Combination Antibiotic Treatment With Linezolid for Staphylococcus Aureus Bacteraemia: a Randomised Controlled Trial
Phase: NA
Conditions: Staphylococcus Aureus Bloodstream Infections (BSI; Bacteremia)
Sponsor: University Hospital, Basel, Switzerland

 
 
 
 
Clinical Trial protocol 
 
 
Combination antibiotic treatment with linezolid for Staphylococcus aureus 
bacteraemia: a randomised controlled trial 
 
Short title: Linezolid plus standard of care 
Trial acronym: LIPS 
 
 
Study Type: 
Clinical trial with Investigational Medicinal Product (IMP) 
 
Study Categorisation: 
B 
 
Study Registration: 
humanresearch-switzerland.ch, clinicaltrials.gov (NCT06958835) 
 
Study Identifier: 
LIPS Trial 
 
Sponsor-Investigator: 
PD Dr. Richard Kühl 
Department of Infectious Diseases 
University Hospital Basel 
Petersgraben 4 
4031 Basel 
Switzerland 
Phone: +41 (0)61 328 66 61 
Email: richardalexander.kuehl@usb.ch  
 
 
Investigational medicinal product: 
Linezolid 600 mg tablet 
Placebo tablet 
 
Protocol Version and Date: 
Version 1.2 (dated 30/07/2025) 
Confidentiality: 
The information contained in this document is explicitly not confidential. We will make the study protocol publicly 
available as a PDF file on clinicaltrials.gov. 
 
 

 
 
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LIST OF PROJECT LEADERS, LOCAL INVESTIGATORS AND OTHER KEY 
PERSONS INVOLVED IN THE TRIAL 
Please refer to the separate document “LIPS list of project leaders” for detailed information on project leaders, local 
investigators and other key persons involved in the trial including their roles and functions. 
 
 
 
 

 
 
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Signature Pages  
 
Study number 
• 
ClinicalTrials.gov Identifier: NCT06958835 
Study Title 
• 
Combination antibiotic treatment with linezolid for Staphylococcus aureus 
bacteraemia: a randomised controlled trial (LIPS Trial) 
 
The Sponsor-Investigator and trial statistician have approved the protocol version 1.2 dated 30/07/2025 and confirm 
hereby to conduct the study according to the protocol, current version of the World Medical Association Declaration 
of Helsinki, the ICH-GCP guidelines and the local legally applicable requirements. 
The Sponsor-Investigator has received the ICF and considers it appropriate for use. 
 
Sponsor-Investigator: PD Dr. Richard Kühl 
 
 
 
Place/Date 
 
 
 
    Signature 
 
 
Co-Principal Investigator: PD Benjamin Speich, PhD 
 
 
 
Place/Date 
 
 
 
 
Signature 
 
 
Co-Principal Investigator: Prof Dr. Nina Khanna 
 
 
 
Place/Date 
 
 
 
 
Signature 
 
 
Trial Statistician: Laura Werlen, PhD 
 
 
 
Place/Date 
 
 
 
 
Signature 
 
 
Trial Manager: Natalie Rose, PhD 
 
 
 
Place/Date 
 
 
 
 
Signature 

 
 
LIPS Trial, Version 1.2 of 30/07/2025 
 
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Local Investigator at study site: 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study protocol, the 
current version of the World Medical Association Declaration of Helsinki, ICH-GCP guidelines and the local legally 
applicable requirements. 
 
I have received the ICF and consider it appropriate for use. 
 
 
Site: 
 
Local investigator: 
 
 
 
 
Place/Date 
 
 
 
 
Signature 
 
 
 

 
 
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Table of Contents 
STUDY SYNOPSIS ................................................................................................................................................. 8 
ABBREVIATIONS ................................................................................................................................................. 13 
SUMMARY OF THE REVISION HISTORY IN CASE OF AMENDMENTS ........................................................... 15 
STUDY SCHEDULE .............................................................................................................................................. 16 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................................... 17 
1.1 
Monitoring institution ................................................................................................................................... 17 
1.2 
Data Safety Monitoring Board ..................................................................................................................... 17 
1.3 
Independent outcome assessment board ................................................................................................... 17 
1.4 
Any other relevant Committee, Person, Organisation, Institution ................................................................ 17 
1.4.1 
Patient and Public Involvement (PPI) ................................................................................................. 17 
1.4.2 
IMP Manufacturer ............................................................................................................................... 17 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................................. 18 
2.1 
Study registration ........................................................................................................................................ 18 
2.2 
Categorisation of study ................................................................................................................................ 18 
2.3 
Competent Ethics Committee (CEC) ........................................................................................................... 18 
2.4 
Swissmedic ................................................................................................................................................. 18 
2.5 
Ethical Conduct of the Study ....................................................................................................................... 18 
2.6 
Declaration of interest ................................................................................................................................. 18 
2.7 
Patient Information and Informed Consent .................................................................................................. 19 
2.8 
Participant privacy and confidentiality ......................................................................................................... 19 
2.9 
Premature termination of the study ............................................................................................................. 19 
2.10 
Protocol amendments ................................................................................................................................. 20 
3. 
BACKGROUND AND RATIONALE.............................................................................................................. 21 
3.1 
Background and Rationale .......................................................................................................................... 21 
3.2 
Investigational Medicinal Product (treatment) and Indication ...................................................................... 22 
3.3 
Preclinical Evidence .................................................................................................................................... 22 
3.4 
Clinical Evidence to Date ............................................................................................................................ 23 
3.5 
Rationale for the dosage, route, regimen .................................................................................................... 23 
3.6 
Explanation for choice of comparator .......................................................................................................... 23 
3.7 
Risks / Benefits............................................................................................................................................ 24 
3.8 
Justification of choice of study population ................................................................................................... 24 
3.9 
Summary of Background and Data on Linezolid ......................................................................................... 25 
4. 
STUDY OBJECTIVES ................................................................................................................................... 26 
4.1 
Overall Objective ......................................................................................................................................... 26 
4.2 
Primary Objective ........................................................................................................................................ 26 
4.3 
Secondary Objectives ................................................................................................................................. 26 
4.4 
Safety Objectives ........................................................................................................................................ 26 
5. 
STUDY OUTCOMES ..................................................................................................................................... 27 
5.1 
Primary Outcome ........................................................................................................................................ 27 
5.2 
Secondary Outcomes .................................................................................................................................. 28 
5.3 
Other Outcomes of Interest ......................................................................................................................... 29 
5.4 
Safety Outcomes ......................................................................................................................................... 29 
6. 
STUDY DESIGN ........................................................................................................................................... 30 
6.1 
General study design and justification of design ......................................................................................... 30 
6.2 
Patient and Public Involvement ................................................................................................................... 30 
6.2.1 
PPI activities before receiving approval from authorities .................................................................... 30 
6.2.2 
PPI activities after receiving approval from authorities ....................................................................... 31 
6.3 
Methods of minimising bias ......................................................................................................................... 31 

 
 
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6.3.1 
Randomisation ................................................................................................................................... 31 
6.3.2 
Blinding procedures ............................................................................................................................ 31 
6.3.3 
Other methods of minimising bias ...................................................................................................... 32 
6.4 
Unblinding Procedures (Code break) .......................................................................................................... 32 
7. 
STUDY POPULATION .................................................................................................................................. 33 
7.1 
Eligibility criteria........................................................................................................................................... 33 
7.2 
Recruitment and screening ......................................................................................................................... 33 
7.3 
Assignment to study groups ........................................................................................................................ 34 
7.4 
Criteria for withdrawal / discontinuation of participants ................................................................................ 34 
8. 
STUDY INTERVENTION ............................................................................................................................... 36 
8.1 
Identity of Investigational Medicinal Products .............................................................................................. 36 
8.1.1 
Experimental Intervention ................................................................................................................... 36 
8.1.2 
Control Intervention (standard/routine/comparator treatment) ............................................................ 36 
8.1.3 
Packaging, Labelling and Supply (re-supply) ..................................................................................... 36 
8.1.4 
Storage Conditions ............................................................................................................................. 36 
8.2 
Administration of experimental and control interventions ............................................................................ 36 
8.2.1 
Experimental Intervention ................................................................................................................... 36 
8.2.2 
Control Intervention ............................................................................................................................ 36 
8.3 
Dose modifications ...................................................................................................................................... 36 
8.4 
Compliance with study intervention ............................................................................................................. 37 
8.5 
Data Collection and Follow-up for withdrawn participants ........................................................................... 37 
8.6 
Trial specific preventive measures .............................................................................................................. 37 
8.7 
Concomitant Interventions (treatments) ...................................................................................................... 37 
8.8 
Study Drug Accountability ........................................................................................................................... 37 
8.9 
Return or Destruction of Study Drug ........................................................................................................... 37 
9. 
STUDY ASSESSMENTS .............................................................................................................................. 38 
9.1 
Study flow chart/ table of study procedures and assessments .................................................................... 38 
9.2 
Assessments of outcomes .......................................................................................................................... 39 
9.2.1 
Assessment of primary outcome ........................................................................................................ 39 
9.2.2 
Assessment of secondary outcomes .................................................................................................. 40 
9.2.3 
Assessment of other outcomes of interest in a subset of participants ................................................ 41 
9.2.4 
Assessment of safety outcomes ......................................................................................................... 41 
9.2.5 
Assessments in participants who prematurely stop the study ............................................................ 42 
9.3 
Procedures at each visit .............................................................................................................................. 42 
9.3.1 
Screening and identification of patients (Up to 72 hours before randomisation) ................................ 42 
9.3.2 
Enrolment of participants (0-72 hours before randomisation) ............................................................. 42 
9.3.3 
Randomisation (day 1) ....................................................................................................................... 43 
9.3.4 
Assessment of baseline characteristics (day 1) ................................................................................. 43 
9.3.5 
Treatment (day 1 – day 5) .................................................................................................................. 43 
9.3.6 
Assessment of routine laboratory measurements (day 1-7) ............................................................... 44 
9.3.7 
Subproject Molecular mechanisms of S. aureus bacteraemia (day 1 until 48h after the patient’s first 
negative blood culture) ................................................................................................................................... 44 
9.3.8 
Follow-up blood cultures (day 2, day 5 ±1) ......................................................................................... 44 
9.3.9 
Assessment of SIRS criteria (day 5 ±1) .............................................................................................. 44 
9.3.10 Measurement of trough levels of linezolid in a subset of participants (day 4-5) ................................. 44 
9.3.11 Assessment of adverse events of special interest (day 1-5, day 14 ±3, discharge day) ..................... 45 
9.3.12 Assessment of serious adverse events and serious adverse reactions (from enrolment until discharge, 
and at day 90 ±7) ............................................................................................................................................ 45 
9.3.13 Assessment of new antibiotic resistance (discharge day) .................................................................. 45 
9.3.14 Assessment of microbiological failure (day 28, discharge day, day 90 ±7) ........................................ 46 

 
 
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9.3.15 Assessment of clinical failure (day 14, day 28, discharge day, day 90).............................................. 46 
9.3.16 Assessment of length of hospital stay and length of ICU stay (discharge day) .................................. 46 
9.3.17 Assessment of all-cause mortality (day 7, day 14, day 28, day 90 ±7) ............................................... 46 
9.3.18 Assessment of return to usual level of function (day 90 ±7) ............................................................... 46 
9.3.19 Assessment of physical and mental health (quality of life, SF-36, day 90 ±7) .................................... 46 
10. SAFETY ........................................................................................................................................................ 48 
10.1 
Drug studies ................................................................................................................................................ 48 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events ................... 48 
10.1.2 Reporting of serious adverse events (SAE) and other safety related events ..................................... 49 
10.1.3 Follow up of (Serious) Adverse Events .............................................................................................. 50 
10.2 
Assessment, notification and reporting on the use of radiation sources ...................................................... 50 
10.3 
Exemption from the documentation requirements of AE ............................................................................. 50 
10.3.1 Exemption from the documentation requirements of AE due to pharmacological arguments ............ 50 
10.3.2 Exemption from the documentation requirements of AE due to clinical arguments ............................ 50 
11. STATISTICAL METHODS ............................................................................................................................ 51 
11.1 
Hypothesis .................................................................................................................................................. 51 
11.2 
Determination of Sample Size ..................................................................................................................... 51 
11.3 
Statistical criteria of termination of trial ........................................................................................................ 51 
11.4 
Planned Analyses ........................................................................................................................................ 51 
11.4.1 Datasets to be analysed, analysis populations ................................................................................... 51 
11.4.2 Primary Analysis ................................................................................................................................. 52 
11.4.3 Secondary Analyses ........................................................................................................................... 52 
11.4.4 Interim analyses ................................................................................................................................. 53 
11.4.5 Safety analysis ................................................................................................................................... 53 
11.4.6 Deviation(s) from the original statistical plan ...................................................................................... 53 
11.5 
Handling of missing data and drop-outs ...................................................................................................... 53 
12. QUALITY ASSURANCE AND CONTROL .................................................................................................... 54 
12.1 
Data handling and record keeping / archiving ............................................................................................. 54 
12.1.1 Electronic Case Report Forms (eCRF) ............................................................................................... 54 
12.1.2 Specification of source documents ..................................................................................................... 54 
12.1.3 Record keeping / archiving ................................................................................................................. 54 
12.2 
Data management ....................................................................................................................................... 54 
12.2.1 Data Management System ................................................................................................................. 54 
12.2.2 Data security, access, and back-up .................................................................................................... 54 
12.2.3 Analysis and archiving ........................................................................................................................ 55 
12.2.4 Electronic and central data validation ................................................................................................. 55 
12.3 
Monitoring ................................................................................................................................................... 55 
12.4 
Audits and Inspections ................................................................................................................................ 55 
12.5 
Confidentiality, Data Protection ................................................................................................................... 55 
12.6 
Storage of biological material and related health data ................................................................................. 55 
13. PUBLICATION AND DISSEMINATION POLICY.......................................................................................... 56 
14. FUNDING AND SUPPORT ........................................................................................................................... 56 
14.1 
Funding ....................................................................................................................................................... 56 
15. INSURANCE ................................................................................................................................................. 56 
16. TRIAL SUB-PROJECT(S) ............................................................................................................................ 57 
16.1 
Molecular mechanisms of S. aureus bacteraemia ....................................................................................... 57 
17. REFERENCES .............................................................................................................................................. 58 
18. APPENDICES ............................................................................................................................................... 64 
18.1 
Linezolid Stada® Summary of Product Characteristics ............................................................................... 64 
18.2 
The Hunter Serotonin Toxicity Criteria: for diagnosing serotonin syndrome ................................................ 64 

 
 
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STUDY SYNOPSIS  
Sponsor 
PD Dr. Richard Kühl 
Department of Infectious Diseases 
University Hospital Basel 
Petersgraben 4 
4031 Basel 
Switzerland 
Phone: +41 (0)61 328 66 61 
Email: richardalexander.kuehl@usb.ch 
Study Title: 
Combination antibiotic treatment with linezolid for Staphylococcus aureus bacteraemia: a 
randomised controlled trial 
Short Title / Study 
ID: 
Linezolid plus standard of care (LIPS) 
Protocol Version 
and Date: 
Version 1.2 (dated 30/07/2025) 
Trial registration: 
ClinicalTrials.gov Identifier: NCT06958835 
humanresearch-switzerland.ch: BASEC Nº2025-00655 
Study category 
and Rationale 
Risk Category B according to ClinO (Art 2)  
• 
Placebo controlled antibiotic treatment with linezolid STADA® authorized in 
Germany  
Clinical Phase: 
Phase 3 
Background and 
Rationale: 
Staphylococcus aureus (S. aureus) is the leading bacterial cause of death in high-income 
countries. Bloodstream infection (bacteraemia) represents a major manifestation of 
S. aureus affecting 20-30 in 100,000 persons yearly. 90-day mortality rates of 20-30% have 
remained unchanged over the last decades. Furthermore, S. aureus spreads to secondary 
body sites in 6-44% of cases, causing long-term impairment in up to a third of survivors, 
with a relapse rate of 4-10%. While more men are affected by S. aureus bacteraemia (ratio 
of approximately 1.5:1), women have 18% higher odds of death (OR 1.18) compared to 
men. So far, more effective treatments have not been identified. Thus, finding better 
treatments for patients suffering from S. aureus bacteraemia is a high unmet medical need. 
S. aureus expression of virulence factors facilitates the persistence and spread of the 
bacteria during infection and causes organ damage. We demonstrated the importance of 
S. aureus virulence factors in patho-mechanistic analyses directly from infected patient 
tissue. This led to our hypothesis that patient outcomes could be improved by adding an 
antibiotic that inhibits virulence factor expression. Several international guidelines 
recommend this strategy for toxin-mediated infections. However, due to a lack of evidence 
from randomised trials, this approach has not become standard clinical practice for 
bacteraemia with S. aureus. Linezolid, an established antibiotic for pneumonia or skin and 
soft tissue infections, strongly inhibited S. aureus virulence factor expression in preclinical 
studies. 
Objectives: 
Primary objective: To investigate whether early addition of 5-day treatment with linezolid 
to standard of care improves outcomes at 90 days in participants with S. aureus 
bacteraemia as measured by the desirability of outcome ranking (DOOR). 
Secondary objectives:  
Secondary objectives include exploring the impact of early addition of 5-day treatment with 
linezolid to standard of care on a number of secondary outcomes such as physical and 
mental health, length of hospital stay and safety (full list in section 5 STUDY OUTCOMES). 
In addition, we aim to explore if potential effects might differ between patient populations 
based on sex (male vs. female), ICU status at baseline (participants on ICU vs. participants 
not on ICU), and focus of infection (vascular catheter, skin and soft tissue, endocarditis, 
osteoarticular, pneumonia, other focus, or focus not identified). 

 
 
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Outcomes: 
Primary outcome: 
The Desirability of Outcome Ranking (DOOR) developed for this study comprises five 
ranks (Table 1) and is assessed at day 90. The primary outcome will be expressed as the 
win ratio, i.e., the ratio of the number of times that participants in the intervention group 
have a lower DOOR compared to those in the control group. In this study, we use the win 
ratio approach of Pocock et al. (2012), i.e., every participant in the linezolid group is 
compared with every participant in the control group. When comparing two participants, the 
winner will be determined by the first component of the DOOR in which the two participants 
differ, the only exceptions being ties when both participants die or if they do not die but 
have the same length of hospitalisation (see section 11 STATISTICAL METHODS for 
details). 
 
Rank 
Alive 
at 90 
days 
Return to 
usual level 
of function 
by day 90 
None 
of 
the 
following 
complications: 
• 
Microbiological or 
clinical failure leading 
to treatment change 
• 
Serious adverse 
reaction 
• 
Adverse event leading 
to study drug 
discontinuation 
Hospital 
length of 
stay 
1 
Yes 
Yes 
Yes  
(no complications occurred) 
Ties will be 
resolved 
using the 
length of 
hospitalisation 
2 
Yes 
Yes 
No  
(complication occurred) 
3 
Yes 
No 
Yes  
(no complications occurred) 
4 
Yes 
No 
No    
(complication occurred) 
5 
No 
Not 
applicable 
Not applicable 
Not applicable 
Table 1: Desirability of Outcome Ranking (DOOR) outcome used for the LIPS trial 
Secondary outcomes: 
Day of randomisation is defined as day 1. 
• 
All-cause mortality at 90 days 
• 
Time to death up to day 90 
• 
Proportion of participants back to their usual level of function at day 90 
• 
Microbiological failure at 14-90 days leading to treatment change 
• 
Early microbiological failure at 5-13 days leading to treatment change 
• 
Clinical failure at 14-90 days leading to treatment change 
• 
Early clinical failure at 5-13 days leading to treatment change 
• 
Hospital length of stay after randomisation 
• 
Time to being discharged alive (assessed by day 90) 
• 
Number of days without being on the Intensive Care Unit (ICU) up to day 90 
• 
Number of days alive and free of antibiotics up to day 90 
• 
Mental health at day 90 (SF-36 questionnaire) 
• 
Physical health at day 90 (SF-36 questionnaire) 

 
 
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• 
Persistent bacteraemia: S. aureus-positive blood culture on day 5 
• 
 2 systemic inflammatory response syndrome (SIRS) criteria on day 5  
• 
Change in C-reactive protein on day 5  
• 
Development of new antibiotic drug resistance in Staphylococcus aureus 
Adverse events/safety: 
• 
Serious adverse reactions until day 90 
• 
Adverse events leading to study drug discontinuation 
• 
Adverse events of special interest: clinical signs of serotonin toxicity, laboratory 
signs of myelosuppression, hyperlactatemia, acute kidney injury, 
Clostridioides difficile-associated diarrhoea within 90 days 
Study design: 
Multi-centric, 1:1 randomised, parallel group, placebo-controlled clinical trial with blinded 
participants, physicians, and outcome assessors conducted in the acute-care hospital 
setting.  
Inclusion / 
Exclusion criteria: 
Inclusion criteria: 
• 
S. aureus grown from at least one blood culture 
• 
Hospitalised at a participating centre 
• 
≥18 years old 
• 
Written informed consent or fulfilling criteria for an emergency exception from 
informed consent requirements 
 
Exclusion criteria: 
• 
Administration of the initial drug treatment not feasible within 72 hours since the 
collection of the first positive blood culture with S. aureus  
• 
Documented history of positive blood cultures for S. aureus occurring between 
72 hours and 180 days prior to the eligibility assessment  
• 
Necrotising fasciitis 
• 
Currently receiving linezolid or clindamycin 
• 
Use of any monoamine oxidase A or B inhibitor within the last two weeks 
• 
Known hypersensitivity to linezolid or any other ingredients of the study drugs 
• 
Current severe thrombocytopenia (i.e. <30 x 109/L) 
• 
Application of study drug not possible (per mouth or per gastric tube) 
• 
Currently breastfeeding 
• 
Local treating team believes that death is imminent and inevitable 
• 
Patient is receiving end of life care and antibiotic treatment is not considered 
appropriate 
• 
Local treating team believes that participation in the study is not in the best 
interest of the patient 
• 
Any indication that the patient is unwilling to participate in the study including an 
advance directive stating such unwillingness 
 
General 
Patients taking serotonergic drugs such as selective serotonin reuptake inhibitors (SSRI) 
or tricyclic antidepressants are not generally excluded. See detailed information on risk 
assessment and precautions in chapter 8.6 Trial specific preventive measures. 
Pregnant women will not be excluded from study participation per se, as linezolid is not 
formally contraindicated during pregnancy. In the event of pregnancy, the treating physician 
and the patient (or the patient’s next of kin) will assess whether the potential benefits for 
the patient outweigh the potential risks to the foetus. 
Linezolid has been shown to pass into breast milk and accordingly, breastfeeding should 
be discontinued prior to and throughout administration of linezolid. 

