documents. 
Participants who deviate from intervention protocols, including premature discontinuation of 
study related antibiotic therapy, will continue to have primary and secondary endpoint 
assessments for analysis.  
 
f. 
Laboratory studies 
 
An aliquot of the initial index blood culture isolate (as a suspension of pure bacterial colonies) 
will be stored at -80°C in glycerol and nutrient broth or in Microbank™ at each hospital site 
microbiology laboratory as per standard practice. These bacterial isolates may be retrieved later 
for confirmatory susceptibility testing and genetic analysis for mechanisms of resistance. Any 
subsequent Gram-negative bacteraemia isolates that show resistance to the randomised antibiotic 
can be stored at the discretion of the site PI and microbiology laboratory, but is not mandated in 
the protocol. 

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Page 24 of 34 
 
7. 
TRIAL MATERIALS 
 
7.1. 
Trial Product (s) 
 
The oral antibiotic options in the intervention arm are fluoroquinolones (most commonly, 
ciprofloxacin) or trimethoprim-sulfamethoxazole. They will be administered from each site’s 
pharmacy. Patients on ciprofloxacin may not take concomitant drugs that can cause 
prolongation of QT interval (e.g. class IA or class III antiarrhythmics) on a case-by-case basis 
determined by the site doctors who will make the final decision as per their clinical discretion. 
The IV antibiotic options in the standard arm will be determined by the treating doctor at the 
study site based on their assessment of the ‘best available treatment’ (e.g. ceftriaxone, cefazolin, 
meropenem) for the Gram-negative bacteraemia episode. All the study drugs are routinely used 
in clinical practice and will be ordered/dispensed from the hospital pharmacy as per site 
institutional practice.  
 
There is considerable variation in clinical practice with regard to the total antibiotic duration and 
more specifically the duration of IV therapy for Gram-negative bacteraemia. Recent data from 
RCTs and a propensity score-matched retrospective study support the adoption of shorter 
course (approximately 7 days of active antibiotics counting from the day of index blood culture 
collection) therapy for uncomplicated Gram-negative bacteraemia.20–22 The recommended 
treatment duration is 7 days of active antibiotics (including empiric therapy), although treatment 
regimen may be longer than 7 days due to regimen extension or requirement for prolonged 
regimen as clinically indicated. 
 
7.2. 
Storage and Drug Accountability 
 
All the study drugs will be stored and administered in accordance with standard pharmacy 
procedures. Storage conditions, temperature monitoring and accountability of the study drugs 
will be as per hospital pharmacy policy. 
 
8. 
TREATMENT 
 
8.1. 
Rationale for Selection of Dose  
 
The dosage, frequency and administration of study drugs for patients in the standard arm will be 
determined by the treating doctor according to their hospital site’s clinical practice as well as 
consideration of patient’s renal function. 
 
The recommended doses of oral antibiotics to be used in the intervention arm would be 
ciprofloxacin 750 mg twice daily (if body weight ≥70 kg) or ciprofloxacin 500 mg twice daily (if 
body weight <70 kg) or trimethoprim-sulfamethoxazole 5 mg/kg (for trimethoprim component) 
every 12 hours up to a maximum trimethoprim-sulfamethoxazole (160 mg / 800 mg; double 
strength) two tablets twice daily. Doses may be adjusted in the setting of renal dysfunction 
according to the recommendations in Tables 2, 3 and 4. 
 
Table 2. Recommended starting and maintenance doses of ciprofloxacin for patients with 
impaired renal function. 

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Creatinine clearance (mL/min) 
Dose of ciprofloxacin 
>50 
750 mg every 12 hours (for patients <70 kg, dose at 500 
mg every 12 hours) 
30–50  
500 mg every 12 hours 
5–29  
500 mg every 24 hours  
Haemodialysis or peritoneal dialysis 
500 mg every 24 hours (after dialysis) 
 
Table 3. Recommended starting and maintenance doses of trimethoprim-sulfamethoxazole for 
patients with impaired renal function (weight based adjustments). 
Creatinine clearance (mL/min) 
Dose of trimethoprim-sulfamethoxazole 
>30 
5 mg/kg (for trimethoprim component) every 12 hours 
15–30  
2.5 mg/kg every 12 hours 
<15 
2.5 mg/kg every 24 hours 
Haemodialysis or peritoneal dialysis 
2.5 mg/kg every 24 hours (after dialysis) 
 