 
 
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Measurements 
and procedures: 
Infectious disease specialists, serving as the local principal investigators at all participating 
centres, are routinely involved in the care of patients with S. aureus bacteraemia. Hence, 
study teams at all participating sites will consider each patient with S. aureus bacteraemia 
for potential inclusion in the LIPS trial. The local investigators (or designated staff) will 
check inclusion and exclusion criteria, initiate the contact, and inform the patient (or a close 
relative or an independent physician if patient is incapable of judgement) about this trial. 
After the written informed consent is obtained, the participant will be randomised to the 
intervention group (i.e. linezolid 600 mg tablets, twice daily for 5 days in addition to standard 
of care antibiotic treatment) or the control group (i.e. placebo tablets in addition to standard 
of care antibiotic treatment). The LIPS trial will mainly use data generated as part of clinical 
routine during hospitalisation. In brief, baseline data (e.g., date of birth, gender, risk 
factors), microbiological results (e.g., blood culture results, resistance patterns), laboratory 
results (e.g., blood count, renal function), and data of concomitant treatments (standard 
antibiotic, source control procedures) will be collected from the hospital electronic medical 
records. Participants will be treated and monitored according to clinical routine. If a 
physician suspects an adverse event (e.g. serotonin toxicity, myelosuppression) they 
should order any assessments and tests necessary for the detection, as in routine clinical 
practice. 
The outcomes “alive at day 90” and "return to usual level of function by day 90" will be 
assessed through a phone call on day 90 (given that the participant did not die during the 
hospitalisation). In addition, the participants will receive a questionnaire at day 90 to assess 
their quality of life (QoL, i.e. physical health and mental health). 
Study Product / 
Intervention:  
Participants in the intervention arm will receive linezolid 600 mg tablets (twice a day for 5 
days) in addition to standard of care antibiotic treatment. 
Control 
Intervention: 
Participants in the control arm will receive oral placebo tablets (twice a day for 5 days) in 
addition to standard of care antibiotic treatment. 
Number of 
Participants with 
Rationale: 
606 participants (303 in control and 303 in the intervention group) 
We will use the win ratio to assess if participants in the intervention group have a better 
overall clinical outcome as defined by the DOOR compared to participants in the control 
group taking the following domains into considerations: i) survival, ii) participant-reported 
level of functioning at 90 days compared to the level before the blood infection, iii) treatment 
change due to persistence or spread of the bacterium within day 14-90 or serious adverse 
events leading to study drug discontinuation, and iv) hospital length of stay in days. 
The sample size was calculated using a simulation approach (including missing data in the 
assumptions), for which 1000 synthetic datasets for each combination of plausible values 
for the relevant parameters were generated and the intended primary analysis was applied. 
With a two-sided significance level of α=0.05 and a desired power of 90% (1:1 allocation), 
an estimated 550 participants will be required to show a significant effect of the intervention. 
Because of possible post-randomisation withdrawal due to missing retrospective consent, 
the sample size was increased by 10% to minimise the risk of being underpowered.  
See section 11 STATISTICAL METHODS for detailed assumptions about (i) occurrence of 
events and potential effect for each DOOR domain and (ii) about the frequency of missing 
data for each DOOR domain. 
Study Duration: 
Estimated duration for the main investigational plan (e.g. from start of screening of first 
participant to last participant processed and finishing the study): 
38 months 
Study Schedule: 
First patient in: September 2025 
Last patient out: October 2028 
Local site-
Investigators: 
Please refer to the separate document “LIPS list of project leaders” for detailed information 
on local investigators.  
Study Centres: 
Approximately 12 institutions in Switzerland will be involved in this multi-centric trial. Please 
refer to the separate document “LIPS trial sites” for the complete list. 
Statistical 
Primary analysis: 

 
 
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Considerations: 
Intervention and control groups will be compared based on the win-ratio approach as 
described by Pocock and colleagues: In brief, participants in the intervention group will be 
compared with participants in the control group. When comparing two participants, the 
winner will be determined by the first component of the DOOR in which the two participants 
differ. The following two scenarios will be considered a tie: (i) both participants died within 
90 days, or (ii) both participants have the same outcomes for all DOOR elements, including 
hospital length of stay. The win ratio will be calculated by dividing the number of cases in 
which participants receiving linezolid win with the number of cases in which participants 
receiving placebo win. We will reject the null hypothesis that the win ratio is equal to 1 if 
the p-value calculated is less than 0.05. 
 
More detailed information and intended approaches for the secondary analyses are listed 
in section 11 STATISTICAL METHODS. A detailed analysis plan will be written before 
closing the study database. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current version of the 
Declaration of Helsinki, ICH-GCP, as well as all national legal and regulatory requirements.  

 
 
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ABBREVIATIONS 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
Art. 
Article 
ASR 
Annual Safety Report 
BASEC 
Business Administration System for Ethical Committees, 
(https://submissions.swissethics.ch/en/) 
C. difficile 
Clostridioides difficile 
CA 
Competent Authority (e.g. Swissmedic) 
CD 
Cluster of Differentiation 
CEC 
Competent Ethics Committee 
CHUV 
Centre hospitalier universitaire vaudois 
CI 
Confidence Interval 
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: OClin, in Italian: 
OSRUm) 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CTCAE 
Common terminology criteria for adverse events 
DKF 
Department of Clinical Research, University Hospital Basel 
DOOR 
Desirability Of Outcome Ranking 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
e.g. 
For example 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOC 
Ospedale Regionale di Lugano  
FOPH 
Federal Office of Public Health 
GCP 
Good Clinical Practice 
gGT 
Gamma-glutamyl Transferase 
Hb 
Haemoglobin 
Ho 
Null hypothesis 
HOCH 
Health Ostschweiz 
HR 
Heart Rate 
HRA 
Federal Act on Research involving Human Beings (in German: HFG, in French: LRH, in Italian: 
LRUm) 
HUG 
Hôpitaux Universitaires de Genève  
i.e. 
That is 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive Care Unit 
ID 
Identification 
IICT 
Investigator-Initiated Clinical Trial 
IIT 
Investigator-Initiated Trial 

 
 
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IMP 
Investigational Medicinal Product 
ITT 
Intention To Treat 
IV 
Intravenous 
KDIGO 
Kidney Disease Improving Global Outcomes 
KSA 
Kantonsspital Aarau 
Lc 
Leukocytes 
LIPS 
Linezolid Plus Standard of Care 
MALDI-TOF 
Matrix-Assisted Laser Desorption/Ionization-Time of Flight 
MF-DAC 
Data Access Committee of the Faculty of Medicine at the University of Basel 
MIC 
Minimal Inhibitory Concentration 
MRSA 
Methicillin-Resistant S. aureus  
MSSA 
Methicillin-Susceptible S. aureus  
OR 
Odds Ratio 
PCR 
Polymerase Chain Reaction 
PD 
Privatdozent 
PI 
Principal Investigator 
PPI 
Patient and Public Involvement 
PROM 
Patient-Reported Outcome Measure 
QoL 
Quality of Life 
RCT 
Randomised Controlled Trial 
RR 
Respiratory Rate 
S. aureus 
Staphylococcus aureus 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SCTO 
Swiss Clinical Trial Organisation 
SDV 
Source Data Verification 
SF-36 
Short Form 36 Survey  
SIRS 
Systemic Inflammatory Response Syndrome  
SNAP  
Staphylococcus aureus Network Adaptive Platform 
SNCPT 
Swiss National Clinical Trials Portal 
SNSF 
Swiss National Science Foundation 
SOP 
Standard Operating Procedure 
SMPC 
Summary of Product Characteristics 
SS 
Serotonin Syndrome 
SSRI 
Selective Serotonin Reuptake Inhibitors 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Tc 
Thrombocytes 
TLS 
Transport Layer Encryption  
TMF 
Trial Master File 
US 
United States of America 
USB 
University Hospital Basel 
USZ 
University Hospital Zurich 
WHO ICTRP 
World Health Organisation International Clinical Trials Registry Platform 
 
 
 

 
 
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SUMMARY OF THE REVISION HISTORY IN CASE OF AMENDMENTS 
Version Nr, 
Version Date 
Chapter 
Description of change 
Reason for the change 
1.0, 27/03/2025 
 
Initial version 
 
1.1, 27/06/2025 
 
Minor changes throughout protocol before 
submission to Swissmedic 
Incorporated feedback from 
competent Ethics committee 
1.2, 30/07/2025 
7.1, 8.6 
Added “Currently breastfeeding” and “Use of 
any monoamine oxidase A or B inhibitor within 
the last two weeks” to exclusion criteria, 
changed wording of hypersensitivity criterion; 
minor changes in assessment description 
Incorporated feedback from 
Swissmedic’s 
further 
information 
request; 
close 
alignment with linezolid SmPC 
 
 
 

 
 
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STUDY SCHEDULE  
The study schedule can be found in chapter 9.1 Study flow chart/ table of study procedures and assessments. 
 
 

 
 
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1. STUDY ADMINISTRATIVE STRUCTURE  
 
1.1 Monitoring institution 
 
Clinical Trial Unit  
Department of Clinical Research 
University Hospital Basel 
Spitalstrasse 8/12, 4031 Basel 
Switzerland 
Tel. +41 61 328 51 48 
ClinicalTrials@usb.ch 
 
1.2 Data Safety Monitoring Board  
The trial will be reviewed by an independent and blinded Data Safety Monitoring Board (DSMB) who assesses 
safety during prespecified interim analyses. The DSMB will consist of at least three infectious disease experts 
unaware of the treatment assignments and not otherwise involved in the study. Members and frequency of meetings 
are described in the DSMB charter. For all serious adverse events (SAEs), the DSMB will assess if it is suspected 
to be related to the study drug (defining the SAE as an SAR). 
 
1.3 Independent outcome assessment board 
The outcomes “microbiological failure” and “clinical failure” (“complications” a and b, see 9.2.1 Assessment of 
primary outcome) will be reviewed by an independent and blinded outcome assessment board. The independent 
outcome assessment board will consist of at least three infectious disease experts unaware of the treatment 
assignments and not otherwise involved in the study. In case of disparity, results by the independent outcome 
assessment board will overrule site/investigator assessments. Members and frequency of meetings are described 
in the independent outcome assessment board charter. 
 
1.4 Any other relevant Committee, Person, Organisation, Institution  
1.4.1 
Patient and Public Involvement (PPI) 
Patient representatives will be involved at all stages of the trial. Detailed information can be found in 6.2 Patient 
and Public Involvement. 
 
1.4.2 
IMP Manufacturer 
Spital-Pharmazie 
Universitätsspital Basel 
Spitalstrasse 26 
4031 Basel 
 
 
 

 
 
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2. ETHICAL AND REGULATORY ASPECTS  
Before the study is conducted, the protocol, the proposed patient information and consent form as well as other 
study-specific documents shall be submitted to a properly constituted Competent Ethics Committee (CEC) and 
Swissmedic, in agreement with local legal requirements, for formal approval. The CEC and Swissmedic approval 
will be communicated to the Sponsor-Investigator in writing before commencement of this study. The study will not 
start recruiting participants until ethical and regulatory approval has been granted. Any amendment to the protocol 
will, if legally required, also be approved by these institutions. 
2.1 Study registration 
This trial will be registered in the following registries before the recruitment of the first participant: 
• 
http://humanresearch-switzerland.ch (BASEC Nº 2025-00655) 
• 
ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT06958835 
2.2 Categorisation of study  
Category B. A placebo-controlled study using an IMP authorized in Germany. Linezolid STADA® 600 mg tablets 
have been authorized in Germany, a country with equivalent medicinal product control in accordance with Article 
13 Therapeutic Products Act, as a generic of Zyvoxid® 600 mg since 2014. Linezolid STADA® 600 mg is authorized 
for the treatment of pneumonia and complicated skin and soft tissue infections caused by Gram-positive bacteria. 
Recommended dose 600 mg twice a day. Recommended treatment duration is 10-14 days, but shorter treatment 
regimen may be sufficient for certain types of infections. Staphylococcus aureus is a Gram-positive bacterium and 
nearly always susceptible to linezolid. The effectiveness of linezolid in S. aureus bacteraemia as an oral 
continuation treatment after initial intravenous antibiotics is well-documented in observational studies. Drugs 
containing linezolid as their active ingredient have been approved in Switzerland for over 20 years.  
2.3 Competent Ethics Committee (CEC)  
The Sponsor-investigator will submit all Swiss centres for approval to the lead CEC (Ethikkommission Nordwest- 
und Zentralschweiz, EKNZ) in collaboration with the local Swiss investigators. No changes are made to the protocol 
without prior sponsor and CEC approval, except where necessary to eliminate apparent immediate hazards to study 
participants. 
The sponsor-investigator will report the premature termination, interruption, or resumption of the study, including 
reasons thereof, to the CEC within 15 days. An interruption lasting more than two years is considered a premature 
termination. The sponsor-investigator will report the first visit of the first participant and the end of the study (defined 
as the last follow-up visit of the last study participant) to the CEC within 30 days. The final study report will be 
submitted within one year after study end or premature study termination. Amendments are reported according to 
chapter 2.10 Protocol amendments. 
2.4 Swissmedic 
The sponsor will obtain approval from Swissmedic before the start of the clinical trial. Reporting duties and timelines 
are the same as for CEC, except for non-substantial amendments that shall be reported as soon as possible. The 
application must be submitted to the CEC within two years of approval by the CA (ClinO Art. 23). An application for 
an extension beyond the two years is a substantial amendment; if this is not complied with, the approval to conduct 
the study lapses.  
Amendments are reported according to chapter 2.10 Protocol amendments. 
2.5 Ethical Conduct of the Study  
The study will be carried out in accordance with the protocol and with principles enunciated in the current version 
of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, and Swiss Law and 
Swiss regulatory authority’s requirements. The CEC and regulatory authorities will receive annual safety reports 
(ASR) and interim reports and be informed about study stop/end in agreement with local requirements. In addition, 
the CEC will be informed annually about the general progress of the clinical trial. 
2.6 Declaration of interest  
There are no potential conflicts of interest to disclose. 

 
 
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2.7 Patient Information and Informed Consent 
Patients will be informed about the study by their treating physician and consent will be obtained from each patient. 
Patients who are conscious and capable of making decisions will be approached to give their consent. The local 
investigator (or a designated physician) will explain the nature of the study, its purpose, the procedures involved, 
the expected duration, the potential risks and benefits and any discomfort it may entail. Each patient will be informed 
that the participation in the study is voluntary, that the patient may withdraw from the study at any time and that 
withdrawal of consent will not affect the patient’s subsequent medical assistance and treatment. The patient will be 
informed that any questions can be asked, and that consulting family members, friends, their treating physicians, 
or other experts before deciding about study participation is possible. Enough time will be given before making the 
decision about study participation. However, it will be noted that the potential effect of the study medication (i.e. 
linezolid) might be greater if treatment can be started earlier. The patient will be informed that authorised individuals 
other than their treating physician may examine the patient’s medical records. 
Due to the nature of S. aureus bacteraemia, we expect approximately 10-20% of patients to be unresponsive and 
incapable of giving informed consent during the acute infection. These patients are particularly at risk of succumbing 
to the infection and should thus not be excluded from the study. In these emergency situations, consent will be 
obtained from the patient’s next of kin. If no next of kin are present, an independent physician who safeguards the 
interests of the patient and is not involved in the conduct of the study can confirm participation (“confirmation by 
independent physician”). If there is any indication that the patient is unwilling to participate in the study including an 
advance directive stating such unwillingness, the patient will be excluded from participation. After patients regain 
capacity of judgement, they will be approached about giving retrospective consent. 
We will provide the following specific information sheet and consent forms which will enable an informed decision 
about study participation:  
1) 
Patient informed consent form 
2) 
Next of kin informed consent form 
3) 
Confirmation by Independent physician 
4) 
Retrospective patient informed consent form 
 
Formal consent, using the approved consent form, will be obtained before the patient is subjected to any 
investigation procedure. The signed consent form is retained as part of the trial records. Consent forms were 
developed in collaboration with patient representatives. 
 
2.8 Participant privacy and confidentiality  
The investigator affirms and upholds the principle of the participant’s right to privacy and that they shall comply with 
applicable privacy laws. In particular, anonymity of the participants will be guaranteed when presenting the data at 
scientific meetings or publishing them in scientific journals. 
Individual participant medical information (i.e. information that would identify an individual participant) obtained as 
a result of this study is considered confidential and disclosure to third parties is prohibited. Participant confidentiality 
will be further ensured by utilizing participant identification code numbers to correspond to treatment data in the 
computer files. 
The investigator has appropriate knowledge and skills in the areas of data security and data protection or is able to 
ensure compliance by calling in appropriate expertise (Art. 6, ClinO). 
For data verification purposes, authorized representatives of the sponsor, a competent authority (e.g., Swissmedic), 
or a CEC may require direct access to parts of the medical records relevant to the study, including participants’ 
medical history. 
2.9 Premature termination of the study  
The Sponsor-Investigator in consultation with the DSMB may terminate the study prematurely before reaching the 
anticipated sample size of 606 participants according to certain circumstances, for example: 
• 
ethical concerns 
• 
insufficient participant recruitment 
• 
when the safety of the participants is doubtful or at risk, respectively 
• 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise  
If the study is terminated earlier than planned, the investigator notifies the CEC and Swissmedic according to the 

 
 
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provisions of ClinO Art. 38. 
2.10 Protocol amendments 
Suggestions for a protocol amendment can be made to the LIPS trial team by any group member and by all 
investigators. Should these impact trial specific procedures, additional on-site or web-based training will be provided 
to all investigators. Substantial amendments are only implemented after approval of the CEC and Swissmedic, 
respectively. Substantial amendments are changes that affect the safety, health, rights and obligations of 
participants, changes in the protocol that affect study objective(s) or central research topic, changes of trial site(s) 
or of trial leader and sponsor (ClinO, Art. 29). 
Under emergency circumstances, deviations from the protocol to protect the rights, safety, and wellbeing of human 
participants may proceed without prior approval of the sponsor and the CEC/Swissmedic. Such deviations shall be 
documented and reported to the sponsor and the CEC/Swissmedic as soon as possible. 
All non-substantial amendments are communicated to Swissmedic and to the CEC within the ASR. 
 
 

 
 
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3. BACKGROUND AND RATIONALE  
3.1 Background and Rationale  
Staphylococcus aureus (S. aureus) is the leading bacterial cause of death in high-income countries and estimated 
second leading bacterial cause of death globally after tuberculosis.1 Bacteraemia (bacteria in the bloodstream) 
represents a common manifestation of S. aureus infection, affecting 20-30 in 100,000 persons annually.2-4 These 
numbers have risen in recent years due to aging of the population and other risk factors such as the use of 
implantable medical devices.2 4-6 Approximately 20-30% of patients with S. aureus bacteraemia die within 90 days.7 
8 This rate has not significantly changed for decades despite active standard antibiotic therapy9 10 representing the 
highest mortality rate among all common bloodstream pathogens.1 S. aureus bacteraemia is reported more often 
in men than in women.11-13 Risk factors, as well as diagnostic and therapeutic management can differ between men 
and women.13 Women may experience worse outcomes and higher mortality.11 14-16 
In addition, S. aureus bacteraemia spreads to secondary body sites in 6-44% of cases,17-20 produces prolonged 
impairment in up to one-third of survivors,21 and is associated with a relapse rate of 4-10%.22-24 Despite the 
magnitude of disease burden with an estimated 2 million people affected yearly worldwide, less than 3000 patients 
have been included in published randomised controlled trials (RCTs) testing treatments for S. aureus 
bacteraemia.25 This leaves us with considerable uncertainty about an effective treatment.  
Methicillin-susceptible S. aureus (MSSA) represents 95% of S. aureus antibiotic resistance profiles in Switzerland.2 
The standard management of MSSA bacteraemia consists of an intravenous treatment with an anti-staphylococcal 
beta-lactam antibiotic such as flucloxacillin or cefazolin for 2-6 weeks and rapid source control if possible.26-29 
Previous studies attempted to increase the antimicrobial efficacy of standard therapy by adding a second antibiotic 
with evidence of additive or synergistic killing capacity in vitro. As identified by a recent systematic review,30 
gentamicin,31-33 rifampicin,34 35 levofloxacin,36 daptomycin,37 or fosfomycin38 have been added to standard 
antibiotics in RCT of bacteraemia with methicillin-susceptible S. aureus (Table 2). Unfortunately, none of these 
RCTs succeeded in demonstrating a significant improvement in clinical outcomes. Several factors may have 
contributed to the shortcomings of these clinical trials. One possible factor is that the interventions may not have 
effectively addressed the underlying pathophysiologic factors responsible for the poor outcomes in patients with 
S. aureus bacteraemia. Limitations of the RCTs also include that the sample sizes were generally small, making it 
difficult to detect small, but relevant differences in mortality. In addition, these RCTs did not prioritise the assessment 
of other important patient-related outcomes, such as post-infection functional status. 
 
Table 2: Overview of published randomised controlled trials (RCT) testing for superiority in methicillin-susceptible S. aureus 
bacteraemia (identified by the systematic review by Grillo et al. 30, and Grillo et al 38)  
Abbreviations: PROM: patient-related outcome measure; I: intervention group, C: control group, MSSA: methicillin-susceptible 
S. aureus; MRSA: methicillin-resistant S. aureus 

 
 
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Thus, there is an urgent clinical need to evaluate new therapeutic strategies through high-quality RCTs with the aim 
of improving patient-relevant outcomes in S. aureus bacteraemia. 
S. aureus is known for its ability to survive and rapidly adapt to new environments in the human body.39 40 It employs 
a wide range of virulence factors, including toxins to attack human (immune) cells41 and proteases to invade human 
tissue42, often eliciting a strong inflammatory response at the site of infection. It can be inferred that most of the 
damage to the body results from direct and indirect effects of these virulence factors. The impact of indirect damage 
and physical strain from the infection is evident, as 40-60% of deaths in people with S. aureus bacteraemia happen 
after the initial infection and cause of death cannot be clearly linked to the infection.17 43 This finding is consistent 
with prior research involving patients with sepsis.44 Furthermore, akin to sepsis as a whole, it is imperative to 
consider not only mortality but also long-term functional and cognitive impairments resulting from the direct and 
indirect consequences of the infection. This aspect represents a thus far underexplored area of research.45 46 
The significance of virulence factor expression has been observed in data obtained directly from patient samples 
as part of our research project within the National Centre of Competence in Research (publication in preparation). 
Determining the role of virulence factors becomes even more important considering that standard treatment with a 
beta-lactam-type antibiotic can augment bacterial toxin production as long as S. aureus is not killed.47 Thus, it has 
been hypothesised that adding an antibiotic agent inhibiting virulence factor expression could reduce direct and 
indirect organ damage thereby improving patient outcomes.48 Linezolid strongly reduced the expression of 
S. aureus virulence factors in preclinical studies,47 making it an ideal candidate to use clinically. Expert opinion and 
some guidelines advocate this strategy for severe infections or for S. aureus strains with known toxin expression.49-
52 However, evidence from RCTs for this approach is still lacking: our systematic literature search for published or 
planned RCTs (in PubMed, Embase, and the Cochrane Central Register of Controlled Trials [indexing planned 
RCTs from clinicaltrials.gov and WHO ICTRP]) that was developed by an information specialist from the University 
Medical Library yielded 943 hits (search conducted in June 2023). None of those reported RCT results or an ongoing 
RCT involving an antibiotic combination treatment with linezolid for S. aureus bacteraemia. 
Currently, an international platform trial called SNAP (“Staphylococcus aureus Network Adaptive Platform”)25 
compares various treatment options for S. aureus bacteraemia including one study domain that assesses open-
label adjunctive treatment with clindamycin — a different antibiotic recognised for its toxin-inhibiting properties. Our 
proposed study, in contrast, will employ linezolid as the adjunctive intervention, thus providing crucial 
complementary evidence to the findings of the SNAP trial's adjunctive clindamycin.  
In summary, effective treatment of S. aureus bacteraemia is a high unmet medical need. Our hypothesis suggests 
that S. aureus virulence factors are responsible for these negative outcomes and that early intervention to suppress 
these factors may lead to improved clinical outcomes. We also consider that the chosen outcomes to date have not 
covered the whole spectrum of effects associated with the disease. Our goal is to evaluate addition of linezolid to 
standard of care in a robust RCT with patient-relevant endpoints to achieve better outcomes for patients with 
S. aureus bacteraemia. 
3.2 Investigational Medicinal Product (treatment) and Indication  
Linezolid STADA® 600 mg tablets and oval placebo tablets (Fagron) will be imported from Germany by Spital-
Pharmazie Basel, Spitalstrasse 26, 4031 Basel. Linezolid STADA® 600 mg is authorized for the treatment of 
pneumonia and complicated skin and soft tissue infections caused by Gram-positive bacteria. Recommended 
treatment duration is 10-14 days, but shorter treatment regimen may be sufficient for certain types of infections53. 
Packaging and labelling will be performed by Spital-Pharmazie Basel to ensure blinding. A sample of the label will 
be enclosed to the Swissmedic application. 
Detailed information on Linezolid STADA® 600 mg can be found in the provided Summary of Product 
Characteristics (SMPC). 
 
3.3 Preclinical Evidence  
Linezolid inhibits bacterial protein synthesis at an early stage by binding to the 50S subunit of the bacterial ribosome. 
Animal data revealed enhanced activity of linezolid combined with vancomycin or imipenem in experimental 
endocarditis models,54 55 as well as in combination with fosfomycin in a murine peritonitis model.56 Additionally, 
linezolid effectively decreased in vivo toxin production57 and was much more effective than vancomycin in protecting 
animals from dying in pneumonia models.57-59  
A summary of relevant preclinical data is included in the SMPC. 
 

 
 
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3.4 Clinical Evidence to Date  
Linezolid is an established antibiotic treatment option for skin- and soft tissue infections as well as for pneumonia, 
especially in case of MRSA due to the low rate of linezolid resistance.60 Detailed information on pivotal studies of 
linezolid can be found in the SMPC. For nosocomial MRSA pneumonia, linezolid has been shown to be superior to 
the commonly administered intravenous vancomycin.59 For MRSA bacteraemia, linezolid is a safe and effective 
alternative to standard-of-care glycopeptide (vancomycin/ teicoplanin).61-63 A trial directly comparing standard-of 
care beta-lactam therapy with linezolid in MSSA bacteraemia is lacking, since beta-lactam therapy is regarded as 
most effective for MSSA. Limited clinical data exist regarding combination therapy with linezolid in S. aureus 
bacteraemia. Two observational cohort studies (involving a total of 54 linezolid treated participants) reported 
favourable outcomes (microbiological response, success rate, mortality) with salvage combination therapy using 
linezolid and a carbapenem.64 65 Successful treatment was also observed in a case of MRSA bacteraemia and 
meningitis with linezolid, daptomycin, and rifampicin.66 Linezolid may be most effective when started as early as 
possible according to the open label RCT by Wilkox et al.67 Even though the study was underpowered, it supports 
the hypothesis that empirically initiated linezolid might result in better survival. Similarly, a prospective observational 
single-centre study found significantly improved survival in participants with MRSA bacteraemia empirically 
receiving linezolid compared to a glycopeptide (adjusted odds ratio for survival 7.7; 95%CI 1.1–53).68  
The potential clinical impact of toxin inhibition by linezolid is demonstrated in a case report on the successful 
treatment of a staphylococcal toxic shock syndrome.69 In addition, a review of 93 cases of S. aureus necrotizing 
pneumonia revealed reduced mortality rates when antibiotic therapy incorporated an anti-toxin agent, such as 
clindamycin or linezolid.70 Our systematic search showed that no RCT has assessed the effect of adding linezolid 
to the standard antibiotic therapy in patients having S. aureus bacteraemia. 
In summary, linezolid is a valuable antibiotic for various S. aureus infections, especially for MRSA cases in which 
beta-lactams are ineffective. Early use of linezolid, as well as late salvage treatment using linezolid in combination 
with a beta-lactam for persistent bacteraemia and toxin-mediated infections has been documented. However, no 
study has evaluated early combined treatment of linezolid with standard therapy for S. aureus bacteraemia to 
mitigate potential toxin-related complications and improve patient relevant outcomes. 
 
3.5 Rationale for the dosage, route, regimen  
Linezolid will be applied in addition to the standard antibiotic treatment prescribed by the treating physician. 
Linezolid is approved according to the Swissmedic-approved prescribing information of a reference product with 
marketing authorisation as follows: 600 mg IV or oral twice daily for 10-14 days in case of nosocomial pneumonia 
and complicated skin and soft tissue infections, and 600 mg IV or oral twice daily for 14-28 days in case of 
vancomycin-resistant enterococcus infections including enterococcal bacteraemia. Treatment duration is variable 
and dependent on pathogen, site and severity of infection, as well as clinical response of the patient. The maximum 
treatment duration is 28 days. Due to linezolid’s excellent oral bioavailability of nearly 100%,71 we selected the oral 
dosing route for our study. This is in line with patient preferences. It has the additional benefit that participants do 
not need an intravenous catheter for the study which would increase the risk of catheter-related infections. Moreover, 
participants are not burdened by the additional administration of fluids, which can have negative cardiovascular 
effects, especially in patients with heart failure. 
We expect the highest therapeutic benefit of linezolid within the first three days following detection of infection. 
Beyond this early period, we hypothesize that damage caused by the expression of virulence factor has already 
occurred, leading to decreased potential efficacy and benefit of linezolid. Thus, in line with our hypothesis we have 
reduced the treatment duration to 5 days which must start within 72 hours after the collection of the first positive 
blood culture.  
 
3.6 Explanation for choice of comparator  
Placebo will be applied in addition to the standard antibiotic treatment prescribed by the treating physician. Some 
primary outcome measures might be influenced by expectations of physicians and participants. The blinded study 
design ensures blinding of caregivers (including nurses, treating physicians), the participant, the investigators, and 
outcome assessors, and mitigates the bias associated with conduct of an open trial. 
 

 
 
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3.7 Risks / Benefits  
Risks 
The most commonly reported adverse event of linezolid is gastrointestinal intolerance, occurring in approximately 
30-40% of patients when linezolid is administered for a longer duration.72 73 Within the first 5 days of treatment, 
gastrointestinal intolerance manifests in approximately 8% leading to early discontinuation in 3%.73 
Myelosuppression, which primarily presents as thrombocytopenia, is another common adverse effect of linezolid 
that affects up to a third of patients74-77 and occurs more frequently during treatment durations of ≥10 days.74 78 
Moreover, linezolid is a weak, reversible, and unselective monoamine oxidase inhibitor.79 Consequently, the 
combination of linezolid with other serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs) or 
tricyclic antidepressants, can potentially lead to an increase in serotonin activity. The clinical effects of serotonin 
excess can range from mild serotonin-related side effects to severe serotonin toxicity.80 81 In the largest meta-
analysis involving 2208 patients receiving linezolid and 5058 patients not receiving linezolid, the observed incidence 
of serotonin toxicity was 0.4% among patients taking linezolid in combination with a serotonergic agent (compared 
to 0.15% in those taking a serotonergic agent alone).82 Similarly, in a large cohort of 1135 patients, fewer than 0.5% 
experienced serotonin toxicity.83 Further, hyperlactatemia is a rare but potentially severe adverse effect of linezolid 
documented in various case reports.72 84 85 The incidence is not well reported, but may be at 1-3% according to 
retrospective studies.73 86 Finally, it should be noted that linezolid can potentially cause peripheral and/or optic 
neuropathy if treatment is administered for more than 28 days.85 87 Given the short treatment duration of 5 days, we 
expect a low incidence of these adverse events in our study. Nevertheless, we will closely monitor the administration 
of the drug and, if necessary, terminate treatment in response to adverse events (see 8.6 Trial specific preventive 
measures). 
 
Benefits 
S. aureus bacteraemia represents a high burden not only on each affected individual person, but also on the 
community and on the healthcare system in general. 88 89 Even a modest improvement in outcomes resulting from 
our intervention would yield significant overall benefits, alleviating both the direct and indirect consequences of this 
still very severe infection. Should our novel approach against S. aureus bacteraemia prove effective, it holds the 
potential to revolutionise the therapeutic management of patients with this condition, not only in Switzerland, but on 
a global scale. Furthermore, it could serve as a catalyst for both basic and clinical research to explore even more 
efficacious treatments with an anti-virulence approach.  
 
3.8 Justification of choice of study population  
A systematic review from 2022 reported that the median age of patients with S. aureus bacteraemia ranged from 
62 to 72 years4 . A retrospective observational study looking at cases of S. aureus bacteraemia in Switzerland 
between 2008 and 2021 found that 92% of all S. aureus patients were adults2. Overall, mortality seems to be lower 
in children (2-15%)90-93 suggesting that the disease may manifest differently in children compared to adults. Due to 
this difference, we will not include children. 
In all participating hospitals, infectious disease specialists serving as the local principal investigators, are routinely 
involved in the care of patients with S. aureus bacteraemia. We will approach all patients with S. aureus 
bacteraemia, regardless of sex or gender, who meet the inclusion criteria and do not meet any exclusion criteria 
about participating in the LIPS trial. Approximately 10-20% of eligible patients will not be able to provide consent 
themselves due to their compromised health status caused by the S. aureus bacteraemia. These patients stand to 
benefit the most from improved treatment and should not be categorically excluded from trial participation. 
Therefore, we will include these patients whenever feasible by obtaining consent from a close relative or 
confirmation by an independent physician not involved in the study. Once the participant's health improves 
sufficiently to make an informed decision, delayed consent will be sought directly from the participant. We will follow 
Swissethics guidelines for obtaining consent in emergency situations.94 
Patients who are pregnant will not be excluded from study participation per se, as linezolid is not formally 
contraindicated during pregnancy. Limited data exist on the treatment of pregnant women with linezolid, mainly 
from clinical trials in treating multidrug-resistant tuberculosis. In 31 recorded pregnancies under linezolid exposure 
in 7 clinical trials, none reported foetal toxicity.95 In the event of pregnancy, the treating physician and the patient 
(or the patient’s next of kin) will assess whether the potential benefits outweigh the potential risks to the foetus. As 
linezolid has been shown to pass into breast milk,96 97 breastfeeding should be discontinued prior to and throughout 
administration of linezolid. 
Linezolid is a weak, reversible, and unselective monoamine oxidase inhibitor.79 Patients whose background 

 
 
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medication includes other serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs) or tricyclic 
antidepressants, can potentially experience an increase in serotonin activity. The clinical effects of serotonin excess 
range from mild serotonin-related side effects to severe serotonin toxicity.80 81 In the largest meta-analysis involving 
2208 patients receiving linezolid and 5058 patients not receiving linezolid, the observed incidence of serotonin 
toxicity was 0.4% among patients taking linezolid in combination with a serotonergic agent (compared to 0.15% in 
those taking a serotonergic agent alone).82 Similarly, in a large cohort of 1135 patients, fewer than 0.5% 
experienced serotonin toxicity.83 Assuming 20% of study participants are on serotonergic drugs, we would expect 
an additional 0-1 participants with serotonin toxicity in the linezolid arm compared to the placebo arm. In view of the 
low incidence of clinically relevant serotonin toxicity combined with the study design ensuring adequate monitoring 
of participants, patients on serotonergic agents are not excluded from study participation. A detailed list of such 
medications can be found in chapter 8.6 Trial specific preventive measures. 
 
3.9 Summary of Background and Data on Linezolid 
 
S. aureus bacteraemia remains a life-threatening condition with high morbidity and a mortality of up to 30% despite 
antibiotic therapy. Emerging evidence suggests that bacterial virulence factors significantly contribute to organ 
damage and poor patient outcomes. Linezolid, a well-established antibiotic with anti-virulence factor properties, 
offers a promising adjunctive treatment option. Preclinical studies demonstrate that linezolid effectively inhibits S. 
aureus virulence factor expression and improves survival in animal models. Clinical data support its safety and 
efficacy in various S. aureus infections, including pneumonia and bacteraemia. 
Since its approval more than 20 years ago, the risk profile of linezolid has been well-documented. The approved 
treatment duration varies from 10-28 days depending on the cause and location of the infection. Notable adverse 
events of linezolid are myelosuppression, serotonin syndrome, kidney injury, C. difficile-associated diarrhoea, lactic 
acidosis, and neuropathy. Myelosuppression is typically associated with prolonged use (≥10 days) and is reversible 
upon linezolid discontinuation. Serotonin syndrome is very rare with monotherapy and remains uncommon even 
with concurrent serotonergic medications. Renal adverse effects including increased creatinine and rare cases of 
renal failure have been reported with linezolid use. Like many antibiotics, linezolid has been associated with C. 
difficile-associated diarrhoea, which can range from mild diarrhoea to fatal colitis. Lactic acidosis is rare but serious 
and is linked to extended treatment durations. Neuropathy has been described in patients with treatment durations 
exceeding the maximum recommendation of 28 days and is thus very unlikely to occur in this trial. 
Since linezolid will be administered for only 5 days in the LIPS trial, a favourable safety profile is expected. In 
addition, hospitalization of study participants facilitates a close monitoring for any adverse events. 
Given the significant unmet clinical need and the favourable safety profile of short-term linezolid therapy, the 
anticipated benefits — including reduction of virulence factor-mediated complications and improvement in patient-
relevant outcomes — clearly outweigh the manageable risks. The trial will provide critical evidence on whether early 
adjunctive treatment with linezolid improves outcomes in S. aureus bacteraemia. If linezolid proves to be effective 
in treating S. aureus bacteraemia, it holds the potential to improve the therapeutic management of millions of 
patients with this condition worldwide. 
 
 
 

 
 
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4. STUDY OBJECTIVES  
4.1 Overall Objective 
The purpose of the LIPS trial is to evaluate whether the addition of linezolid to standard therapy in participants with 
S. aureus bacteraemia leads to an overall improvement in patient-related outcomes such as mortality, health-
related quality of life, complications, and duration of hospitalisation. 
 
4.2 Primary Objective 
The primary objective is to investigate whether early addition of 5-day treatment with linezolid to standard of care 
improves outcomes at 90 days in participants with S. aureus bacteraemia as measured by the desirability of 
outcome ranking (DOOR).98 99 
 
4.3 Secondary Objectives 
Secondary objectives include exploring the impact of early addition of 5-day treatment with linezolid to standard of 
care on a number of secondary outcomes such as physical and mental health, length of hospital stay (full list in 
section 5 STUDY OUTCOMES). In addition, we aim to explore if potential effects might differentiate between patient 
population based on sex (male vs. female), ICU status at baseline (participants on ICU vs. participants not on ICU), 
and focus of infection (vascular catheter, skin and soft tissue, endocarditis, osteoarticular, pneumonia, other focus, 
or focus not identified). 
 
4.4 Safety Objectives 
The LIPS study aims to assess the safety of early addition of 5-day treatment with linezolid to standard of care 
treatment for S. aureus bacteraemia in a real-world setting. Details on adverse events of special interests can be 
found in chapters 5.4 Safety Outcomes and 9.2.4 Assessment of safety outcomes. 
 
 

 
 
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5. STUDY OUTCOMES  
5.1 Primary Outcome 
The primary outcome utilises the Desirability of Outcome Ranking (DOOR), which has been specifically introduced 
as a patient-centred outcome for S. aureus bacteraemia.100 101 This hierarchical composite outcome ranking has 
the advantage that it can incorporate multiple outcomes (both beneficial and harmful) to measure if patients 
experience better overall outcomes after receiving a specific intervention compared with an appropriate comparator 
(“Good Studies Evaluate the Disease While Great Studies Evaluate the Patient”100). In contrast to composite 
outcomes, the DOOR outcome does not have the limitation that events of different importance are weighted 
equally.102 We modified the proposed ranking based on the feedback of our patient representatives and the ongoing 
SNAP trial.103 The most important outcome for patient representatives was surviving the infection. The second most 
important aspect was that they “are the same as before the disease”, meaning that they have the same level of 
function as before the S. aureus infection. Patient representatives with a history of S. aureus bacteraemia informed 
us that results of their bacterial blood culture were of highest relevance to them during their hospital stay due to 
high uncertainty of the progression of the disease. This was particularly important because diagnostic evidence of 
persistent, relapsing or new S. aureus infection results in new diagnostic steps, interventions and/or new exposure 
to antibiotics with their accompanying toxicities. Therefore, we have implemented the third domain complications, 
including microbiological and clinical failure leading to treatment change, and serious adverse reactions or adverse 
events leading to study drug discontinuation. Finally, hospital length of stay was included as the fourth DOOR 
component, since patient representatives mentioned it as an important outcome. We will use outcome definitions 
consistent with the SNAP trial to facilitate data comparisons.  
DOOR comprises five ranks (Table 3: Desirability of Outcome Ranking (DOOR) outcome used for the LIPS trial). 
This outcome is assessed at day 90. The overall distribution of rankings can then be compared between the control 
and intervention arms, with the final treatment effect estimate being the win ratio, i.e., the probability that a 
participant randomly assigned to the intervention arm has a superior DOOR compared to a participant randomly 
assigned to the control arm99 (see section 11 STATISTICAL METHODS). 
 