Table 4. Recommended starting and maintenance doses of trimethoprim-sulfamethoxazole for 
patients with impaired renal function (tablet based adjustments). 
Creatinine 
clearance 
(mL/min) 
If usual 
recommended 
dose is 2 SSa 
tablets (1 DSb 
tablet) every 24 
hours or 3 times 
per week 
If usual 
recommended 
dose is 2 SS tablets 
(1 DS tablet) every 
12 hours 
If usual 
recommended 
dose is 4 SS tablets 
(2 DS tablets) 
every 12 hours 
If usual 
recommended 
dose is 4 SS tablets 
(2 DS tablets) 
every 8 hours 
>30 
No dose 
adjustment  
No dose 
adjustment  
No dose 
adjustment  
No dose 
adjustment  
15–30  
Reduce dose to 
~50% of usual 
dose. 
 
Example: 1 SS 
tablet every 24 
hours or 3 times 
per week 
Reduce dose to 
~50% of usual 
dose. 
 
Example: 2 SS 
tablets once, 
followed by 1 SS 
tablet every 12 
hours 
Reduce dose to 
~50% of usual 
dose. 
 
Example: 2 SS 
tablets every 12 
hours 
Reduce dose to 
~50% of usual 
dose. 
 
Example: 3 SS 
tablets every 12 
hours 
<15 
Reduce dose to 
~25 to 50% of 
usual dose. Use 
with caution and 
appropriate 
monitoring. 
 
Example: 1 SS 
tablet every 24 
hours or 3 times 
per week 
Reduce dose to 
~25 to 50% of 
usual dose. Use 
with caution and 
appropriate 
monitoring. 
 
Example: 2 SS 
tablets once, 
followed by 1 SS 
tablet every 12 or 
Reduce dose to 
~25 to 50% of 
usual dose. Use 
with caution and 
appropriate 
monitoring. 
 
Example: 2 SS 
tablets every 12 
hours OR 2 SS 
tablets once, 
Reduce dose to 
~25 to 50% of 
usual dose. Use 
with caution and 
appropriate 
monitoring. 
 
Example: 3 SS 
tablets every 12 
hours or 24 hours 

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24 hours 
followed by 1 SS 
tablet every 12 
hours 
a Abbreviation: SS, single strength (trimethoprim-sulfamethoxazole 80 mg / 400 mg) 
b Abbreviation: DS, double strength (trimethoprim-sulfamethoxazole 160 mg / 800 mg)  
 
 
8.2. 
Study Drug Formulations 
 
Study drugs in the standard arm will be administered intravenously while study drugs in the 
intervention arm will be administered orally. 
 
8.3. 
Study Drug Administration 
 
Patients randomised to the standard arm will receive an IV antibiotic deemed to be the ‘best 
available treatment’ by the treating doctor. Patients randomised to the intervention arm will 
receive either oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-
sulfamethoxazole. The participant’s drug charts (electronic and/or paper) will be reviewed for 
compliance with study treatment. Any missed dose(s) and non-study drugs administered will be 
recorded in the CRF. 
 
8.4. 
Specific Restrictions / Requirements  
 
Patients on ciprofloxacin may not take concomitant drugs that can cause prolongation of QT 
interval (e.g. class IA or class III antiarrhythmics) on a case-by-case basis determined by the site 
doctors who will make the final decision as per their clinical discretion. 
 
8.5. 
Blinding 
 
This will be an open-label study as the drugs in the standard and intervention arms have 
different routes of administration. 
 
8.6. 
Concomitant therapy 
 
Concomitant antibiotics taken by the participant will be documented in the CRF. 
 
8.7. 
Safety Monitoring Plan 
 
A Data and Safety Monitoring Board (DSMB) comprising two independent ID doctors and an 
independent statistician will be established prior to commencing the study. An interim analysis, 
including efficacy and safety endpoints, will be performed after the first 50, 100 and 350 subjects 
have completed the 90-day study period or as determined by DSMB. A DSMB Charter detailing 
the required interim analysis will be prepared at the beginning of the trial. If there is a significant 
safety concern raised or the observed difference in proportion of patients reaching the primary 
endpoint exceeds the non-inferiority margin of 6%, the DSMB may recommend the trial should 
be stopped. The timing of additional interim analyses will be determined by the DSMB. 
 
8.8. 
Complaint Handling 

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Complaints may be made to the PI or approving institutional review board (IRB) / ethics 
committee (EC). Complaints will be handled according to the normal procedures in operation at 
the recruiting hospital. 
 
9. 
DATA ANALYSIS 
 
9.1. 
Data Quality Assurance 
 
Clinical record forms will be monitored by an independent monitoring team to ensure data 
quality and accuracy. In addition, the study may be audited by regulatory authorities who must 
be allowed access to CRF, source documents and other study files. 
 
9.2. 
Data Entry and Storage 
 
A trial database using the REDCap data management system will be developed with a secured 
web hosting facility. The CRF will collect clinical and laboratory related information, and will 
contain validation ranges for each variable to minimise data entry errors. The database will 
include information on demographics, underlying illnesses, antibiotic history, baseline and 
follow-up laboratory data including microbiologic data, and assessments of vital signs and 
adverse events for the purpose of clinical outcome assessment. Data on hospital admission and 
discharge summaries will also be recorded. Source of bacteraemia, if known, will be noted. Trial 
data will be stored in a re-identifiable manner in the database using a unique screening number 
for each participant. For each potential participant screened (even those who are not eligible), 
the screening CRF will be completed by the site PI or their delegate. For each participant 
enrolled, CRF must be completed. This also applies to records for those participants who fail to 
complete the study. The site PI should ensure the accuracy, completeness and timeliness of the 
data entered into the CRF and in all required reports. A comprehensive validation check 
program will verify the data and automatically generate discrepancies for resolution by the 
investigator. Manual discrepancies can also be raised if necessary. 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 data 
management team and monitor) and will be resolved prior to database lock and analysis. An 
audit trail will be maintained for tracking purposes. The Clinical Study Report(s) and all analyses 
performed as well as the final data set will be archived together according to standard operating 
procedures.  
 
10. 
SAMPLE SIZE AND STATISTICAL METHODS 
 
10.1. Determination of Sample Size  
 
In a recent RCT comparing 7 days versus 14 days of antibiotic therapy for uncomplicated Gram-
negative bacteraemia, 30-day all-cause mortality occurred in 4.9% of patients in the 7-day 
duration arm and 4.4% of patients in the 14-day duration arm.21 In a recent retrospective 
multicentre study of propensity score-matched cohort with monomicrobial Enterobacterales 
bacteraemia, 30-day all-cause mortality was 13.1% for patients who received early oral step-down 
therapy and 13.4% for those who continued to receive IV therapy.7 Accurate estimation of 
mortality (for this study) is complicated by significant variability in reported mortality of past 

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studies – likely influenced by geography and isolate resistance phenotype. We assumed 30-day 
mortality of 8% in the standard and intervention arms of this study – determined as the 
approximate mid-range from the two aforementioned studies.7,21 With a 6% non-inferiority 
margin, a total of 720 patients are needed to achieve 80% power with a one-sided 0.025 -level 
after adjustment for 5% drop-out. Based on an expected mortality of 80% under a hypothetical 
situation where bacteraemic patients received no antibiotic treatment,23,24 the standard arm 
treatment would have reduced mortality by 72% (from 80% to 8%). The pre-specified, 6% non-
inferiority margin requires a 30-day mortality of ≤14% in the intervention arm, which preserves 
more than 90% of the 72% treatment effect of standard arm treatment to conclude non-
inferiority. This is in accordance with requirements by U.S. FDA on non-inferiority margin to 
maintain at least 50% of treatment effect of the standard treatment. 
 