Rank 
Alive at 90 
days 
Return to usual 
level of 
function by day 
90 
None of the following complications: 
● 
Microbiological or clinical 
failure leading to treatment 
change 
● 
Serious adverse reaction 
● 
Adverse event leading to study 
drug discontinuation 
Hospital length 
of stay 
1 
Yes 
Yes 
Yes (no complications occurred) 
Ties will be 
resolved using 
the length of 
hospitalisation 
2 
Yes 
Yes 
No (complication occurred) 
3 
Yes 
No 
Yes (no complications occurred) 
4 
Yes 
No 
No (complication occurred) 
5 
No 
Not applicable 
Not applicable 
Not applicable 
Table 3: Desirability of Outcome Ranking (DOOR) outcome used for the LIPS trial 
Detailed definitions of DOOR components: 
Alive at 90 days: defined as alive at 90 days after randomisation 
 
Return to usual level of function by day 90: defined as return to baseline value (or better score) according to the 
modified functional bloodstream infection score104. Baseline is defined as the best score within the 4 weeks before 
randomisation. The scores used will be the following: 
6: Out of hospital, able to complete daily activities without assistance (no limitations) 
5: Out of hospital, able to complete daily activities without assistance but with some limitations (e.g. slow, pain) 
4: Out of hospital, unable to complete daily activities without assistance 
3: Out of hospital; significant disability; requires a high level of care and assistance daily (this includes residential 

 
 
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aged care and nursing homes) 
2: Hospitalised (or equivalent) 
1: On palliative care in terminal phases of life (in hospital or at home) 
 
Complications: 
• 
Microbiological or clinical failure leading to treatment change: This includes any type of adaptation of the 
treatment such as new intervention or surgery, or re-start, prolongation or change of antibiotic treatment 
o 
Microbiological failure: Any positive sterile site culture with S. aureus between 14 and 90 days after 
randomisation. A sterile site means any site of the body where microorganisms are usually absent, 
i.e. below the outer and inner colonised surfaces of the skin and mucous membranes. Positive sterile 
sites cultures include deep visceral and musculoskeletal abscesses obtained in a sterile manner. 
o 
Clinical failure: Newly identified focus of S. aureus between 14 and 90 days after randomisation as 
determined by the site investigator (or delegated physician). This can incorporate clinical, radiological, 
microbiological and pathological findings. 
• 
Serious adverse reaction (SAR, see definition below) 
• 
Any adverse event (irrespective of grade) leading to study drug discontinuation 
 
Hospital length of stay: This corresponds to the duration of the index acute hospital stay from randomisation until 
the day of hospital discharge. Transfers to another acute care hospital for continuation of acute treatment will be 
included in the assessment of hospital length of stay. Days after transfer to rehabilitation centres or switch to 
outpatient parenteral ambulatory treatment will not be included in the acute hospital stay.  
 
5.2 Secondary Outcomes 
The secondary outcomes include each part of the DOOR outcome separately as well as additional patient-relevant 
outcomes and specific outcomes of interest to assess the influence on infection dynamic and control. The secondary 
outcomes have been aligned to the SNAP trial to allow comparison of the data at a later time point.  
 
Separate parts of the DOOR outcome: 
• 
All-cause mortality at 90 days 
• 
Return to usual level of function at day 90 
• 
Microbiological treatment failure 14-90 days after randomisation leading to treatment change 
• 
Clinical treatment failure 14 and 90 days after randomisation leading to treatment change 
• 
Length of hospital stay of acute index hospitalisation 
Adverse events leading to study drug discontinuation 
 
Clinical outcomes: 
• 
Time to death up to day 90 
• 
Time to being discharged alive  
• 
Number of days without being on the ICU up to day 90 
 
Infection dynamics and control: 
• 
Persistent bacteraemia: positive blood culture on day 5 (±1 day) after randomisation 
• 
Two or more systemic inflammatory response syndrome (SIRS) criteria on day 5 after randomisation  
• 
Change in C-reactive protein (CRP) from day 1 until day 5 (±1 day) after randomisation  
• 
Early microbiological treatment failure 5-13 days after randomisation leading to treatment change 
• 
Early clinical treatment failure 5-13 days after randomisation leading to treatment change 

 
 
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• 
Development of any new antibiotic drug resistance in S. aureus until day 90 
• 
Number of days alive and free of antibiotics in the 90 days 
 
Patient-reported outcomes: 
• 
Physical health at day 90 as assessed by the short form 36 (SF-36) questionnaire.105-107 
• 
Mental health at day 90 as assessed by the short form 36 (SF-36) questionnaire.105-107 
  
5.3 Other Outcomes of Interest 
Additional laboratory outcomes for a subset of participants only in participating centres: 
• 
Linezolid plasma concentrations at day 4 or 5 
• 
Minimal inhibitory concentration (MIC) of linezolid for the respective S. aureus strain 
 
5.4 Safety Outcomes 
Safety outcomes encompass any serious adverse events (SAE) and serious adverse reactions (SAR) until day 90 
as well as adverse events of special interest. Definitions can be found in chapter 10.1.1 Definition and assessment 
of (serious) adverse events and other safety related events. 
 
Adverse events of special interest  
(details on how they are assessed is provided in chapter 9.2.4.1 Adverse events: 
• 
Clinical signs of serotonin toxicity until day 7 
• 
Laboratory signs of myelosuppression until day 7 
• 
Hyperlactatemia until day 7 
• 
Acute kidney injury 
• 
C. difficile-associated diarrhoea within 90 days 
 
Further information on safety outcomes (mortality, SAR, AEs leading to discontinuation of trial intervention) can be 
found in chapters 5.1 Primary Outcome and 5.2 Secondary Outcomes.  
 
 

 
 
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6. STUDY DESIGN  
6.1 General study design and justification of design  
LIPS is a pragmatic, multicentre, 1:1 randomised, parallel-group, placebo-controlled, superiority trial with blinded 
participants, physicians, and outcome assessors in the acute-care hospital setting (see Figure 1). 
 
 
 
 
 
 
 
 
 
The LIPS trial was designed with the involvement of four patient representatives to make sure that the assessed 
outcomes are patient relevant and that the burden due to the trial remains minimal for the participants. We have 
chosen a pragmatic trial mainly following routine care (i.e. the majority or outcomes are collected during routine 
care and the additional follow-up consists only of one phone call at day 90 and a quality-of-life questionnaire at day 
90). However, as the outcomes can be influenced by expectations from participants (i.e. level of function) as well 
as the treating physicians (i.e. hospital length of stay) we have chosen a blinded study design to eliminate this 
source of bias.  
 
6.2 Patient and Public Involvement 
The following Patient and Public Involvement (PPI) has been and will be conducted to ensure that the trial is highly 
relevant to patients. We have been collaborating with four PPI representatives (two patient representatives who 
had complicated S. aureus bacteraemias as well as two patient experts) since the preparation of the funding 
application. These PPI representatives have agreed to lend their expertise for the duration of the trial up to the 
dissemination of the trial results. Ahead of every meeting, the PPI representatives are briefed on the current stage 
of the trial and the purpose of the meeting in layman’s terms. Before the finalisation of the first protocol and patient 
informed consent draft, we conducted 3 focus group discussions with the four PPI representatives (2-4 
hours/meeting). 
6.2.1 
PPI activities before receiving approval from authorities 
PPI contribution 
Outcome 
- 
Advised on the patient relevance of the 
proposed outcomes.  
- 
Informed the researchers about important 
aspects not covered by the proposed 
outcomes. 
- 
Discussed what the primary outcome 
should be and help with the exact 
definition. 
- 
Trial outcomes that are relevant to patients 
were chosen and ranked in order of 
importance (DOOR outcome). 
- 
PPI representatives advised to include a 
patient-reported outcome measure on quality 
of life at day 90. 
- 
Reviewed the eligibility criteria with a 
focus on inclusivity and making the trial 
results generalizable. 
- 
Broad inclusion criteria were chosen as 
recommended by the PPI representatives. 
- 
Exclusion criteria focus on safety aspects.  
- 
Provided feedback on how 
understandable the provided lay summary 
was. 
- 
Parts of lay summary were flagged as 
needing further explanation or simplifications 
and edited accordingly. 
- 
Advised on the chosen time points and if 
the study visits are useful and patient 
friendly.  
- 
Outcomes may also be collected by asking 
the participant’s relatives or general 
practitioner. 
- 
Burden for participants with the proposed trial 
Figure 1: Schematic overview of the trial 

 
 
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- 
Assessed burden for patients and 
identified ways to decrease burden, 
dropout rates and incomplete data 
selection.  
design was deemed very low. 
- 
Defined the further study phases during 
which PPI is critical and what form such 
involvement should take (guided by SCTO 
template). 
- 
PPI activities during and after trial conduct 
were planned (see chapter 6.2.2 PPI activities 
after receiving approval from authorities). 
- 
Provided feedback on draft patient 
information and informed consent form 
(ICF) in German. 
- 
Some PPI representatives will also assess 
patient information in other languages 
- 
ICF is concise and comprehensible, giving 
enough information without frightening 
patients regarding their diagnosis. 
- 
Patient-relevant information on background of 
the underlying disease, study procedures, 
risks and adverse events in layman’s terms 
are included. 
 
6.2.2 
PPI activities after receiving approval from authorities 
Planned PPI contribution 
Objective 
- 
Advise on how to approach patients and 
relatives to inform them about study 
participation. 
- 
Incorporating PPI feedback into trainings of 
study sites on how to approach patients and 
relatives in a sensitive manner. 
- 
Participation in DSMB during prespecified 
interim analyses 
- 
Including the patient perspective when 
serious adverse are assessed in the interim 
analysis. 
- 
Discussing which of the results/effects are 
patient relevant and how to best visualise 
the data. 
- 
We will report all outcomes independent of 
the assessed effect. The objective of this 
exchange is to receive feedback which effects 
are most relevant for patients and how data 
should be visualised so that they can be 
understood easily 
- 
Advise on which form the results should 
be communicated.  
- 
Assuring that the study results are 
disseminated to a wide audience.  
- 
Support the communication of results in 
lay language.  
- 
Ascertaining that the study results can be 
communicated to participating patients and 
the general public. 
- 
Discussing the impact and the next steps 
with the researchers.  
- 
Making sure that appropriate action is taken 
based on the study results taking into 
consideration the patient perspective.  
- 
Evaluating the PPI involvement  
- 
Learning how best to involve PPI in future 
collaborative research projects 
 
6.3 Methods of minimising bias  
6.3.1 
Randomisation  
Participants will be allocated 1:1 to either linezolid or placebo for 5 days using block randomisation with varying 
random block sizes of 2 or 4 implemented in the data capture system REDCap®. For more details see chapter 7.3 
Assignment to study groups.  
 
6.3.2 
Blinding procedures  
The treatment allocation will not be revealed to any study staff or participants (i.e., physicians, study nurses, 
participants, outcome assessors). Only the unique randomization number will be visible for blinded personnel. The 
randomisation list will only be accessible to designated staff from Spital-Pharmazie Basel for manufacturing, 

 
 
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labelling and blinding the study medication, and the statistician who will prepare the randomisation list and upload 
it in REDCap®. The study medication will be packaged and dispensed by Spital-Pharmazie Basel to ensure that all 
participants, treating physicians, clinical investigators and study nurses involved in the study (including outcome 
assessors) will remain blinded to treatment allocation throughout the study. 
 
6.3.3 
Other methods of minimising bias  
Not applicable. 
 
6.4 Unblinding Procedures (Code break)  
The study medication (10 tablets per container) with a unique randomisation number will be distributed to the study 
centres. For each unique randomisation number, the study centre will receive a sealed opaque envelope with the 
information if the container contains linezolid or placebo. The treating physician will only be allowed to open an 
envelope if safety concerns require knowing a participant’s allocated intervention. All unblinding procedures must 
be entered within the eCRF. The envelopes will be checked during monitoring visits and after the completion of the 
study. 
 

 
 
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7. STUDY POPULATION  
7.1 Eligibility criteria  
Inclusion criteria: 
• 
S. aureus grown from at least one blood culture 
• 
Hospitalised at a participating centre 
• 
≥18 years old 
• 
Written informed consent or fulfilling criteria for an emergency exception from informed consent 
requirements 
 
Exclusion criteria: 
• 
Administration of the initial drug treatment not feasible within 72 hours since the collection of the first 
positive blood culture with S. aureus  
• 
Documented history of positive blood cultures for S. aureus occurring between 72 hours and 180 days 
prior to the eligibility assessment  
• 
Necrotising fasciitis 
• 
Currently receiving linezolid or clindamycin 
• 
Use of any monoamine oxidase A or B inhibitor within the last two weeks 
• 
Known hypersensitivity to linezolid or any other ingredients of the study drugs 
• 
Current severe thrombocytopenia (i.e. <30x109/l) 
• 
Oral application of study drug not possible (per mouth or per gastric tube) 
• 
Currently breastfeeding 
• 
Local treating team believes that death is imminent and inevitable 
• 
Patient is receiving end of life care and antibiotic treatment is not considered appropriate 
• 
Local treating team believes that participation in the study is not in the best interest of the patient 
• 
Any indication that the patient is unwilling to participate in the study including an advance directive stating 
such unwillingness 
 
General: 
Patients taking serotonergic drugs such as selective serotonin reuptake inhibitors (SSRI) or tricyclic antidepressants 
are not generally excluded. See detailed information on risk assessment and precautions in chapter 8.6 Trial 
specific preventive measures. 
Pregnant women will not be excluded from study participation per se, as linezolid is not formally contraindicated 
during pregnancy. Limited data exist on the treatment of pregnant women with linezolid, mainly from clinical trials 
in treating multidrug-resistant tuberculosis. In 31 pregnancies under linezolid exposure, none reported foetal 
toxicity.95 In the event of pregnancy, the treating physician and the patient (or the patient’s next of kin) will assess 
whether the potential benefits outweigh the potential risks to the foetus. 
Linezolid has been shown to pass into breast milk and accordingly, breastfeeding should be discontinued prior to 
and throughout administration of linezolid. 
7.2 Recruitment and screening  
We anticipate that patients will be recruited at the infectious disease departments of these 12 Swiss hospitals: 
● Basel, University Hospital Basel (Sponsor Investigator centre) 
● Aarau, Cantonal Hospital Aarau 
● Basel, St. Clara Hospital Basel 
● Bern, University Hospital Bern 
● Delémont, Cantonal Hospital Jura 

 
 
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● Lausanne, University Hospital Lausanne 
● Lugano, Cantonal Hospital Lugano 
● Geneva, University Hospital Geneva 
● St. Gallen, HOCH Health Ostschweiz, Cantonal Hospital St. Gallen 
● Winterthur, Cantonal Hospital Winterthur 
● Zürich, University Hospital Zürich 
● Zürich, City Hospital Zürich 
 
Patients will be recruited during their hospitalisation at participating centres. Patients will be flagged as soon as 
S. aureus is detected in a blood culture. The time required from blood collection to the confirmation of S. aureus, 
typically ranging from 12 to 36 hours, will depend on factors such as the time to positivity and the method employed 
for S. aureus identification.108 The results will be immediately reported to the study team according to each centre’s 
infrastructure - either via an automated electronic alarm system or via verbal communication from the clinical 
microbiology laboratory. Infectious disease specialists, serving as the local principal investigators at all participating 
centres, are routinely involved in the care of patients with S. aureus bacteraemia. Their involvement is well 
established and recognized for its positive impact on patient outcomes.109-112 Patients with blood cultures positive 
for S. aureus will be immediately screened for eligibility using the inclusion and exclusion criteria by the local PI or 
delegated physician. Eligible patients will be approached by the local study team as soon as possible. They will be 
informed about the LIPS trial via verbal and written study explanation, which consists of a printed summary in lay 
language including details of the intervention and potentially associated benefits and risks. Each participant will 
receive a consent form offering sufficient details to enable them to make an informed decision about their 
participation. For patients unable to give informed consent due to severe illness or other circumstances, it must be 
checked if a statement of wishes formulated in a state of capacity is available. If no such statement if available, an 
appropriate substitute (i.e., a close relative or a physician not involved in the research project) may make decisions 
based on the presumed wishes and the best interests of the patient as recommended by Swissethics.113 
Participants who were included after receiving consent from their next of kin or confirmation by an independent 
physician will be asked to provide retrospective consent as soon as their health status allow an informed decision. 
The randomisation and intervention will start immediately upon the receipt of a formal written consent. Participants 
will not receive any financial compensation for their participation. The participating centres will receive financial 
reimbursement for establishing the local trial infrastructure and workflow as well as a reimbursement per participant 
to compensate for the costs of the study staff and other resources. 
The sponsor notifies the CEC and the CA of the first study participant, in accordance with Art. 23a ClinO. If the first 
participating person is not included in the trial within two years following the issuance of the last authorization, the 
trial is considered interrupted. The clinical trial may then not be commenced until an application for an extension of 
the time limit has been approved. The application for the extension is submitted to the CEC, and to CA as a 
substantial amendment.  
 
7.3 Assignment to study groups  
Participants will be allocated 1:1 to either linezolid for 5 days or placebo for 5 days. The randomisation will be 
stratified by centre and ICU status at time of enrolment and done using block randomisation with varying random 
block sizes of 2 or 4. The trial statistician will generate the randomisation list outside of the data capture system 
REDCap®. This list will then be uploaded into the data capture system. The goal is to randomise participants such 
that the groups are as balanced as possible with respect to study centre and ICU status at time of enrolment.  
After informed consent has been obtained and all eligibility criteria have been reviewed and met, the local 
investigator (or designated staff) enters the minimal required data into REDCap® (i.e., participant ID, year of birth, 
if participant is on ICU). The allocation is done by REDCap® which will display a unique, randomisation number 
that remains the same throughout the study. Each randomisation number will correspond to a drug container which 
is labelled with the unique randomisation number. 
 
7.4 Criteria for withdrawal / discontinuation of participants  
Participants can withdraw from the study at any time without providing a reason. Participants who discontinue the 
intervention will still be encouraged to complete follow-up assessments. Reasonable effort should be made to 

 
 
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establish the reason for discontinuation while fully respecting the participant’s rights so reasons may be analysed. 
In case of adverse events, the treating physician decides (if possible, together with participants or close relatives) 
whether the study drug must be discontinued. Outcomes of these participants will still be collected, and they remain 
in the intention-to-treat analysis as randomised.  
Participants who were included after receiving consent from their next of kin or confirmation by an independent 
physician will be asked to provide retrospective consent as soon as their health status allow an informed decision. 
If the participant refuses to give this retrospective consent, we will not collect any further data. However, we will 
analyse the data that has been collected up to this timepoint, as excluding these data could bias the analysis. 
 
 

 
 
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8. STUDY INTERVENTION  
8.1 Identity of Investigational Medicinal Products 
8.1.1 
Experimental Intervention 
The IMP in this study is linezolid 600 mg tablets (Linezolid STADA®) as described in chapter 3.2 Investigational 
Medicinal Product (treatment) and Indication. The IMP will be administered orally from day 1 until day 5, twice daily. 
 
8.1.2 
Control Intervention (standard/routine/comparator treatment)  
Participants in the control arm will be receiving oral placebo tablets. Procedures regarding route of administration, 
study treatment duration and treatment phases will be identical in the IMP- and the placebo-group (see chapter 
8.1.1 Experimental Intervention).  
 
8.1.3 
Packaging, Labelling and Supply (re-supply)  
Linezolid STADA® and placebo tablets will be provided as trial supplies to the study centres re-packaged in identical 
opaque containers by Spital-Pharmazie Basel. Each container will contain 10 tablets of either linezolid 600 mg or 
placebo. The containers will be labelled identically except for the unique randomisation number on each container.  
Spital-Pharmazie Basel will be responsible for the labelling, packaging, and shipping of the IMPs. Each centre will 
be supplied with a minimum number of containers at site initiation. The label contains the information required by 
the authorities.  
The trial manager will monitor the recruitment progress of the individual study centres and will inform Spital-
Pharmazie Basel if re-supply is needed. Spital-Pharmazie Basel will arrange for the shipment of the re-supply to 
the centres following instructions by the trial manager. 
 
8.1.4 
Storage Conditions  
The IMP must be kept in a secure, limited access storage area under the recommended storage conditions (i.e. 
identical storage conditions apply as for linezolid tablets that are used in routine practice at the study centre).  
 
8.2 Administration of experimental and control interventions  
8.2.1 
Experimental Intervention  
One linezolid 600 mg tablet will be administered orally twice a day on 5 consecutive days (chapter 3.4 Clinical 
Evidence to Date). For hospitalised participants, the study drug will be distributed in the same manner as a 
participant’s other oral medication. The local investigator or delegated staff will hand over the study drug to the 
nursing team who will distribute the study drug to the participant according to the instructions by the physician and 
according to the site-specific local procedures. In general, each dose/each tablet will be distributed separately to 
the participant and only just before intake. If, based on the treating team's assessment, a participant is unable to 
swallow the study medication, tablets may be crushed and resuspended for easier consumption or for administration 
via a nasogastric tube according to clinical routine and following site-specific SOPs. 
In the unlikely event that participants are discharged home before day 5, they will receive the remaining study 
medication along with detailed instructions on how and when to take them at home.  
 
8.2.2 
Control Intervention 
Dosing and administration of the placebo tablets are the same as for participants in the experimental intervention 
arm.  
 
8.3 Dose modifications  
Drug-related AEs leading to discontinuation of the drug are expected to be extremely rare when linezolid is used 
for 5 days. Discontinuation of IMP may occur in the situations listed in chapter 6.4 Unblinding Procedures (Code 

 
 
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break) and chapter 7.4 Criteria for withdrawal / discontinuation of participants. The study medication will be given 
twice a day for 5 days (in total 10 administrations) with approx. 12 hours interval between each administration. If 
maintaining a fixed 12-hour interval is challenging due to the start time (e.g. if subsequent doses would need to be 
administered in the middle of the night), the treating physician may adjust the first dosing interval according to 
standard practice. However, the interval should not be shortened or extended by more than 6 hours. Further dose 
modifications are not allowed. 
8.4 Compliance with study intervention  
The intake of the study medication will be documented for each tablet (date and time) either electronically in the 
participant's eCRF or directly on a separate leaflet (which will be later transferred to the eCRF). Any missed doses, 
along with the reasons for missing them, must also be documented. The participant will receive instructions for the 
correct storage and administration of IMP at the ward if discharge occurs before completion of the 5-day intervention 
phase. 
8.5 Data Collection and Follow-up for withdrawn participants  
Participants can discontinue the trial intervention at any time without providing a specific reason. Participants who 
wish to withdraw from the study will commonly receive further measurements as part of clinical routine. We will ask 
these participants if we are allowed to collect the corresponding routine clinical data and/or to contact them on day 
90 to assess the primary outcome.  
8.6 Trial specific preventive measures 
Thrombocytopenia is a common adverse event of linezolid, but it is usually associated with treatment durations of 
10 or more days. Given the lifespan of thrombocytes and the short intervention duration of five days in our study, 
we expect a low risk of linezolid-mediated thrombocytopenia. However, thrombocytopenia is also commonly seen 
in participants undergoing sepsis. If participants develop severe thrombocytopenia during the intervention, the local 
investigator should assess if this may be associated with the trial medication and decide on stopping or continuing 
the intervention for this participant. 
Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B 
(e.g. the antidepressant moclobemide or the Parkinson’s medications rasagiline and safinamide) or within two 
weeks of taking any such medicinal product. 
For participants taking serotonergic agents, the local investigator should evaluate if pausing the serotonergic 
medication for the duration of the trial is possible. If not, the local investigator (or delegate) should decide if the 
participant can be included ensuring that potential signs of serotonin toxicity are monitored for the duration of the 
study intervention phase, or if the patient should be excluded. On trial days 1-5, clinical observation for signs of 
serotonin toxicity is required for participants taking any of the following medications: serotonin re-uptake inhibitors, 
tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), directly and indirectly acting 
sympathomimetic agents (including the adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), 
vasopressive agents (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), 
pethidine or buspirone.  
8.7 Concomitant Interventions (treatments)  
All participants receive standard of care treatment for S. aureus bacteraemia as clinically indicated and according 
to local and international recommendations. This includes targeted antibiotic treatment for at least 2 to 6 weeks, 
mostly applied intravenously. The choice of standard of care antibiotic will not be affected by the study. In case 
clindamycin is administered after enrolment, this must be documented in the eCRF. 
8.8 Study Drug Accountability 
Study drugs will be accurately and adequately monitored from shipment to the site until return or disposal.  
Dates of receipt/expiry/use/return will be recorded. 
8.9 Return or Destruction of Study Drug 
Study sites will destroy the left-over study medication according to site-specific SOP. In the rare cases that 
participants are discharged from the hospital before completing the study medication, they will be provided with the 
necessary tablets to continue their treatment at home until the 5-day course is completed. They will be instructed 
to return any unused tablets (e.g., if they are unable to take a dose for any reason) to a pharmacy for proper disposal. 

 
 
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9. STUDY ASSESSMENTS 
9.1 Study flow chart/ table of study procedures and assessments 
 
Study Schedule 
 
Abbreviations: S. aureus – Staphylococcus aureus; SAE – Severe Adverse Event; SAR – Severe Adverse Reaction; SIRS - Systemic 
Inflammatory Response Syndrome; ICU – Intensive Care Unit; CRP – C-Reactive Protein; ALT – Alanine Transaminase; gGT – Gamma-glutamyl 
Transferase; Hb – Haemoglobin; Tc – Thrombocytes; Lc – Leukocytes; SF-36 – Short Form-36 
1 Baseline data include: date of hospital admission, index blood culture, linezolid susceptibility, ethnicity, vital signs, comorbidities, standard 
antibiotic treatment, markers of severity (mechanical ventilation, cardiac arrest, use of vasopressors, ICU), injection drug use, mental health 
diagnosis. 
2 Assessment of persistent bacteraemia. Only required if day 2 blood culture is positive or recorded if done as part of standard of care. 
3 Choose the result that represents the highest level recorded between day 6-14. 
4 Linezolid trough concentration is only measured in a subset of participants in participating centres. 
5 Adverse events of special interest until day 7 include: serotonin toxicity, myelosuppression, hyperlactatemia; until day 14: acute kidney injury; 
until day 90: C. difficile-associated diarrhoea. 
 
 
Screening
Enrolment
Close-out
Time point
Day 1
Day 2
Day 3
Day 4
Day 5 
Day 7
Day 14
Day 28
Discharge 
day
Day 90
S. aureus  positive 
blood culture
X
Identification of 
patient
X
Eligibility checks
X
Informed consent
X
Randomisation
X
IMP administration
X
X
X
X
X
Time point
Day 1
(-1 day)
Day 2
Day 3
(±1 day)
Day 4
Day 5
(±1 day)
Day 7
(±1 day)
Day 14 
(±3 days)
Day 28
(±4 days)
Discharge 
day
Day 90
(±7 days)
Baseline data
 X1
SIRS criteria
X
All-cause mortality
Clinical failure
X
X
X
Length of hospital 
stay
X
Length of ICU stay
X
Antibiotic and/or 
surgical treatment 
X
Blood cultures
X 
 X2
Creatinine
X
X
  X3
CRP 
X
X
ALT and gGT
X
X
  X3
Blood count 
(Hb, Tc, Lc)
X
X
X
X
Linezolid trough 
conc.
 X4
Microbiological 
failure
X
X
X
New antibiotic 
resistance 
X
Quality of life 
(SF-36)
X
Return to usual level 
of function
X
Serotonin toxicity, 
myelosuppression, 
hyperlactatemia5
X
X
X
X
X
X
Acute kidney injury5
X
X
C. difficile -
associated 
diarrhoea5
X
SAE / SAR
Collected until day 90
Assessed until day 90
0-72h before 
randomisation
Intervention phase  
In-Hospital Follow-Up 
(applicable only if participant remains hospitalised)
Safety assessments
Patient reported outcomes
Clinical assessments
Laboratory assessments
0-72h before 
randomisation

 
 
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9.2 Assessments of outcomes  
9.2.1 
Assessment of primary outcome  
The primary outcome utilises the Desirability of Outcome Ranking (DOOR) and is comprised of the following 4 
assessments: 
i) 
“Alive on day 90” and “return to usual level of function by day 90” will be documented by local investigators 
or delegated staff. Participants who did not die during hospitalisation will be called on day 90 (±7 days). If 
a routine patient visit coincides with this time point, the assessment may be done in person. If the 
participant can’t be reached, the local investigator or designated personnel will make at least 5 attempts 
at different times of the day to reach the participant. If these fail, reasonable attempt will be made to acquire 
the information from relatives, caregivers, or the participant’s emergency contact or primary care physician.  
 
ii) 
During the phone call at day 90 (±7 days), the participant will be asked to rate their level of function in 
the 4 weeks prior to their bacteraemia and their current level of function from 6 to 1 according to the 
modified functional bloodstream infection score104:  
6: Out of hospital, able to complete daily activities without assistance (no limitations) 
5: Out of hospital, able to complete daily activities without assistance but with some limitations (e.g. 
slow, pain) 
4: Out of hospital, unable to complete daily activities without assistance 
3: Out of hospital; significant disability; requires a high level of care and assistance daily (this includes 
residential aged care and nursing homes) 
2: Hospitalised (or equivalent) 
1: On palliative care in terminal phases of life (in hospital or at home) 
Baseline is defined as the best score within the 4 weeks before randomisation. If the participant is alive 
but unable to answer the questions, their caregiver, relatives, or primary care physician will answer the 
questions to their best knowledge. 
 
iii) “Complications” will be assessed by evaluation of the participant during hospitalisation either by direct 
observation or by laboratory assessments. The data are accessed from hospital information systems and 
entered into the RedCap® database by the local investigator or designated personnel. 
a. 
Microbiological failure: Any positive sterile site culture with S. aureus between 14 and 90 days after 
randomisation. A sterile site means any site of the body where microorganisms are usually absent, 
i.e. below the outer and inner colonised surfaces of the skin and mucous membranes. Positive sterile 
sites cultures include deep visceral and musculoskeletal abscesses obtained in a sterile manner. 
b. 
Clinical failure: Newly identified focus of S. aureus between 14 and 90 days after randomisation as 
determined by the site investigator. This can incorporate clinical, radiological, microbiological, and 
pathological findings. 
c. 
Treatment change: This includes any type of adaptation of the treatment such as new intervention or 
surgery, or re-start, prolongation or change of antibiotic treatment initiated and documented by the 
treating physician. 
d. 
Serious adverse reactions are assessed and documented by the treating physician. 
e. 
Any adverse event (irrespective of grade) leading to study drug discontinuation is documented by the 
treating physician. 
 
“Complications” a and b will be routinely captured in the eCRF by the local investigator (or a delegated 
physician), based on hospital information system data on day 28, 42, and 90 and at the day of hospital 
discharge. An independent and blinded outcome assessment board will review all microbiological and 
clinical failures to ensure consistency.  
On day 90, information on treatment changes (“complication” c) will be assessed from hospital information 
system data. SAE (“complication” d) will be documented as soon as an investigator becomes aware of a 
SAE (see chapter 10.1.1 Definition and assessment of (serious) adverse events and other safety related 
events). For all serious adverse events (SAEs), the independent and blinded data safety monitoring board 
(DSMB) will review any suspected relation to the study drug (defining the SAE as an SAR). In cases where 
the participant is transferred to another hospital, the local investigator must contact the new hospital to 
assess the hospital length of stay and potential SAE. Adverse events (“complication” e) will be assessed 

 
 
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as outlined in chapter 9.2.4 Assessment of safety outcomes. 
 
iv) “Hospital length of stay” corresponds to the duration of the acute hospital stay from the day of 
randomisation into the LIPS trial until day of hospital discharge. These data are assessed using hospital 
information system data. In case participants are transferred to another acute care hospital (“new hospital”), 
the local investigator (or delegated personnel) must contact the “new hospital” to receive the information 
when the participant was discharged from the “new hospital”. Outpatient parenteral antibiotic treatment or 
transfer to rehabilitation centres are not part of the acute hospital stay.  
 
9.2.2 
Assessment of secondary outcomes 
The secondary outcomes include each part of the DOOR outcome separately as described in chapter 9.2.1 
Assessment of primary outcome and time to death up to day 90.  
Further secondary outcomes will be assessed as follows: 
Clinical outcomes: 
• 
Time to being discharged alive (assessed until day 90) 
In the eCRF, we collect the day of hospital discharge (see 5.1 Primary Outcome for detailed definition of 
primary outcome). For participants who die during the hospitalisation, 90 days will be recorded.  
• 
Number of days without being on the Intensive Care Unit (ICU) up to day 90 (i.e. mean number of days 
being alive without being on the ICU between randomisation until day 90). 
After day 90 we will collect from the hospital information system data how many days the participant spent 
on the ICU. Together with the available data on mortality, we will calculate the “Number of days without 
being on the ICU”. 
 
Infection dynamics and control: 
Information on these outcomes is collected from the hospital information system data. 
• 
Persistent bacteraemia: positive blood culture on day 5 (±1 day) after randomisation. If blood culture on 
day 2 or 3 is negative, then day 5 blood culture will be assumed to be negative (in case it is not carried 
out).  
• 
Two or more systemic inflammatory response syndrome (SIRS) criteria on day 5 after randomisation. This 
includes: 1. Abnormal body temperature (<36°C or >38°C), 2. tachypnoea or mechanical ventilation (RR 
>20 breaths per minute), 3. tachycardia (HR >90 beats per minute in an adult, 4. abnormal leukocyte count 
(from routine blood sampling on day 5 ±1 day, defined as >12.0 x 109/L or <4.0 x 109/L or >10% of immature 
(band) forms). 
• 
Change in C-reactive protein (CRP) from randomisation until day 5 (±1 day). Day 1 CRP means any blood 
CRP measurement taken on randomisation day 1 or the calendar day prior to randomisation. If there is 
more than one measurement, the value recorded is the one taken closest before randomisation.  
• 
Early clinical treatment failure between 5 and 13 days after randomisation leading to treatment change. 
Newly identified focus of S. aureus between 14 and 90 days after randomisation as determined by the site 
investigator. This can incorporate clinical, radiological, microbiological, and pathological findings.  
• 
Early microbiological treatment failure between 5 and 13 days after randomisation leading to treatment 
change. Any positive sterile site culture with S. aureus between 5 and 13 days after randomisation. A 
sterile site means any site of the body where microorganisms are usually absent, i.e. below the outer and 
inner colonised surfaces of the skin and mucous membranes. Positive sterile site cultures include deep 
visceral and musculoskeletal abscesses obtained in a sterile manner. 
• 
Development of any new antibiotic drug resistance in S. aureus until day 90. This includes any new 
resistance absent in the S. aureus from the initial blood culture and detected in any S. aureus cultured 
after the start of the intervention.  
• 
Days alive and free of antibiotics up to day 90 
• 
At hospital discharge, the number of days a patient received antibiotics will be recorded. At day 90, an 
additional check will be conducted in case additional antibiotics were prescribed after hospital discharge. 
 

 
 
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Patient-reported outcomes: 
SF-36 questionnaire:105-107 This represents a validated patient-reported outcome measure and will give more 
detailed information of the patient’s physical, mental, emotional, and social well-being. Participants will receive this 
questionnaire on day 90 after randomisation either via mail or E-mail (based on participant preference). The 
questionnaire will be available in German, English, French, and Italian. From the SF-36, the following two outcome 
measures are derived: 
• 
Physical health at day 90 (measured with the SF-36 questionnaire, Mental Component Summary) 
• 
Mental health at day 90 (measured with the SF-36 questionnaire, Physical Component Summary) 
 
9.2.3 
Assessment of other outcomes of interest in a subset of participants 
The following other outcomes of interest will only be collected at participating study centres and therefore will only 
be collected from a subset of trial participants. 
• 
Linezolid trough plasma concentration at day 4 or 5 
• 
Linezolid minimal inhibitory concentration of the respective S. aureus strain from the blood 
Measurement of linezolid trough levels is an established assay that is routinely performed by the USB diagnostic 
laboratory and can be ordered from the standard catalogue of analyses. The laboratory will perform linezolid trough 
analyses in batches on plasma samples collect and frozen by the participating centres (see 9.3.10 Measurement 
of trough levels of linezolid in a subset of participants (day 4-5)). 
For the same participants, the minimal inhibitory concentration (MIC, in mg/l) of linezolid for the respective S. aureus 
strain will be measured according to microbiological standard procedures used for clinical routine. In general, this 
will be done by the gradient diffusion method (Etest).114 
 
9.2.4 
Assessment of safety outcomes 
9.2.4.1 
Adverse events  
Adverse events that will be documented by the local investigator or a delegated physician are the following: 
Adverse events of special interest: 
• 
Clinical signs of serotonin toxicity until day 7 
Serotonin toxicity will be assessed during clinical routine. In case of clinical signs of serotonin toxicity, the 
Hunter criteria and diagnostic algorithm will be used (including spontaneous or inducible clonus, ocular 
clonus, tremor, hypertonia and hyperthermia, agitation or diaphoresis, hyperreflexia). Written instructions on 
how to assess the hunter criteria (only in case of clinical suspicion of serotonin toxicity) are provided in the 
appendix, chapter 18.2 The Hunter Serotonin Toxicity Criteria: for diagnosing serotonin syndrome.  
• 
Laboratory signs of myelosuppression until day 7 
Participants will be monitored for signs of myelosuppression (thrombocytopenia, anaemia, leukopenia) as 
part of the clinical routine blood sampling and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) of the US National Institute of Health/National Cancer Institute 115. This includes 
for thrombocytopenia grade 1: platelet between lower limit of normal – 75 x 109/L, grade 2: 75 – 50 x 109/L, 
grade 3: 50-25 x 109/L, grade 4, < 25 x 109/L; for anaemia: grade 1: haemoglobin between lower limit of 
normal – 100 g/l, grade 2: < 100-80 g/l, grade 3: < 80 g/l, grade 4: life-threatening consequences; urgent 
intervention indicated, grade 5: death; and for leukopenia: grade 1 leukocytes between lower limit of normal 
– 3.0 x 109/L, grade 2: <3.0 – 2.0 x 109/L, grade 3: <2.0 – 1.0 x 109/L, grade 4: < 1.0 x 109/L. 
• 
Evidence of hyperlactatemia until day 7 
In case of a clinical suspicion of hyperlactatemia, local investigators must collect a blood sample to assess 
if the lactate level is above the upper norm according to specific laboratory-defined reference ranges. For 
increased lactate levels, the causality with the study treatment will be assessed (see chapter 10.1.1 
Definition and assessment of (serious) adverse events and other safety related events). 
• 
Acute kidney injury until day 14 
Acute kidney injury according to the modified Kidney Disease Improving Global Outcomes (KDIGO) stage 1 
is defined as an increase in serum creatinine of ≥26.5 µmol/L from randomisation (baseline) to study day 5 
or an increase in serum creatinine by 1.5 times or more the level of randomisation within 14 days of 

 
 
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randomisation. To collect this outcome, the serum creatinine at baseline (on randomisation day 1 or the 
calendar day prior to randomisation), day 5 (±1 day), and only if participant remains hospitalised, at day 14 
(±3 days) will be documented in the eCRF. The values will be captured from available data in the hospital 
information system or from the participant’s primary care physician, respectively. 
• 
C. difficile-associated diarrhoea within 90 days.  
The treating clinicians will assess for C. difficile infection based on the centre-specific diagnostic algorithm 
if clinical suspicion arises due to diarrhoea during antibiotic treatment. C. difficile infection will be evaluated 
on day 14, at discharge, and on day 90 by reviewing the participant’s electronic health records. If a participant 
reports severe diarrhoea during a 90-day follow-up phone call, occurring after discharge and managed 
outside the centre, the responsible physician may be contacted to determine if a C. difficile infection was 
diagnosed. 
 
9.2.4.2 
Laboratory parameters 
Blood sampling will be done according to clinical routine. Laboratory-specific adverse events will be measured as 
part of the clinical routine as outlined above. No additional tissue sampling or body fluids are necessary. 
 
9.2.4.3 
Vital signs 
Vital signs are measured according to clinical routine. No additional study-specific vital sign measurements are 
necessary. 
 
9.2.5 
Assessments in participants who prematurely stop the study 
Participants who withdraw from the study will receive further measurements as part of clinical routine. This includes 
all relevant assessments of adverse events.  
 
9.3 Procedures at each visit 
All visits except the 90-day follow-up will take place during the index hospitalisation and will be integrated or part of 
the clinical routine management of the participants.  
 
9.3.1 
Screening and identification of patients (Up to 72 hours before randomisation) 
In patients suspected of having a bloodstream infection, blood is routinely drawn into blood culture bottles. These 
bottles are sent to the respective centre-specific laboratory for diagnostic microbiology to be incubated at 
approximately 37°C. When growth is detected in the bottles, pathogen identification diagnostics are initiated 
according to the laboratory-specific work instructions. If it is a case of S. aureus bacteraemia, blood culture bottles 
typically become positive (detection of bacterial growth in the bottle) after about 9 hours to 1 day of incubation. 
Eligible patients will be identified by having positive blood cultures with S. aureus. Therefore, screening for eligible 
patients will primarily be done through regular review of the results of blood culture results sent to the diagnostic 
microbiology laboratory of each centre. Each centre will implement centre-specific procedures to ensure prompt 
notification of a positive blood culture result with S. aureus. This can occur through an electronic alert system or 
through other communication channels, depending on what is available and practical. Infectious diseases 
specialists of each centre are routinely involved in all patients with S. aureus bacteraemia. The goal is to identify 
potential participants as quickly as possible. Any microbiological identification method to identify S. aureus used in 
routine practice can be applied to positive blood cultures: PCR (polymerase chain reaction) results as well as other 
methods (e.g., MALDI-TOF: Matrix-Assisted Laser Desorption/Ionization-Time of Flight) are acceptable. PCR 
results (usually part of commercially available multiplex panel PCR) are typically available about 3 hours after 
detecting growth in the blood cultures; without PCR, pathogen identification is usually available within 24 hours. 
 
9.3.2 
Enrolment of participants (0-72 hours before randomisation) 
Once a patient with S. aureus bacteraemia has been identified, the responsible centre-specific study team will 
assess whether the patient meets the inclusion criteria for the study. If this is the case, the site investigator or a 
delegated and study-specific trained person will approach the hospitalized patient. The patient will be informed 

 
 
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about the study and asked if they wish to participate. The patient should be given time to discuss any questions or 
uncertainties they may have. The patient will receive the informed consent form along with written explanations 
about the purpose and procedures of the study. Once the patient agrees to participate in the study, they will have 
to provide written consent by signing the appropriate form.  
If a patient is unable to give an informed consent due to medical reasons (e.g., lack of consciousness due to severity 
of illness), a family member or a study-independent, treating physician should decide on the inclusion in the study 
on behalf of the patient. If the patient can be included, the patient representative should sign the corresponding 
informed consent form. When such a participant regains the ability to make decisions, the study inclusion will be 
reviewed with them by the study team, and a new informed consent will be signed. The participant may choose to 
withdraw from the study at any point. 
The study team informs the care team (doctors, nursing staff) about the participant's participation in the study. Each 
centre will establish its own process how to distribute this information.  
 
9.3.3 
Randomisation (day 1) 
Once a participant is enrolled via informed consent, the participant will be randomly assigned to a study arm through 
electronic randomisation within the REDCap® database. This will be initiated and coordinated by the local 
investigator (or designated personnel). All involved persons (participant, treating team, study team) will remain 
blinded to the allocation throughout the entire study duration – except in the case of emergency unblinding (see 
chapter 6.4 Unblinding Procedures (Code break)) 
 
9.3.4 
Assessment of baseline characteristics (day 1) 
Most study-specific baseline characteristics are assessed as part of the clinical routine and can be extracted from 
the patient charts of each centre. The baseline characteristics include date of hospital admission, index blood 
culture, linezolid susceptibility, ethnicity, vital signs, polymicrobial bacteraemia (defined as more than one organism 
[at species level] in the index blood cultures, excluding those organisms judged to be contaminants by the treating 
clinicians), comorbidities, standard antibiotic treatment, markers of severity (mechanical ventilation, cardiac arrest, 
use of vasopressors, ICU), labour force status, injection drug use, and mental health diagnosis. The data closest 
to the time before start of the study treatment should be used. The study team of each site will check at the time of 
randomisation if all relevant information is available from the clinical routine assessment and – if necessary – will 
add the missing information by contacting the treating team or the participant directly. Together with the participant, 
the local investigator (or a delegated physician) will assess the level of function 4 weeks before randomisation. In 
case the participant is not able to provide this information, this data will be assessed at day 90 (asking about their 
level of function 4 weeks before their S. aureus bacteraemia). 
 