10.2. Statistical and Analytical Plans 
 
The primary analysis for this study will be performed on the modified intention-to-treat (mITT) 
population, which consists of all randomised patients excluding (i) those who did not have 30-
day all-cause mortality data, (ii) intervention arm patients who did not receive any oral 
fluoroquinolones or oral trimethoprim-sulfamethoxazole post-randomisation, and (iii) standard 
arm patients who did not receive any IV antibiotics post-randomisation. Risk difference of 30-
day all-cause mortality and its 95% confidence interval between intervention and standard arms 
will be estimated and compared using chi-squared test. If the upper limit of the 95% confidence 
interval falls below the 6% non-inferiority margin, non-inferiority will be concluded for early oral 
step-down therapy relative to continuing IV therapy. As a special case of non-inferiority, if the 
upper limit of the 95% confidence interval falls below zero, superiority will be declared for early 
oral step-down therapy. Supportive analysis of the primary endpoint will be performed with the 
per-protocol population, which consists of patients included in the mITT population excluding 
those with major protocol deviation that may significantly affect the primary endpoint. The 
following will be considered as major protocol deviations:  
 
1. 
Administration of at least one dose of incorrect drug; 
2. 
Study drug compliance of below 90%; 
3. 
Randomisation of ineligible participant 
 
As sensitivity analysis, the primary outcome will also be analysed on the intention-to-treat (ITT) 
population if there is a difference of least 5% between the ITT population size and the mITT 
population size. In the ITT population analysis, any subjects who are missing mortality data at 
any time point will be considered alive at that particular time point. 
 
Superiority of early oral step-down therapy over continuing IV therapy will be evaluated with 
respect to outcomes such as LOS in hospital, as well as infection and health economic outcomes. 
Secondary outcome measures expressed as proportions will be compared between intervention 
and standard arms 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 
interval scale, and comparison between study arms will be done using a two-sample t-test. 
 
Subgroup analysis of the primary endpoint will also be performed as part of exploratory analysis 
although the study power in subgroups may be low. The subgroups include a) countries grouped 
by region, b) age group (< 70 years, ≥ 70 years), c) gender (female, male), d) source of 

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bacteraemia at baseline (UTI, non-UTI), e) bacteraemia isolate at baseline (Escherichia coli, 
Klebsiella spp, others), f) empiric therapy effectiveness (effective, not effective, unknown 
effectiveness), and g) resistance of index Gram-negative bacteria (multidrug-resistant, non-
multidrug-resistance, unknown). The definitions of multidrug resistance are below. 
• Extended-spectrum beta-lactamase (ESBL) or AmpC producing Enterobacterales isolates 
are considered multidrug-resistant. Enterobacterales demonstrating resistance to oxyimino-
beta-lactam substrates (cefotaxime and ceftazidime) are also considered multidrug-
resistant as they are likely to be ESBL or AmpC positive. 
• Pseudomonas spp. isolates resistant to ≥3 of the following antimicrobial agents are 
considered 
multidrug-resistant: 
antipseudomonal 
penicillins 
(e.g. 
piperacillin), 
antipseudomonal 
cephalosporins 
(e.g. 
ceftazidime), 
fluoroquinolones 
(e.g. 
ciprofloxacin), carbapenems (e.g. imipenem, meropenem) and aminoglycosides. 
• Acinetobacter spp. isolates resistant to ≥3 of the following antimicrobial agents are 
considered multidrug-resistant: imipenem (or meropenem), levofloxacin (or other 
fluoroquinolones), ceftazidime, colistin, tobramycin (or other aminoglycosides) and 
piperacillin–tazobactam. 
 
In addition to exploring the efficacy and safety of early oral step-down therapy, this study will 
also analyse the economic viability of the proposed approach through a health economic 
evaluation according to ITT principle from healthcare system as well as patient perspectives. For 
base case analysis, private rate of each resource utilisation will be applied to calculate the average 
cost and savings. The health economic analysis will have two components: 
1. If the RCT results confirm the non-inferiority of early oral step-down therapy relative to 
continuing IV therapy, a cost saving analysis will be conducted to estimate the economic 
impact of the new treatment regimen; 
2. If the RCT results fail to confirm the non-inferiority, a cost effectiveness analysis will be 
conducted to estimate the incremental cost effectiveness ratio (ICER) by comparing the 
difference in cost and clinical outcomes as well as quality-of-life between the two treatment 
arms (ICER=∆C/∆E). 
 
To address possible variations in patient medical conditions and outcomes, a series of one-way 
sensitivity analyses will be conducted to address the potential impact of each parameter 
uncertainty and assess the robustness of study estimations for generalisability. Based on the 
sensitivity analysis, tornado plot will be generated to assess how much influence each of the 
variables have on the overall model. Additionally, probabilistic sensitivity analysis using the 
Monte Carlo simulation will be performed.  Simulated results will be plotted in the cost-
effectiveness plane to present the distribution of cost-effectiveness ratios.  Cost-effectiveness 
acceptability curves will be generated to assess the probability variations of accepting each 
strategy by changing the threshold of willingness-to-pay. 
 