9.3.5 
Treatment (day 1 – day 5) 
Each centre will implement the trial-specific procedures in accordance with local circumstances to ensure the 
administration and documentation of the study medication. The study medication should be prescribed and handled 
by the medical team in the same way as other oral medication during hospitalisation. The study team will hand over 
the study medication to the responsible medical treatment team on the respective ward. The study medication will 
be clearly labelled and stored in a designated location according to the centre’s guidelines and prespecified 
workflow for the study. The study medication should be administered alongside the participant's other medications 
during hospitalization, generally by the nursing staff. The study medication should be administered as soon as 
possible once a participant has been enrolled and randomised. Thus, the first dose may also be given at night or 
at any time during the day. The study medication will be given twice daily for five days (in total 10 administrations) 
with approx. 12 hours interval between each administration. If maintaining a fixed 12-hour interval is challenging 
due to the start time (i.e., if subsequent doses would need to be administered in the middle of the night), the treating 
physician may adjust the interval according to standard practice. However, the interval should not be shortened or 
extended by more than 6 hours. It must be ensured that the start and stop of the treatment, the timing of each 
individual administration, and any missed doses are documented and can be traced for each participant. If a dose 
was not administered, the reason for this should be documented. 
Most study-specific baseline characteristics are assessed as part of the clinical routine and can be extracted from 
the patient charts of each centre. The baseline characteristics include date of hospital admission, index blood 
culture, ethnicity, vital signs, comorbidities, standard antibiotic treatment, markers of severity (mechanical 
ventilation, cardiac arrest, use of vasopressors, ICU), injection drug use, and mental health diagnosis. The data 

 
 
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closest to the time before start of the study treatment should be used. The study team of each site will check at the 
time of treatment start if all relevant information is available from the clinical routine assessment and – if necessary 
– will add the missing information by contacting the treating team or the participant directly. 
 
9.3.6 
Assessment of routine laboratory measurements (day 1-7)  
Laboratory assessments at start and during treatment will be part of the clinical routine. Either on the day before or 
on the day of study treatment start, participants will receive routine blood sampling which includes blood count (Hb, 
Tc, Lc), measurement of renal function (creatinine) and liver function (ALT, gGT), as well as inflammatory parameter 
(CRP). The study team will review the blood samples at start and during treatment and will re-order any missing 
laboratory measurements from the collected blood samples if, in rare cases, the necessary measurements for the 
study according to the visit plan were not routinely performed. No additional blood should be drawn to assess clinical 
routine measurements. The blood count should be measured 4 times between day 1 (-1) and day 7 (±1), creatinine 
and CRP at least on day 1 and day 5 (±1), creatinine also on day 14 (±3) if a participant is still hospitalised.  
 
9.3.7 
Subproject Molecular mechanisms of S. aureus bacteraemia (day 1 until 48h after the patient’s 
first negative blood culture) 
Only for a subgroup of patients included in Basel, Switzerland.  
Blood will be used to determine the location of S. aureus in the blood (intra- or extracellular). 
For this, a maximum of one additional 7.5 ml EDTA tube of blood per day will be collected from day 1 until follow-
up blood cultures remain negative for 48 hours. 
• 
For patients who consented to further analysis of S. aureus in their blood, blood samples will be collected 
daily. If no routine blood work is performed on an eligible day, an additional blood draw should be 
performed to collect the sample. 
• 
For patients enrolled via the confirmation of an independent physician under emergency exception from 
informed consent requirements, blood samples will only be collected during routine blood drawing. 
• 
For patients who refused consent to further analysis in the blood, no additional blood samples for the 
subproject will be taken. 
  
9.3.8 
Follow-up blood cultures (day 2, day 5 ±1) 
Follow-up blood cultures are routinely performed and repeated in S. aureus bacteraemia until blood cultures 
become negative. This belongs to the guidelines-supported management of such infections. At day 2 after trial 
enrolment one further pair of blood culture should be drawn. This needs to be ordered by the treating physician. If 
the prior blood cultures were still positive for S. aureus, then these follow-up blood cultures will be routinely ordered 
and drawn. If the prior blood cultures were negative, then the blood cultures at day 2 need to be ordered additionally 
to the clinical routine. If day 2 blood culture stayed positive, then further follow-up cultures are mandated at day 5 
(±1) and will be part of the clinical routine as outlined above. 
 
9.3.9 
Assessment of SIRS criteria (day 5 ±1) 
The components of the SIRS criteria (abnormal body temperature, mechanical ventilation, tachycardia, and 
abnormal leucocytes) are routinely assessed and documented during clinical management of the hospitalised 
participants. The vital parameters (body temperatures, respiratory rate, pulse) are usually measured at least once 
daily. Leukocytes are usually measured every 1-3 days. Tachypnoea is assessed when clinically indicated. Thus, 
these criteria will be collected from the hospital information system data. 
 
9.3.10 
Measurement of trough levels of linezolid in a subset of participants (day 4-5) 
Participating centres will collect one 7.5 ml Monovette® Li-Heparin from participants between day 4 and 5 after 
randomisation for a representative linezolid trough measurement. Plasma sampling may be combined with the 
routine blood draw but should be timed immediately before the next linezolid dose. 
Plasma should be isolated by centrifugation and frozen as soon as possible after blood draw, but at the latest within 
6 hours. Samples will be stored at -80°C until shipment. Periodically, samples are shipped on dry ice to the 
University Hospital Basel where linezolid trough levels will be analysed by the diagnostic laboratory. 

 
 
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9.3.11 
Assessment of adverse events of special interest (day 1-5, day 14 ±3, discharge day) 
• 
Clinical signs of serotonin toxicity until day 7: Serotonin toxicity will be assessed during clinical routine. 
Participants will routinely be visited daily by the treating physician. Daily measurement of vital signs including 
blood pressure is part of the clinical routine. In case of clinical signs of serotonin toxicity, the Hunter criteria 
and diagnostic algorithm will be used (including spontaneous or inducible clonus, ocular clonus, tremor, 
hypertonia and hyperthermia, agitation or diaphoresis, hyperreflexia). In case of clinical signs of serotonin 
toxicity, the IMP administration will be halted. The local investigator will be involved to re-assess the clinical 
picture and to confirm or reject the observation. The local investigator will then decide if the participant can 
continue taking the IMP or needs to stop the intervention.  
• 
Laboratory signs of myelosuppression until day 7: Participants will be monitored for signs of 
myelosuppression (thrombocytopenia, anaemia, leukopenia) as part of the clinical routine blood sampling. 
If blood count shows signs of myelosuppression, the local investigator will be involved to assess the potential 
causality between the IMP and the laboratory measurements. The local investigator will then decide if the 
participant needs to stop the intervention. 
• 
Evidence of hyperlactatemia until day 7: In case of a clinical suspicion of hyperlactatemia, the local 
investigators must collect a blood sample to assess if the lactate level is above the upper norm according to 
specific laboratory-defined reference ranges. For increased lactate levels, the causality with the study 
treatment will be assessed. The local investigator will then decide if the participant needs to stop the 
intervention. 
• 
Acute kidney injury: the kidney function is measured in the blood (creatinine) regularly as part of the clinical 
routine. To collect this outcome, the serum creatinine at baseline, on day 5 (±1), and only if participant 
remains hospitalised, at day 14 (±3 days) will be documented. The values will be captured from available 
data from the hospital information system. 
• 
C. difficile-associated diarrhoea within 90 days: The treating clinicians will assess for C. difficile infection 
based on the centre-specific diagnostic algorithm if clinical suspicion arises due to diarrhoea during antibiotic 
treatment. C. difficile infection will be evaluated on day 14, at discharge, and on day 90 by reviewing the 
participant’s electronic health records. If a participant reports severe diarrhoea during a 90-day follow-up 
phone call, occurring after discharge and managed outside the centre, the responsible physician may be 
contacted to determine if a C. difficile infection was diagnosed. 
 
9.3.12 
Assessment of serious adverse events and serious adverse reactions (from enrolment until 
discharge, and at day 90 ±7)  
All assessments of serious adverse events (SAE) and serious adverse reactions (SAR) during acute care 
hospitalisation will be part of the routine clinical work-up and monitoring of the participants. This generally includes 
a daily routine visit and evaluation of the participant by the treating physician. Further, the vital signs (blood pressure, 
pulse, body temperature, oxygenation) will be measured regularly by the nursing staff. Blood samples will regularly 
be taken to measure organ function (myelopoiesis, liver, kidney). For severely ill participants treated on the 
intensive-care unit, the clinical as well as laboratory evaluation is generally much more frequent. Any serious 
adverse event will be reported to the study-site principal investigator, who then assesses whether there is a 
reasonable causal relationship with the IMP. Assessment will take place from enrolment until acute care hospital 
discharge. Further, any post-discharge occurrence of an SAE/SAR will be assessed during the phone call at day 
90 follow-up. 
 
9.3.13 
Assessment of new antibiotic resistance (discharge day) 
Any S. aureus detected at a new site of infection in a participant will routinely be tested for its antibiotic susceptibility 
as part of the clinical microbiological work-up and according to the respective standards of the responsible 
laboratory. In case of persistent or repetitive detection of S. aureus in the blood, the microbiological laboratory will 
decide if an antibiotic susceptibility testing should be repeated. Detection of any new resistance not present in the 
S. aureus from the initial blood culture will count as new antibiotic resistance. The standard susceptibility testing 
suffices; additional determination of the MIC of an antibiotic is not necessary except if clinically indicated. The data 
will be gathered from the hospital information system. 
 

 
 
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9.3.14 
Assessment of microbiological failure (day 28, discharge day, day 90 ±7) 
“Early microbiological failure” and “microbiological failure” are defined as the identification of any new focus of 
S. aureus between 5 and 13 days, or 14 and 90 days after randomisation, respectively. This will be assessed by 
reviewing the participant’s microbiological results in the electronic health records. Any detection of S. aureus (by 
culture or by culture-independent methods such PCR) within the time frame will be further investigated in detail by 
reviewing the corresponding clinical health records. Thereby it can be determined – if necessary - whether the 
S. aureus originated from a sterile site. Any change of the initial antibiotic (and/or surgical) treatment plan will be 
analysed if it occurred due to proven detection of S. aureus at a sterile site. During the 90-day telephone call, it will 
be asked if any microbiological samples were taken outside of the corresponding centre. If this is the case, the 
responsible laboratory will be directly contacted to ask to provide the corresponding results. The principal 
investigator of each site will finally decide if a microbiological failure occurred. Furthermore, the independent 
outcome assessment board will review each documented microbiological failure on a case-by-case basis. 
 
9.3.15 
Assessment of clinical failure (day 14, day 28, discharge day, day 90) 
“Early clinical failure” and “clinical failure” are defined as the identification of any new focus of S. aureus between 5 
and 13 days, or 14 and 90 days after randomisation, respectively. This encompasses not only microbiological 
findings (i.e. detection of S. aureus) but also clinical, radiological and histological results. Clinical failure will be 
assessed by screening of patient history on multiple levels in the available electronic health records and during the 
telephone call at day 90: any change of the initial antibiotic (and/or surgical) treatment plan will be analysed if it 
occurred due to proven or assumed new focus of S. aureus. Further, all available microbiological results, 
histological results as well as radiological examens will be screened for signs of newly identified S. aureus focus/foci. 
In case of ambiguous interpretations, the treating physicians can be contacted directly to inquire his/her 
interpretation of the results. The principal investigator of each site will finally decide if a clinical failure occurred. 
Furthermore, a blinded panel of experts, selected by the trial investigators, will review each documented clinical 
failure on a case-by-case basis. 
 
9.3.16 
Assessment of length of hospital stay and length of ICU stay (discharge day) 
At the time of acute care hospital discharge, the length of hospital stay will be documented according to the hospital 
records. Similarly, length of stay on the ICU will be extracted from the electronic hospital records. 
 
9.3.17 
Assessment of all-cause mortality (day 7, day 14, day 28, day 90 ±7) 
The data will be examined in both the hospital records and, when available, external documents to ascertain 
whether the participant has died during the follow-up period. If the participant cannot be reached for the 90-day 
telephone follow-up, their emergency contact or primary care physician will be contacted. Documentation of the 
presumed cause of death is not mandatory. 
 
9.3.18 
Assessment of return to usual level of function (day 90 ±7) 
During the phone call at day 90, the participant will be asked to rate their level of function in the 4 weeks prior to 
their bacteraemia and their current level of function from 6 to 1 according to the modified functional bloodstream 
infection score (see chapter 5.1 Primary Outcome for the corresponding scale). All levels of the scale will be 
presented orally in a clear and precise manner, ensuring that the participant has adequate time to self-assess. In 
the event of any misunderstanding regarding the classifications, the scale will be repeated as necessary. If the 
participant is unable to perform the self-assessment (whether due to medical reasons or limited communication 
abilities over the phone), efforts will be made to contact a family member or the participant's primary care physician 
to obtain the information. 
 
9.3.19 
Assessment of physical and mental health (quality of life, SF-36, day 90 ±7) 
Quality of life (i.e. mental health and physical health) will be assessed at day 90 through the SF-36 questionnaire. 
Participants will have the option to complete it either electronically or on paper. At the time of enrolment in the study, 
participants will be asked which method they prefer. For the electronic version, participants will be requested to 
provide their email address and/or mobile phone number. This information will be encrypted and accessible only to 
the local Investigator of the respective centre. On day 90, participants will be notified via email or mobile phone 

 
 
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message about the task and will be directed to the corresponding online version of the study-specific SF-36 
questionnaire. For participants who prefer the written version, a letter with a printed version of the SF-36 
questionnaire will be sent by postal mail, including an envelope for returning the filled questionnaire. We expect that 
participants will need approximately 10 minutes to complete the questionnaire. At the time of the 90-day telephone 
call, participants will be asked whether they have already completed the questionnaire and if they have any 
questions regarding it. It is not intended for the questionnaire to be filled out verbally over the phone, as this could 
potentially introduce bias. 
 
 
 

 
 
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10. SAFETY  
10.1 Drug studies 
During the entire duration of the study, all serious adverse events (SAEs) are collected, fully investigated and 
documented in source documents and case report forms (CRF). Predefined adverse events of special interest (AE) 
critical to the safety evaluation will be assessed as outlined in the study protocol. Study duration encompasses the 
time from when the participant signs the informed consent form until the last protocol-specific procedure has been 
completed, including a safety follow-up period. 
 
10.1.1 
Definition and assessment of (serious) adverse events and other safety related events 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have a causal relationship with the study 
procedure. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product, whether or not 
related to the investigational medicinal product. ICH E6 1.2 
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
• 
results in death, 
• 
is life-threatening, 
• 
requires in-patient hospitalization or prolongation of existing hospitalisation, 
• 
results in persistent or significant disability/incapacity, or 
• 
is a congenital anomaly/birth defect. 
In addition, important medical events that may not be immediately life-threatening or result in death, or require 
hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the other outcomes 
listed above should also usually be considered serious. ICH E2A 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at study termination 
(including safety follow-up visit) will be further followed up until recovery or until stabilisation of the disease after 
termination.  
 
Assessment of Causality 
Both Investigator and Sponsor make a causality assessment of the event to the study investigational medicine 
product, based on the criteria listed in the ICH E2A guidelines: 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after de-challenge* 
Recurrence after re-challenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after de-challenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after de-challenge only taken into consideration if applicable to reaction 
 
Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which is not consistent with 
the applicable product information (e.g. Investigator’s Brochure for drugs that are not yet approved and Product 
Information for approved drugs, respectively). ICH E2A 
 

 
 
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Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor evaluates the SAE that has been reported regarding seriousness, causality and expectedness. If the 
event is related to the investigational medicinal product and is both serious and unexpected, it is classified as a 
SUSAR.  
Assessment of Severity 
Severity of any AEs will be graded by the local Investigator as well as the Sponsor-Investigator based on the 
following criteria according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 published 
November 27, 2017 116. 
 
Severity  
Description  
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A semi-colon indicates ‘or’ within the description of the grade. ADL: Activities of Daily Living 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
 
10.1.2 
Reporting of serious adverse events (SAE) and other safety related events  
 
Reporting of SAEs 
All SAEs must be reported immediately and within a maximum of 24 hours of becoming aware of the SAE to the 
Sponsor-Investigator of the study. The Sponsor-Investigator will re-evaluate the SAE in a separate eCRF form and 
provide feedback to the site in case the Sponsor-Investigator’s opinion differs. In addition, SAEs will also be 
evaluated during the interim analyses with the DSMB (including external clinical experts as well as patient and 
public representatives; see also chapter 11.4.4 Interim analysis). 
 
Reporting of SUSARs 
A SUSAR must be reported to the Ethics Committee (local event via local Investigator) via BASEC and to 
Swissmedic (via the Sponsor-Investigator) within 7 days of becoming aware of the SUSAR if the event is life-
threatening or fatal. For all other SUSARs, the report must be made within 15 days. 
The reporting obligations of SUSAR also apply if the investigator or the sponsor becomes aware of a suspected 
case after termination of the clinical trial.  
 
Reporting of immediate safety and protective measures 
All suspected new risks and relevant new aspects of known adverse reactions that require immediate safety-related 
measures, must be reported to the Sponsor-Investigator within 24 hours of becoming aware of the new risks. The 
Sponsor-Investigator must report these measures within 7 days to the Ethics Committee (local event via local 
Investigator) via BASEC and to Swissmedic.  
The Sponsor must immediately inform all participating Investigators about the immediate safety and protective 
measures. 
 
Reporting and Handling of Pregnancies 
In the event of pregnancy, the treating physician and the participant (or the participant’s next of kin) will determine 

 
 
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whether the potential benefits for the participant outweigh the potential risks to the foetus. The course and outcome 
of the pregnancy should be followed up carefully, and any abnormal outcome regarding the mother or the child 
must be documented and reported. 
 
Periodic reporting of safety and general progress of the clinical trial. 
Once a year, the Sponsor-Investigator submits to the CEC and Swissmedic a list of the safety events including the 
severity of the events, their causality to the intervention and the safety of the study participants. This report also 
includes an update on the general progress of the study.  
The safety and general progress reports encompass the time from the date of the sponsor’s first authorisation to 
conduct the clinical trial in any country worldwide until the Last Patient Last Visit in Switzerland.  
The safety and general progress report is submitted yearly to the CEC and to Swissmedic throughout the duration 
of the clinical trial in Switzerland, and the last submission of the safety report will cover the Last Patient Last Visit 
in Switzerland.  
 
10.1.3 
Follow up of (Serious) Adverse Events 
SAEs occurring during hospitalisation will be followed-up until they are resolved during the hospital stay. If any 
study personnel become aware of an SAE outside of hospital, the responsible local investigator must conduct 
regular follow-ups until the SAE is resolved. At least 5 attempts at different times of the day to reach the participant 
will be conducted by the treating physician (or a delegated physician). If these fail, reasonable attempt will be made 
to acquire the information from relatives, caregivers, or the participant’s emergency contact or primary care 
physician. 
 
10.2 Assessment, notification and reporting on the use of radiation sources 
Not applicable. 
 
10.3 Exemption from the documentation requirements of AE  
10.3.1 
Exemption from the documentation requirements of AE due to pharmacological arguments 
Not applicable. 
 
10.3.2 
Exemption from the documentation requirements of AE due to clinical arguments  
Not applicable. 
 
 

 
 
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11. STATISTICAL METHODS  
11.1 Hypothesis 
Primary research hypothesis: Inhibition of virulence factor expression by early 5-day treatment with linezolid (600 
mg twice daily) in addition to treatment with standard antibiotics will result in superior outcomes at 90 days compared 
to placebo in participants with S. aureus bacteraemia. 
11.2 Determination of Sample Size  
We collected retrospective data on the DOOR components from all S. aureus bacteraemia patients treated at the 
University Hospital Basel in 2022 (n=119). Our assumptions for the sample size are based on these data along with 
what is known from the literature to derive plausible estimates for the DOOR components. Patients who died in the 
first three days after a S. aureus bacteraemia diagnosis were excluded so that we do not overestimate the mortality 
of the planned trial (of note, most of these patients would probably have died before they could have been included 
in our study (n = 8)). Following extensive consultations with patient representatives, we have established that, for 
mortality at 90 days, a trial should demonstrate a meaningful relative difference of 10% (equating to an absolute 
difference of 2.2%). Meanwhile, for the remaining domains, the following relative reductions were deemed 
acceptable: 15% for level of function and 20% for complications and length of hospital stay).  
The sample size was calculated using a simulation approach, for which 1000 synthetic datasets for each 
combination of plausible values for the relevant parameters were generated. We calculated the p-value of the win 
ratio for each of the simulated datasets and tested for statistical significance at α = 0.05 using the unmatched win-
ratio approach described in Pocock et al.117. The final sample size is based on the following specific assumptions: 
• 
The statistical tests are conducted at a two-sided significance level of α=0.05, and the desired power is 90% 
• 
The two treatment arms are equal in size (1:1 allocation)  
• 
The proportion of deaths within 90 days in the control group is expected to be 22.5% and 20.3% in the linezolid 
group (relative reduction of 10%; absolute reduction of 2.2%) 
• 
The proportion of participants with worse level of function in the control group is expected to be 25.0% 21, and 
21.3% in the linezolid group (relative reduction of 15%; absolute reduction of 3.7%) 
• 
The proportion of participants with any complications (defined DOOR component) will be 6.3% in the control 
group and 5.0% in the linezolid group (relative reduction of 20%; absolute reduction of 1.3%). 
• 
We modelled hospital length of stay using a log-normal model with any of the complications listed in the 
definition above as an independent variable; the parameters for this model were derived from the 
retrospective USB data, and the expected 20% relative reduction in hospital length of stay due to the 
intervention was applied to the mean of the log-transformed data when generating synthetic datasets. 
• 
Missing data were accounted for in the simulations (i.e., 10% for worse level of function and only 3% for all 
other components as these data will be available from routinely collected data). In case of missing DOOR 
components, the comparison among participants was made with the following DOOR domain. 
Under the assumptions listed above, 550 participants are required to show a significant effect of the intervention. 
Since it is possible that some patients themselves or their next of kin withdraw consent post-randomisation, we 
increased the target sample size by 10% to minimise the risk of being underpowered. Hence, we plan to include 
606 participants (303 participants in each study arm). 
 