 
11. 
ETHICAL CONSIDERATIONS 
 
11.1. Informed Consent 
 
The site PI is responsible for obtaining IRB/EC approval for the protocol, and ensuring the 
participant information sheet and informed consent form (ICF) are in compliance with local 
regulatory requirements prior to enrolling any participant into the study. The approval 
letter/document must clearly identify the protocol and all documents approved by the IRB/EC. 

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These include the version number and date of the protocol as well as the version number and 
date of the participant information sheet and ICF. The site PI must also obtain approval for any 
amendments to the protocol or participant information sheet and ICF. The site PI must comply 
with all IRB/EC and regulatory reporting requirements for adverse events, study status updates, 
end of study reports, and must agree to abide by any IRB/EC conditions of approval. The site 
PI (or designee) is responsible for ensuring freely given consent by each potential participant 
prior to the conduct of any protocol-specific procedures. The site PI may delegate the task of 
obtaining consent to appropriately qualified co-investigator(s). Consent must be documented by 
the participant’s dated signature on the participant information sheet and ICF together with the 
dated signature of the person conducting the consent discussion. 
 
If the participant is illiterate or a translator is required, an impartial witness should be present 
during the entire consent discussion. Once the discussion is complete, the participant must sign 
and date the ICF, if capable. The impartial witness must also sign and date the ICF along with 
the person who conducts the consent discussion. If the participant does not have the capacity to 
consent, the written consent from a legal representative must be obtained. Capacity to consent 
should be assessed using the same process that is used when assessing consent capacity for 
treatment in the general hospital setting. This will take into account any potential legal authorities 
already in place and the patient’s baseline presentation. Capacity will be assessed in consultation 
with the treating team and the family if applicable. The investigator responsible for the consent 
process is responsible for ensuring the participant has the capacity to consent.  
 
A copy of the signed and dated participant information sheet and ICF must be given to the 
participant prior to study participation. The participant or his/her legal representative must be 
informed in a timely manner of any new information that becomes available during the course of 
the study that may affect his/her willingness to continue study participation. 
 
This study shall be conducted in accordance with the ethical principles laid out in the 
Declaration of Helsinki (most current issued version) and the National Statement on Ethical 
Conduct in Research Involving Humans (most current issued version). 
 
12. 
SAFETY MEASUREMENTS 
 
12.1. Definitions 
 
An adverse event is defined in the ICH-GCP as “any untoward medical occurrence in a patient 
or clinical investigation subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment.” 
 
An elective procedure not reflecting a worsening of a known underlying medical condition is not 
considered an adverse event, and therefore will not be considered an SAE despite requiring 
hospitalisation. However, complications of a procedure will be considered an adverse event and 
may be considered an SAE if hospitalisation is prolonged (or any other SAE criteria is met). A 
hospitalisation or prolongation of a hospitalisation for reasons other than an adverse event 
would not be considered an SAE. 
 
Adverse events include any occurrences that are new in onset or aggravated in severity or 
frequency from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. Concurrent medical conditions present at baseline that worsen will 

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be considered as adverse events. Lack of efficacy, aggravation, or relapse of current infection are 
not an adverse event in the study and therefore also not an SAE (except death). 
 
Events will be reviewed and classified by the site PI. The relationship of the event to the study 
drug and whether the event is an expected event or not will be assessed using the listing of 
adverse effects contained in the summary of product characteristics for the antibiotics used. 
 
The treating team has the primary responsibility for reviewing laboratory test results and 
determining whether an abnormal value in an individual study participant requires action. In 
general, abnormal laboratory results without clinical significance (based on clinical judgment) 
should not be recorded as adverse events. However, laboratory value changes requiring therapy 
or adjustment in prior therapy are considered adverse.  The investigators should liaise closely 
with the treating teams and remain aware of any such adverse events. 
 