11.3 Statistical criteria of termination of trial  
Not applicable. In brief, we do not have statistical criteria of early termination of the trial. Safety will be monitored 
by the independent DSMB (which includes patient representatives). If the DSMB observes a major safety concern 
(i.e. which would also be unacceptable if linezolid is superior to compared to standard of care) the DSMB will have 
the power to initiate the early termination of the trial. 
 
11.4 Planned Analyses  
11.4.1 
Datasets to be analysed, analysis populations 
Analyses will be performed on the full analysis set (i.e., all randomised participants) and the per protocol dataset 

 
 
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(i.e., those who received at least 7 out of 10 doses of linezolid or placebo). The primary estimand to be calculated 
in this study is the effect (summarised as the win ratio) of being randomly assigned to treatment with linezolid in the 
patient population (i.e., equivalent to an intention-to-treat analysis). We will also estimate the treatment effect among 
the treated participants (i.e., the per protocol dataset).  
A detailed analysis plan will be written before closing the study database. Of note, we are currently conducting a 
systematic scoping review, assessing current practices how to analyse a hierarchical composite outcome. These 
results will inform our pre-specified analysis plan. Furthermore, we will consider further developments in risk-score 
classifications for S. aureus bacteraemia (e.g. for a potential use of a matched win-ratio versus unmatched win-
ratio). The statistical analysis plan will be made publicly available (on clinicaltrials.gov). Currently we intend to 
conduct the following analyses:  
11.4.2 
Primary Analysis 
Treatment and placebo will be compared on the basis of the win-ratio approach as described by Pocock and 
colleagues:117 In brief, each participant in the treatment group will be compared with each participant in the placebo 
group. When comparing two participants, the winner will be determined by the first component of the DOOR in 
which the two participants differ. The following two scenarios will be considered as a tie: (i) when both participants 
died within 90 days, or (ii) when participants have the same outcomes for all DOOR elements, including length of 
hospital stay. The win ratio will be calculated by dividing the number of cases in which participants receiving linezolid 
win compared with the number of cases in which participants receiving placebo win. We will reject the null 
hypothesis that the win ratio is equal to 1 if the p-value is less than 0.05.  
Subgroup analyses: For the primary outcome and for all DOOR components separately, we will assess if treatment 
effects differ by sex (male vs. female), ICU status at baseline (participants on ICU vs. participants not on ICU) and 
focus of infection (vascular catheter, skin and soft tissue, endocarditis, osteoarticular, pneumonia, other focus, or 
focus not identified). All subgroup analyses will be exploratory in nature. 
 
11.4.3 
Secondary Analyses 
We intend to conduct the following analyses for the secondary outcomes: 
 
Logistic regression 
• 
Returning to usual level of function by day 90 
• 
Microbiological treatment failure 14-90 days after randomisation 
• 
Early microbiological treatment failure 5-13 days after randomisation 
• 
Clinical treatment failure 14-90 days after randomisation  
• 
Persistent bacteraemia defined as positive blood culture on day 5 after randomisation 
• 
Meeting two or more SIRS criteria simultaneously on day 5 after randomisation 
 
Log-normal linear regression 
• 
Length of hospital stay of acute index inpatient hospitalisation (in days) 
 
Poisson regression 
• 
Number of days without being on the Intensive Care Unit (ICU) up to day 90 
• 
Number of days alive and free of antibiotics up to day 90 
 
Cox proportional hazards model 
• 
Time to death up to day 90 
 
Fine & Gray competing risk model 
• 
Time to being discharged alive (assessed until day 90) 
 
The models listed above will include sex, ICU stay at baseline, and centre as adjustment factors (will be further pre-
specified in separate data analysis plan). 

 
 
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Wilcoxon-Mann-Whitney test 
• 
Physical health at day 90 as assessed by the short form 36 (SF-36) questionnaire 
• 
Mental health at day 90 as assessed by the short form 36 (SF-36) questionnaire 
 
Subgroup analyses: We will conduct the following subgroup analyses on the primary outcome to assess if treatment 
effects differ by sex (male vs. female), ICU status at baseline (participants on ICU vs. participants not on ICU), and 
dominant focus of infection (vascular catheter, skin and soft tissue, endocarditis, osteoarticular, pneumonia, other 
focus, or focus not identified). 
 
11.4.4 
Interim analyses 
After the treatment of 50 participants and again after 200 participants, the independent Data and Safety Monitoring 
Board (DSMB, including external clinical experts as well as patient and public representatives) will meet to discuss 
summary statistics about safety outcomes (see section 10 SAFETY). In addition, the adherence to treatment will 
be assessed in these interim analyses. If the proportion of non-adherence is above 10% (i.e., more than 10% of 
participants received fewer than 7 of the planned 10 doses), the study team will assess the reasons why doses 
were missed and implement actions (e.g., additional training) to increase adherence.  
 
11.4.5 
Safety analysis 
The following adverse events and safety outcomes will be analysed descriptively by study group: 
• 
Serious adverse reactions or serious adverse events in the 90 days following study entry 
• 
The following adverse events of special interest until 14 days after study entry during the index hospital 
stay: 
- 
Clinical signs compatible with serotonin syndrome 
- 
Laboratory signs of haematotoxicity 
• 
Acute kidney injury defined using modified Kidney Disease Improving Global Outcomes (KDIGO) criteria, 
modified according to SNAP trial: 
- 
Increase in serum creatinine by 26.5 µmol/l or more at any time from baseline entry to day 5 
OR 
- 
Increase in serum creatinine by 1.5 times or more the level at study entry (baseline) within 14 days 
of study entry 
• 
Clostridioides difficile-associated diarrhoea 
 
11.4.6 
Deviation(s) from the original statistical plan  
If substantial deviations of the analysis as outlined in these chapters are needed for whatever reason, the protocol 
will be amended. All deviations of the analysis from the protocol or from the detailed analysis plan will be listed and 
justified in a separate chapter of the final statistical report. 
 
11.5 Handling of missing data and drop-outs 
The primary analysis will be performed on the data available (complete cases). In the sample size calculation, we 
have included expected proportions of missing data for the individual DOOR components. To keep as many 
participants as possible in the analysis, we will use the components of the DOOR that are not missing in cases 
where not all components are missing. For the secondary outcomes, we will consider multiple imputation if the 
proportion of excluded participants is larger than 5% (the imputation strategy will be pre-specified for each outcome 
in a separate data analysis plan). 
 
 

 
 
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12. QUALITY ASSURANCE AND CONTROL  
Written standard operating procedures (SOPs) and manuals of operation will be issued to all sites and adherence 
to guidance is monitored during site visits. 
12.1 Data handling and record keeping / archiving  
12.1.1 
Electronic Case Report Forms (eCRF) 
Relevant clinical study data for each enrolled study participant, i.e., observations, tests and assessments specified 
in the protocol, are recorded in eCRFs via the web-based electronic data capture (EDC) system implemented in 
REDCap® at the study centres. The participant’s name and address will not be recorded. The EDC system includes 
guidance for study sites on how to perform data entry and will also be used for query handling. 
Local investigators and site trial members will be authorized for the eCRF entries of study participants enrolled at 
the site. Investigators will be trained to use the EDC system during the site initiation visit. The investigators ensure 
the accuracy, completeness, and timeliness of the data recorded and provide answers to data queries, as specified 
in the study protocol and in accordance with additional instructions. The identity of the local investigator entering 
data, and date and time of data entry will be recorded as meta-data in the study database. 
12.1.2 
Specification of source documents  
Source data will include all study documents (e.g. informed consent forms, online AE/SAE forms, patient data in 
hospital information system). Source data will be available at all sites and may be found in paper or electronic form. 
 
12.1.3 
Record keeping / archiving  
The sponsor retains all data relating to the clinical trial for at least twenty years after completion or premature 
termination of the clinical trial. The local investigators retain all documents necessary for the identification and 
follow-up of the trial participants and all other original data for at least twenty years after completion or 
discontinuation of the clinical trial. Data will be stored in the REDCap study database located on servers of the 
University of Basel. Any study relevant paper documents will be archived at each site for a minimum of 20 years. 
 
12.2 Data management  
12.2.1 
Data Management System  
Study data will be captured via the web-based electronic data capture system REDCap®. The system is developed 
by Vanderbilt University, US and licensed and hosted by the Department of Clinical Research of the University 
Basel. The REDCap® software installation and periodical updates are validated by the Department of Clinical 
Research. All data is stored on servers of the University Hospital Basel in Switzerland. Password protection and 
user-right management safeguard access, ensuring that only authorized personnel can view or modify the data.  
Patients will be entered into REDCap® with a unique study ID. Patient data entry in REDCap® is facilitated by 
manually entering the unique hospital identification number, which is used to locate and input data at predefined 
time points. Using data-access groups in REDCap® will ensure that each local investigator (or delegated personnel) 
can only access data from their respective centre. To enhance data security and confidentiality, the unique hospital 
identification number is designated as an identifier field in REDCap®, preventing its inclusion in exported datasets. 
In these exports only the unique study ID of each participant will be included. To ensure that patients can still be 
correctly identified, each centre will maintain a separate key list that also serves as a site screening and enrolment 
log file. All data collected is entered into study specific case report forms. An audit trail maintains a record of initial 
entries and any changes made; time and date of entry; and username of person authorizing entry or change. 
 
12.2.2 
Data security, access, and back-up  
Data is encrypted at rest and protected by advanced threat detection software according to the security policy of 
the University Hospital Basel. REDCap® is accessible via a standard browser on devices with internet connection. 
The data transfer between clients and servers is encrypted using Transport Layer Encryption (TLS) cryptography 
protocol. Password protection and user-right management ensure that only authorized study investigators, 
monitors, data managers and local authorities (if necessary) will have access to the data during and after the study. 

 
 
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User administration and user training is performed by the Department of Clinical Research (DKF) Basel according 
to predefined processes. The built-in audit trail will register any unplanned deviations from the study protocol. 
Backup of the REDCap® database is performed daily according to established processes. 
 
12.2.3 
Analysis and archiving 
REDCap database will be locked after all data has been monitored and cleaned, and all raised queries have been 
resolved. Data will be archived by the Sponsor for a minimum of 20 years. 
 
12.2.4 
Electronic and central data validation  
The data managers of the DKF Basel will implement validation rules in REDCap®. When data gets saved in a case 
report form, it will be validated for discrepancies. The data will be reviewed by the responsible investigator as well 
as an independent monitor. The monitor will raise queries using the query management system implemented in 
REDCap®. Designated investigators must respond to the query and confirm or correct the corresponding data. 
Thereafter the monitor can close the query. 
 
12.3 Monitoring  
The Department of Clinical Research of the University of Basel will perform the monitoring of this trial. A monitor 
from the Department of Clinical Research will, in accordance with the Sponsor, contact all sites for initiation of the 
trial. According to the scope of the monitoring plan, the monitor will visit the trial site during the study or perform 
remote monitoring visits, regularly if necessary, and after closing. The monitor will verify the adherence to the 
protocol, completeness, consistence, and accuracy of the data being entered on eCRF and will thus require access 
to all patient medical records including laboratory test results and surgery, pathology and radiology reports and 
supporting documents. The investigator (or his/her delegate) should collaborate with the monitor. They must ensure 
that source data verification forms, source data and documents are made accessible to the study monitor, and they 
should answer questions by the Study Monitor in detail to ensure that any problems detected during these visits 
are resolved. Open action items will be listed and explained by the monitor in follow-up letters and are expected to 
be resolved in reasonable time.  
 
12.4 Audits and Inspections  
In accordance with ICH GCP guidelines [2], audits may be performed by the CEC and CA during the course of the 
study. The audits will include control of adherence to the protocol, standard operating procedures, ICU GSP 
guidelines and national legislation. Source data verification and checking of the data entered in the eCRF will be 
used for assessment of complete and reliable documentation. The local investigators ensure that source data and 
documents are made accessible to auditors and inspectors and answer their questions. All involved parties must 
keep the participant data strictly confidential. 
 
12.5 Confidentiality, Data Protection  
Direct access to source documents will be permitted for purposes of monitoring, audits and inspections. 
Study data entered into the eCRF is only accessible to authorized personnel. Once all data is entered into the 
REDCap platform and monitoring is completed, the database will be locked and closed for further data entry. The 
complete dataset is then exported and transferred to the study statistician as well as the principal investigator 
through a secure channel. 
 
12.6 Storage of biological material and related health data  
Plasma samples used for linezolid trough measurement will be coded and stored until the analyses are performed. 
Samples will be stored locally at the participating centre until shipment to the sponsor site (University Hospital 
Basel). Any leftover samples will be stored in the LIPS biobank. Detailed information can be found in the LIPS 
biobanking regulation.  

 
 
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13. PUBLICATION AND DISSEMINATION POLICY  
The trial results will be published in a peer-reviewed open access journal. Results will also be published if they are 
negative or if the trial was discontinued. The full protocol will be made publicly available on clinicaltrials.gov. A 
detailed analysis plan will be written before closing the study database. The statistical analysis plan will be made 
publicly available on clinicaltrials.gov. Furthermore, we will consider publishing a short peer-reviewed version of the 
trial protocol. Authorship to publications will be granted according to the rules of the International Committee of 
Medical Journal Editors (ICMJE). After publication of the main results, the full dataset will be submitted to the Data 
Access Committee of the Faculty of Medicine (MF-DAC) at the University of Basel. Other researchers interested in 
re-using the study data may then contact the independent Data Access Committee from the University Hospital of 
Basel.  
The sponsor will enter and publish a summary of the trial results in a public register in accordance with ClinO Art. 
65a within one year of completion or premature termination of the trial. An interruption lasting more than two years 
is considered a premature termination of the trial. 
For the purpose of publication in the public register the sponsor also ensures that a lay summary of the trial results 
in German, French, and Italian is entered in BASEC within one year of completion or premature termination of the 
trial. 
The investigator will provide each study participants with the lay summary of the trial results at the end of the study, 
directly and inform them where they can find the study results.  
 
14. FUNDING AND SUPPORT  
14.1 Funding  
The LIPS trial is funded by the Swiss National Science Foundation (SNSF) under the Investigator initiated clinical 
trials (IICT) funding call (SNSF ID: 221668). 
 
15. INSURANCE  
Insurance with a policy value in accordance with ClinO Annex 2 will be provided by the Sponsor University Hospital 
Basel. A copy of the certificate is filed in each investigator site file and the trial master file. The certificate will be 
provided as soon as ethics approval has been obtained. 
 
 

 
 
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16. TRIAL SUB-PROJECT(S) 
16.1 Molecular mechanisms of S. aureus bacteraemia 
Hypothesis: S. aureus uses intracellular survival inside immune cells as a main survival strategy in the blood for 
persistence of infection. 
Objective: Identification of human cells harbouring S. aureus in bacteraemia. 
Background: Despite extensive research, the mechanisms underlying S. aureus persistence in the bloodstream 
for more than 48 hours despite active antibiotic therapy remain unclear8 9. The associated stark increase of mortality 
and risk of metastatic spread18 in these courses of infection underline the importance of further research. Current 
investigations are limited to in vitro and animal studies, lacking sufficient predictive power for the relevant patient 
setting. Based on these previous findings, S. aureus can survive and proliferate within human neutrophils and 
monocytes118 and could, as hypothesized119, use the intracellular niche as a crucial way of evading antibiotic 
exposure. The existence and relevance of intracellular S. aureus in bacteraemia in humans has not yet been shown.  
Methods: Blood samples will be drawn daily in routine or study-specific blood draws and sent to the research facility 
as described in 9.3.7 until 48h after the patient’s first negative blood culture. Samples will be divided to perform 
several analyses: i) Quantification of intracellular and extracellular viable bacteria will be achieved by plating of 
serum respectively plating of lysed cells on agar plates for counting of colony forming units ii) blood smears stained 
with fluorescent vancomycin derivate VAN-JF669120 for intracellular bacterial staining and other standard stainings 
(e.g. RAB5, RAB7, fibrinogen) will be analysed on a Nikon Ti2 confocal microscope iii) Flow cytometry analysis will 
be performed on a subsection of blood cells. Using Percoll separation, specific blood cell types are obtained and 
stained with VAN-JF669 and for cell type markers (e.g. CD14, CD16, CD68). Cells will be analysed using spectral 
flow cytometry (Cytek Aurora) or image flow cytometry (Amnis ImageStreamX Mark II).  
 
 

 
 
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17. REFERENCES  
1. Collaborators GBDAR. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis 
for the Global Burden of Disease Study 2019. Lancet 2022;400(10369):2221-48. doi: 10.1016/S0140-
6736(22)02185-7 [published Online First: 20221121] 
2. Renggli L, Gasser M, Buetti N, et al. Increase in methicillin-susceptible Staphylococcus aureus bloodstream 
infections in Switzerland: a nationwide surveillance study (2008-2021). Infection 2023;51(4):1025-31. doi: 
10.1007/s15010-023-01980-6 [published Online First: 20230202] 
3. Laupland KB, Lyytikainen O, Sogaard M, et al. The changing epidemiology of Staphylococcus aureus 
bloodstream infection: a multinational population-based surveillance study. Clin Microbiol Infect 
2013;19(5):465-71. doi: 10.1111/j.1469-0691.2012.03903.x [published Online First: 20120523] 
4. Hindy JR, Quintero-Martinez JA, Lee AT, et al. Incidence Trends and Epidemiology of Staphylococcus aureus 
Bacteremia: A Systematic Review of Population-Based Studies. Cureus 2022;14(5):e25460. doi: 
10.7759/cureus.25460 [published Online First: 20220529] 
5. Benfield T, Espersen F, Frimodt-Moller N, et al. Increasing incidence but decreasing in-hospital mortality of adult 
Staphylococcus aureus bacteraemia between 1981 and 2000. Clin Microbiol Infect 2007;13(3):257-63. 
doi: 10.1111/j.1469-0691.2006.01589.x 
6. Mathe P, Gopel S, Hornuss D, et al. Increasing numbers and complexity of Staphylococcus aureus bloodstream 
infection-14 years of prospective evaluation at a German tertiary care centre with multi-centre validation 
of findings. Clin Microbiol Infect 2023;29(9):1197 e9-97 e15. doi: 10.1016/j.cmi.2023.05.031 [published 
Online First: 20230603] 
7. Bai AD, Lo CK, Komorowski AS, et al. Staphylococcus aureus bacteremia mortality across country income 
groups: A secondary analysis of a systematic review. Int J Infect Dis 2022;122:405-11. doi: 
10.1016/j.ijid.2022.06.026 [published Online First: 20220618] 
8. Kaasch AJ, Barlow G, Edgeworth JD, et al. Staphylococcus aureus bloodstream infection: a pooled analysis of 
five prospective, observational studies. J Infect 2014;68(3):242-51. doi: 10.1016/j.jinf.2013.10.015 
[published Online First: 20131116] 
9. Bai AD, Lo CKL, Komorowski AS, et al. Staphylococcus aureus bacteraemia mortality: a systematic review and 
meta-analysis. Clin Microbiol Infect 2022;28(8):1076-84. doi: 10.1016/j.cmi.2022.03.015 [published Online 
First: 20220323] 
10. Wiggli BJ, Frei R, Laffer R, et al. Survival from methicillin-sensitive Staphylococcus aureus bloodstream 
infections over 20 years: a cohort of 1328 patients. Swiss Med Wkly 2017;147:w14508. doi: 
10.4414/smw.2017.14508 [published Online First: 20170930] 
11. Smit J, Lopez-Cortes LE, Kaasch AJ, et al. Gender differences in the outcome of community-acquired 
Staphylococcus aureus bacteraemia: a historical population-based cohort study. Clin Microbiol Infect 
2017;23(1):27-32. doi: 10.1016/j.cmi.2016.06.002 [published Online First: 20160622] 
12. Nambiar K, Seifert H, Rieg S, et al. Survival following Staphylococcus aureus bloodstream infection: A 
prospective multinational cohort study assessing the impact of place of care. J Infect 2018;77(6):516-25. 
doi: 10.1016/j.jinf.2018.08.015 [published Online First: 20180901] 
13. Westgeest AC, Ruffin F, Kair JL, et al. The association of female sex with management and mortality in patients 
with 
Staphylococcus 
aureus 
bacteraemia. 
Clin 
Microbiol 
Infect 
2023;29(9):1182-87. 
doi: 
10.1016/j.cmi.2023.06.009 [published Online First: 20230614] 
14. Yahav D, Yassin S, Shaked H, et al. Risk factors for long-term mortality of Staphylococcus aureus bacteremia. 
Eur J Clin Microbiol Infect Dis 2016;35(5):785-90. doi: 10.1007/s10096-016-2598-8 [published Online 
First: 20160212] 
15. Mansur N, Hazzan R, Paul M, et al. Does sex affect 30-day mortality in Staphylococcus aureus bacteremia? 
Gend Med 2012;9(6):463-70. doi: 10.1016/j.genm.2012.10.009 [published Online First: 20121107] 
16. Humphreys H, Fitzpatick F, Harvey BJ. Gender differences in rates of carriage and bloodstream infection 
caused by methicillin-resistant Staphylococcus aureus: are they real, do they matter and why? Clin Infect 
Dis 2015;61(11):1708-14. doi: 10.1093/cid/civ576 [published Online First: 20150722] 
17. Holland TL, Cosgrove SE, Doernberg SB, et al. Ceftobiprole for Treatment of Complicated Staphylococcus 
aureus Bacteremia. N Engl J Med 2023 doi: 10.1056/NEJMoa2300220 [published Online First: 20230927] 
18. Kuehl R, Morata L, Boeing C, et al. Defining persistent Staphylococcus aureus bacteraemia: secondary analysis 
of a prospective cohort study. Lancet Infect Dis 2020;20(12):1409-17. doi: 10.1016/S1473-
3099(20)30447-3 [published Online First: 20200804] 
19. Souli M, Ruffin F, Choi SH, et al. Changing Characteristics of Staphylococcus aureus Bacteremia: Results From 
a 21-Year, Prospective, Longitudinal Study. Clin Infect Dis 2019;69(11):1868-77. doi: 10.1093/cid/ciz112 
20. Eichenberger EM, de Vries CR, Ruffin F, et al. Microbial Cell-Free DNA Identifies Etiology of Bloodstream 
Infections, Persists Longer Than Conventional Blood Cultures, and Its Duration of Detection Is Associated 
With Metastatic Infection in Patients With Staphylococcus aureus and Gram-Negative Bacteremia. Clin 