SAE are defined as an adverse event that: 
• is fatal 
• 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 
• other significant medical hazard 
 
For criteria "AST or ALT > 3 × ULN and TBL > 2 × ULN or prothrombin time and 
international normalised ratio (PT-INR) > 1.5, if PT-INR measured (potential Hy’s law)", the 
case must be reported as an SAE (if baseline AST or ALT is ≤ ULN). If baseline AST or ALT is 
> ULN, the case that meets the following criteria must be reported as an SAE. AST or ALT > 3 
× increase from baseline AST or ALT and TBL > 2 × increase from baseline TBL. 
The following criteria will be used when assessing kidney injury: 
- 
Grade 1: Creatinine > 1.5 to 2× baseline and < 350 μmol/L 
- 
Grade 2: Creatinine > 2 to 3× baseline and < 350 μmol/L 
- 
Grade 3: Creatinine > 3× baseline and/or > 350 μmol/L 
- 
Grade 4: Dialysis (if previously not on dialysis) 
 
Death within 30 days from time of randomisation is the primary outcome measure of the study, 
and death within 14 and 90 days are the secondary outcome measures. Given the variability of 
mortality associated with Gram-negative bacteraemia (approximately 5–12%), death itself cannot 
be considered an ‘unanticipated’ event. 
 
If any member of the trial team becomes aware of an unexpected death or SAE at any stage of 
the trial, the PI will be alerted. The PI should report all deaths and relevant SAEs as appropriate 
to their local regulatory authority, and all deaths and adverse events that are related or possibly 
related to the study treatment will be recorded and reported in the final analysis. Unforeseen 
adverse events will be discussed with collaborating investigators at other centres; such 
information will be reviewed by regular teleconference. 
 
12.2. Collecting, Recording and Reporting of “Unanticipated Problems Involving 
Risk to Subjects or Others” – UPIRTSO events to the National Healthcare 
Group (NHG) Domain Specific Review Board (DSRB) 
 

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UPIRTSO events and SAEs are defined below. Events will be reviewed and classified by the site 
PI or other investigator. Severity will be classified using a standard set of criteria for grading 
adverse events (Common Terminology Criteria for Adverse Events version 5.0). The 
relationship of the event to the study drug and whether the event is an expected event or not will 
be assessed using the listing of adverse effects contained in the summary of product 
characteristics for the antibiotics used. 
 
Any events that are unexpected (in terms of severity or frequency), that can reasonably be 
attributed to the drug under study and that may expose other subjects to harm will be reported.   
UPIRTSO events refers to problems, in general, to include any incident, experience, or outcome 
(including adverse events) that meets ALL of the following criteria: 
 
Unexpected 
In terms of nature, severity or frequency of the problem as described in the study 
documentation (e.g. Protocol, Consent documents, etc). 
 
Related or possibly related to participation in the research 
Possibly related means there is a reasonable possibility that the problem may have been caused 
by the procedures involved in the research; and  
 
Risk of harm 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognised. 
 
Reporting Timeline for UPIRTSO Events to the NHG DSRB: 
 
Urgent Reporting: All problems involving local deaths, whether related or not, should be 
reported immediately – within 24 hours after first knowledge by the local PI. 
 
Expedited Reporting: All other problems must be reported as soon as possible but not later 
than 7 calendar days after first knowledge by the local investigator 
 
12.3. Collecting, Recording and Reporting of Serious Adverse Events (SAEs) to 
the Health Science Authority (HSA) 
 
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life-threatening 
and/or result in death or hospitalisation. However, if it is determined that the event may 
jeopardise the subject and/or may require intervention to prevent one of the other adverse event 
outcomes, the important medical event should be reported as serious. All SAEs that are 
unexpected and related to the study drug will be reported to HSA. The investigator will be 
responsible for informing HSA no later than 15 calendar days after first knowledge that the case 
qualifies for expedited reporting. Follow up information will be actively sought and submitted as 
it becomes available. For fatal or life-threatening cases, HSA will be notified as soon as possible 
but no later than 7 calendar days after first knowledge that a case qualifies, followed by a 
complete report within 8 additional calendar days. 
 
12.4. IRB Review 
 

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All relevant documents will be approved by the National Healthcare Group (NHG) Domain 
Specific Review Board (DSRB) before trial initiation in Singapore (or the respective IRB/EC for 
the other international participating sites). 
 
12.5. Confidentiality of Data and Patient Records 
 
All study findings and documents will be regarded as confidential. The site PIs, co-investigators 
and other study personnel must not disclose such information without prior written approval 
from the chief PI. Subject confidentiality will be strictly maintained to the extent possible under 
the law and local hospital policy. Identifiable information will be removed from any published 
data. 
 
13. 
PUBLICATIONS 
 
The data obtained from all participating sites will be pooled and analysed together as soon as 
possible after trial completion. Individual researchers will not publish data from the trial until the 
main study publication has been released. The trial steering committee will form the main writing 
committee. 
 
14. 
RENTENTION OF TRIAL DOCUMENTS 
 
The PI will keep any records, study files or source documentation for a minimum of 6 years after 
the completion of the trial before being destroyed or erased. These documents may be retained 
for a longer period if required by the applicable regulatory requirements or institutional policy. 
 
15. 
REFERENCES 
 
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European Antimicrobial Resistance Surveillance System. Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. 
Microbiol. Infect. Dis. 19, 860–868 (2013). 
2. Laupland, K. B. Incidence of bloodstream infection: a review of population-based studies. Clin. 
Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 19, 492–500 (2013). 
3. Mermel, L. A. et al. Clinical practice guidelines for the diagnosis and management of intravascular 
catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 
Off. Publ. Infect. Dis. Soc. Am. 49, 1–45 (2009). 
4. Rieger, K. L. et al. Intravenous-only or Intravenous Transitioned to Oral Antimicrobials for 
Enterobacteriaceae-Associated Bacteremic Urinary Tract Infection. Pharmacotherapy 37, 1479–1483 
(2017). 
5. Talan, D. A. et al. Comparison of Ciprofloxacin (7 Days) and Trimethoprim-Sulfamethoxazole (14 
Days) for Acute Uncomplicated Pyelonephritis in Women: A Randomized Trial. JAMA 283, 1583 
(2000). 
6. Talan, D. A. et al. Once daily, extended release ciprofloxacin for complicated urinary tract infections 
and acute uncomplicated pyelonephritis. J. Urol. 171, 734–739 (2004). 
7. Tamma, P. D. et al. Association of 30-Day Mortality With Oral Step-Down vs Continued Intravenous 
Therapy in Patients Hospitalized With Enterobacteriaceae Bacteremia. JAMA Intern. Med. (2019) 
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8. Keller, S. C., Dzintars, K., Gorski, L. A., Williams, D. & Cosgrove, S. E. Antimicrobial Agents and 
Catheter Complications in Outpatient Parenteral Antimicrobial Therapy. Pharmacotherapy 38, 476–481 
(2018). 

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9. Keller, S. C. et al. Rates of and Risk Factors for Adverse Drug Events in Outpatient Parenteral 
Antimicrobial Therapy. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 66, 11–19 (2018). 
10. 
Lau, B. D., Pinto, B. L., Thiemann, D. R. & Lehmann, C. U. Budget impact analysis of 
conversion from intravenous to oral medication when clinically eligible for oral intake. Clin. Ther. 33, 
1792–1796 (2011). 
11. 
Béïque, L. & Zvonar, R. Addressing Concerns about Changing the Route of Antimicrobial 
Administration from Intravenous to Oral in Adult Inpatients. Can. J. Hosp. Pharm. 68, 318–326 (2015). 
12. 
Chui, D., Cheng, L. & Tejani, A. M. Clinical Equivalency of Ciprofloxacin 750 mg Enterally and 
400 mg Intravenously for Patients Receiving Enteral Feeding: Systematic Review. Can. J. Hosp. Pharm. 
62, 127–134 (2009). 
13. 
Sutton, J. D., Sayood, S. & Spivak, E. S. Top Questions in Uncomplicated, Non-Staphylococcus 
aureus Bacteremia. Open Forum Infect. Dis. 5, ofy087 (2018). 
14. 
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). 
15. 
Ho, J. M.-W. & Juurlink, D. N. Considerations when prescribing trimethoprim-
sulfamethoxazole. Can. Med. Assoc. J. 183, 1851–1858 (2011). 
16. 
Kutob, L. F. et al. Effectiveness of oral antibiotics for definitive therapy of Gram-negative 
bloodstream infections. Int. J. Antimicrob. Agents 48, 498–503 (2016). 
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