 
 
LIPS Trial, Version 1.2 of 30/07/2025 
 
Page 59 of 64 
Infect Dis 2022;74(11):2020-27. doi: 10.1093/cid/ciab742 
21. Jacobsson G, Gustafsson E, Andersson R. Outcome for invasive Staphylococcus aureus infections. Eur J Clin 
Microbiol Infect Dis 2008;27(9):839-48. doi: 10.1007/s10096-008-0515-5 [published Online First: 
20080501] 
22. Vogel M, Schmitz RP, Hagel S, et al. Infectious disease consultation for Staphylococcus aureus bacteremia - 
A systematic review and meta-analysis. J Infect 2016;72(1):19-28. doi: 10.1016/j.jinf.2015.09.037 
[published Online First: 20151009] 
23. Thorlacius-Ussing L, Sandholdt H, Nissen J, et al. Comparable Outcomes of Short-Course and Prolonged-
Course Therapy in Selected Cases of Methicillin-Susceptible Staphylococcus aureus Bacteremia: A 
Pooled Cohort Study. Clin Infect Dis 2021;73(5):866-72. doi: 10.1093/cid/ciab201 
24. Tong SYC, Lye DC, Yahav D, et al. Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal 
beta-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: 
A Randomized Clinical Trial. JAMA 2020;323(6):527-37. doi: 10.1001/jama.2020.0103 
25. Tong SYC, Mora J, Bowen AC, et al. The Staphylococcus aureus Network Adaptive Platform Trial Protocol: 
New Tools for an Old Foe. Clin Infect Dis 2022;75(11):2027-34. doi: 10.1093/cid/ciac476 
26. Holland TL, Arnold C, Fowler VG, Jr. Clinical management of Staphylococcus aureus bacteremia: a review. 
JAMA 2014;312(13):1330-41. doi: 10.1001/jama.2014.9743 
27. Tong SY, Davis JS, Eichenberger E, et al. Staphylococcus aureus infections: epidemiology, pathophysiology, 
clinical 
manifestations, 
and 
management. 
Clin 
Microbiol 
Rev 
2015;28(3):603-61. 
doi: 
10.1128/CMR.00134-14 
28. Hagel SK, A.; Weis, S.; Seifert, H.; Pletz, M.; Rieg, S. Staphylococcus-aureus-Blutstrominfektion – eine 
interdisziplinäre Herausforderung. Anästhesiol Intensivmed Notfallmed Schmerzther 2019;54:206-16. 
29. Kimmig A, Hagel S, Weis S, et al. Management of Staphylococcus aureus Bloodstream Infections. Front Med 
(Lausanne) 2020;7:616524. doi: 10.3389/fmed.2020.616524 [published Online First: 20210305] 
30. Grillo S, Puig-Asensio M, Schweizer ML, et al. The Effectiveness of Combination Therapy for Treating 
Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Systematic Literature Review and a Meta-
Analysis. Microorganisms 2022;10(5) doi: 10.3390/microorganisms10050848 [published Online First: 
20220420] 
31. Abrams B, Sklaver A, Hoffman T, et al. Single or combination therapy of staphylococcal endocarditis in 
intravenous drug abusers. Ann Intern Med 1979;90(5):789-91. doi: 10.7326/0003-4819-90-5-789 
32. Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in 
patients addicted to parenteral drugs and in nonaddicts: A prospective study. Ann Intern Med 
1982;97(4):496-503. doi: 10.7326/0003-4819-97-4-496 
33. Ribera E, Gomez-Jimenez J, Cortes E, et al. Effectiveness of cloxacillin with and without gentamicin in short-
term therapy for right-sided Staphylococcus aureus endocarditis. A randomized, controlled trial. Ann Intern 
Med 1996;125(12):969-74. doi: 10.7326/0003-4819-125-12-199612150-00005 
34. Van der Auwera P, Klastersky J, Thys JP, et al. Double-blind, placebo-controlled study of oxacillin combined 
with rifampin in the treatment of staphylococcal infections. Antimicrob Agents Chemother 1985;28(4):467-
72. doi: 10.1128/AAC.28.4.467 
35. Thwaites GE, Scarborough M, Szubert A, et al. Adjunctive rifampicin for Staphylococcus aureus bacteraemia 
(ARREST): 
a 
multicentre, 
randomised, 
double-blind, 
placebo-controlled 
trial. 
Lancet 
2018;391(10121):668-78. doi: 10.1016/S0140-6736(17)32456-X [published Online First: 20171214] 
36. Ruotsalainen E, Jarvinen A, Koivula I, et al. Levofloxacin does not decrease mortality in Staphylococcus aureus 
bacteraemia when added to the standard treatment: a prospective and randomized clinical trial of 381 
patients. J Intern Med 2006;259(2):179-90. doi: 10.1111/j.1365-2796.2005.01598.x 
37. Cheng MP, Lawandi A, Butler-Laporte G, et al. Adjunctive Daptomycin in the Treatment of Methicillin-
susceptible Staphylococcus aureus Bacteremia: A Randomized, Controlled Trial. Clin Infect Dis 
2021;72(9):e196-e203. doi: 10.1093/cid/ciaa1000 
38. Grillo S, Pujol M, Miro JM, et al. Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible 
Staphylococcus aureus bacteremia: a randomized trial. Nat Med 2023 doi: 10.1038/s41591-023-02569-0 
[published Online First: 20231002] 
39. Kwiecinski JM, Horswill AR. Staphylococcus aureus bloodstream infections: pathogenesis and regulatory 
mechanisms. Curr Opin Microbiol 2020;53:51-60. doi: 10.1016/j.mib.2020.02.005 [published Online First: 
20200312] 
40. Howden BP, Giulieri SG, Wong Fok Lung T, et al. Staphylococcus aureus host interactions and adaptation. Nat 
Rev Microbiol 2023;21(6):380-95. doi: 10.1038/s41579-023-00852-y [published Online First: 20230127] 
41. Ahmad-Mansour N, Loubet P, Pouget C, et al. Staphylococcus aureus Toxins: An Update on Their Pathogenic 
Properties and Potential Treatments. Toxins (Basel) 2021;13(10) doi: 10.3390/toxins13100677 [published 
Online First: 20210923] 
42. Liu Y, Gao W, Yang J, et al. Contribution of Coagulase and Its Regulator SaeRS to Lethality of CA-MRSA 923 

 
 
LIPS Trial, Version 1.2 of 30/07/2025 
 
Page 60 of 64 
Bacteremia. Pathogens 2021;10(11) doi: 10.3390/pathogens10111396 [published Online First: 20211028] 
43. van der Vaart TW, Prins JM, Soetekouw R, et al. All-Cause and Infection-Related Mortality in Staphylococcus 
aureus Bacteremia, a Multicenter Prospective Cohort Study. Open Forum Infect Dis 2022;9(12):ofac653. 
doi: 10.1093/ofid/ofac653 [published Online First: 20221130] 
44. Quartin AA, Schein RM, Kett DH, et al. Magnitude and duration of the effect of sepsis on survival. Department 
of Veterans Affairs Systemic Sepsis Cooperative Studies Group. JAMA 1997;277(13):1058-63. 
45. Prescott HC, Iwashyna TJ, Blackwood B, et al. Understanding and Enhancing Sepsis Survivorship. Priorities 
for Research and Practice. Am J Respir Crit Care Med 2019;200(8):972-81. doi: 10.1164/rccm.201812-
2383CP 
46. King HA, Doernberg SB, Miller J, et al. Patients' Experiences With Staphylococcus aureus and Gram-negative 
Bacterial Bloodstream Infections: A Qualitative Descriptive Study and Concept Elicitation Phase To Inform 
Measurement of Patient-reported Quality of Life. Clin Infect Dis 2021;73(2):237-47. doi: 
10.1093/cid/ciaa611 
47. Hodille E, Rose W, Diep BA, et al. The Role of Antibiotics in Modulating Virulence in Staphylococcus aureus. 
Clin Microbiol Rev 2017;30(4):887-917. doi: 10.1128/CMR.00120-16 
48. Dotel R, Tong SYC, Bowen A, et al. CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus 
aureus treatment evaluation: study protocol for a randomised controlled trial. Trials 2019;20(1):353. doi: 
10.1186/s13063-019-3452-y [published Online First: 20190613] 
49. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and 
soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis 
2014;59(2):147-59. doi: 10.1093/cid/ciu296 [published Online First: 20140618] 
50. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america 
for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive 
summary. Clin Infect Dis 2011;52(3):285-92. doi: 10.1093/cid/cir034 
51. Gillet Y, Dumitrescu O, Tristan A, et al. Pragmatic management of Panton-Valentine leukocidin-associated 
staphylococcal 
diseases. 
Int 
J 
Antimicrob 
Agents 
2011;38(6):457-64. 
doi: 
10.1016/j.ijantimicag.2011.05.003 [published Online First: 20110705] 
52. Brown NM, Goodman AL, Horner C, et al. Treatment of methicillin-resistant Staphylococcus aureus (MRSA): 
updated guidelines from the UK. JAC Antimicrob Resist 2021;3(1):dlaa114. doi: 10.1093/jacamr/dlaa114 
[published Online First: 20210203] 
53. STADAPHARM. Linezolid STADA® 600 mg SPC.  
54. Chiang FY, Climo M. Efficacy of linezolid alone or in combination with vancomycin for treatment of experimental 
endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 
2003;47(9):3002-4. doi: 10.1128/AAC.47.9.3002-3004.2003 
55. Jacqueline C, Navas D, Batard E, et al. In vitro and in vivo synergistic activities of linezolid combined with 
subinhibitory concentrations of imipenem against methicillin-resistant Staphylococcus aureus. Antimicrob 
Agents Chemother 2005;49(1):45-51. doi: 10.1128/AAC.49.1.45-51.2005 
56. Pachon-Ibanez ME, Ribes S, Dominguez MA, et al. Efficacy of fosfomycin and its combination with linezolid, 
vancomycin and imipenem in an experimental peritonitis model caused by a Staphylococcus aureus strain 
with reduced susceptibility to vancomycin. Eur J Clin Microbiol Infect Dis 2011;30(1):89-95. doi: 
10.1007/s10096-010-1058-0 [published Online First: 20100916] 
57. Diep BA, Afasizheva A, Le HN, et al. Effects of linezolid on suppressing in vivo production of staphylococcal 
toxins and improving survival outcomes in a rabbit model of methicillin-resistant Staphylococcus aureus 
necrotizing pneumonia. J Infect Dis 2013;208(1):75-82. doi: 10.1093/infdis/jit129 [published Online First: 
20130326] 
58. Yanagihara K, Kihara R, Araki N, et al. Efficacy of linezolid against Panton-Valentine leukocidin (PVL)-positive 
meticillin-resistant Staphylococcus aureus (MRSA) in a mouse model of haematogenous pulmonary 
infection. Int J Antimicrob Agents 2009;34(5):477-81. doi: 10.1016/j.ijantimicag.2009.06.024 [published 
Online First: 20090807] 
59. Wunderink RG, Rello J, Cammarata SK, et al. Linezolid vs vancomycin: analysis of two double-blind studies of 
patients 
with 
methicillin-resistant 
Staphylococcus 
aureus 
nosocomial 
pneumonia. 
Chest 
2003;124(5):1789-97. 
60. Zahedi Bialvaei A, Rahbar M, Yousefi M, et al. Linezolid: a promising option in the treatment of Gram-positives. 
J Antimicrob Chemother 2017;72(2):354-64. doi: 10.1093/jac/dkw450 [published Online First: 20161220] 
61. Dagher M, Fowler VG, Jr., Wright PW, et al. A Narrative Review of Early Oral Stepdown Therapy for the 
Treatment of Uncomplicated Staphylococcus aureus Bacteremia: Yay or Nay? Open Forum Infect Dis 
2020;7(6):ofaa151. doi: 10.1093/ofid/ofaa151 [published Online First: 20200505] 
62. Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled 
analysis of randomized studies. J Antimicrob Chemother 2005;56(5):923-9. doi: 10.1093/jac/dki355 
[published Online First: 20050929] 

 
 
LIPS Trial, Version 1.2 of 30/07/2025 
 
Page 61 of 64 
63. Falagas ME, Siempos, II, Vardakas KZ. Linezolid versus glycopeptide or beta-lactam for treatment of Gram-
positive bacterial infections: meta-analysis of randomised controlled trials. Lancet Infect Dis 2008;8(1):53-
66. doi: 10.1016/S1473-3099(07)70312-2 
64. Park HJ, Kim SH, Kim MJ, et al. Efficacy of linezolid-based salvage therapy compared with glycopeptide-based 
therapy in patients with persistent methicillin-resistant Staphylococcus aureus bacteremia. J Infect 
2012;65(6):505-12. doi: 10.1016/j.jinf.2012.08.007 [published Online First: 20120814] 
65. Jang HC, Kim SH, Kim KH, et al. Salvage treatment for persistent methicillin-resistant Staphylococcus aureus 
bacteremia: efficacy of linezolid with or without carbapenem. Clin Infect Dis 2009;49(3):395-401. doi: 
10.1086/600295 
66. Kelesidis T, Humphries R, Ward K, et al. Combination therapy with daptomycin, linezolid, and rifampin as 
treatment option for MRSA meningitis and bacteremia. Diagn Microbiol Infect Dis 2011;71(3):286-90. doi: 
10.1016/j.diagmicrobio.2011.07.001 [published Online First: 20110819] 
67. Wilcox MH, Tack KJ, Bouza E, et al. Complicated skin and skin-structure infections and catheter-related 
bloodstream infections: noninferiority of linezolid in a phase 3 study. Clin Infect Dis 2009;48(2):203-12. 
doi: 10.1086/595686 
68. Gomez J, Garcia-Vazquez E, Banos R, et al. Predictors of mortality in patients with methicillin-resistant 
Staphylococcus aureus (MRSA) bacteraemia: the role of empiric antibiotic therapy. Eur J Clin Microbiol 
Infect Dis 2007;26(4):239-45. doi: 10.1007/s10096-007-0272-x 
69. Stevens DL, Wallace RJ, Hamilton SM, et al. Successful treatment of staphylococcal toxic shock syndrome with 
linezolid: a case report and in vitro evaluation of the production of toxic shock syndrome toxin type 1 in the 
presence of antibiotics. Clin Infect Dis 2006;42(5):729-30. doi: 10.1086/500265 
70. Li HT, Zhang TT, Huang J, et al. Factors associated with the outcome of life-threatening necrotizing pneumonia 
due to community-acquired Staphylococcus aureus in adult and adolescent patients. Respiration 
2011;81(6):448-60. doi: 10.1159/000319557 [published Online First: 20101106] 
71. Pfizer AG Zürich. Zyvoxid Fachinformation Schweiz, 2023. 
72. Bishop E, Melvani S, Howden BP, et al. Good clinical outcomes but high rates of adverse reactions during 
linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. 
Antimicrob Agents Chemother 2006;50(4):1599-602. doi: 10.1128/AAC.50.4.1599-1602.2006 
73. Veerman K, Goosen J, Spijkers K, et al. Prolonged use of linezolid in bone and joint infections: a retrospective 
analysis of adverse effects. J Antimicrob Chemother 2023 doi: 10.1093/jac/dkad276 [published Online 
First: 20230908] 
74. Boak LM, Rayner CR, Grayson ML, et al. Clinical population pharmacokinetics and toxicodynamics of linezolid. 
Antimicrob Agents Chemother 2014;58(4):2334-43. doi: 10.1128/AAC.01885-13 [published Online First: 
20140210] 
75. Attassi K, Hershberger E, Alam R, et al. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 
2002;34(5):695-8. doi: 10.1086/338403 [published Online First: 20020117] 
76. Gerson SL, Kaplan SL, Bruss JB, et al. Hematologic effects of linezolid: summary of clinical experience. 
Antimicrob Agents Chemother 2002;46(8):2723-6. doi: 10.1128/AAC.46.8.2723-2726.2002 
77. Lin YH, Wu VC, Tsai IJ, et al. High frequency of linezolid-associated thrombocytopenia among patients with 
renal insufficiency. Int J Antimicrob Agents 2006;28(4):345-51. doi: 10.1016/j.ijantimicag.2006.04.017 
[published Online First: 20060828] 
78. Nukui Y, Hatakeyama S, Okamoto K, et al. High plasma linezolid concentration and impaired renal function 
affect development of linezolid-induced thrombocytopenia. J Antimicrob Chemother 2013;68(9):2128-33. 
doi: 10.1093/jac/dkt133 [published Online First: 20130426] 
79. Shaw KJ, Barbachyn MR. The oxazolidinones: past, present, and future. Ann N Y Acad Sci 2011;1241:48-70. 
doi: 10.1111/j.1749-6632.2011.06330.x 
80. Ener RA, Meglathery SB, Van Decker WA, et al. Serotonin syndrome and other serotonergic disorders. Pain 
Med 2003;4(1):63-74. doi: 10.1046/j.1526-4637.2003.03005.x 
81. Gillman PK. The spectrum concept of serotonin toxicity. Pain Med 2004;5(2):231-2; author reply 33. doi: 
10.1111/j.1526-4637.2004.04033.x 
82. Butterfield JM, Lawrence KR, Reisman A, et al. Comparison of serotonin toxicity with concomitant use of either 
linezolid or comparators and serotonergic agents: an analysis of Phase III and IV randomized clinical trial 
data. J Antimicrob Chemother 2012;67(2):494-502. doi: 10.1093/jac/dkr467 [published Online First: 
20111202] 
83. Bai AD, McKenna S, Wise H, et al. Association of Linezolid With Risk of Serotonin Syndrome in Patients 
Receiving 
Antidepressants. 
JAMA 
Netw 
Open 
2022;5(12):e2247426. 
doi: 
10.1001/jamanetworkopen.2022.47426 [published Online First: 20221201] 
84. Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med 2003;348(1):86-7. doi: 
10.1056/NEJM200301023480123 
85. Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin 

 
 
LIPS Trial, Version 1.2 of 30/07/2025 
 
Page 62 of 64 
syndrome. Pharmacotherapy 2007;27(8):1189-97. doi: 10.1592/phco.27.8.1189 
86. Santini A, Ronchi D, Garbellini M, et al. Linezolid-induced lactic acidosis: the thin line between bacterial and 
mitochondrial ribosomes. Expert Opin Drug Saf 2017;16(7):833-43. doi: 10.1080/14740338.2017.1335305 
[published Online First: 20170601] 
87. Douros A, Grabowski K, Stahlmann R. Drug-drug interactions and safety of linezolid, tedizolid, and other 
oxazolidinones. 
Expert 
Opin 
Drug 
Metab 
Toxicol 
2015;11(12):1849-59. 
doi: 
10.1517/17425255.2015.1098617 [published Online First: 20151012] 
88. Klein EY, Jiang W, Mojica N, et al. National Costs Associated With Methicillin-Susceptible and Methicillin-
Resistant Staphylococcus aureus Hospitalizations in the United States, 2010-2014. Clin Infect Dis 
2019;68(1):22-28. doi: 10.1093/cid/ciy399 
89. Nelson RE, Lautenbach E, Chang N, et al. Attributable Cost of Healthcare-Associated Methicillin-Resistant 
Staphylococcus aureus Infection in a Long-term Care Center. Clin Infect Dis 2021;72(Suppl 1):S27-S33. 
doi: 10.1093/cid/ciaa1582 
90. Cardenas-Comfort C, Kaplan SL, Vallejo JG, et al. Follow-up blood cultures in children with Staphylococcus 
aureus bacteremia. Pediatrics 2020;146(6) 
91. Iwamoto M, Mu Y, Lynfield R, et al. Trends in invasive methicillin-resistant Staphylococcus aureus infections. 
Pediatrics 2013;132(4):e817-e24. 
92. Friedland IR, Du Plessis J, Cilliers A. Cardiac complications in children with Staphylococcus aureus bacteremia. 
The Journal of pediatrics 1995;127(5):746-48. 
93. Duguid RC, Al Reesi M, Bartlett AW, et al. Impact of infectious diseases consultation on management and 
outcome of Staphylococcus aureus bacteremia in children. Journal of the Pediatric Infectious Diseases 
Society 2021;10(5):569-75. 
94. Swissethics. Forschung in Notfallsituationen  [Available from: https://swissethics.ch/en/templates/forschung-in-
notfallsituationen accessed 24.01.2025. 
95. Navarro S, Keith K, Stafylis C, et al. Safety of Linezolid During Pregnancy. Sexually Transmitted Diseases 
2023;50(11):e37-e40. doi: 10.1097/olq.0000000000001860 
96. Rowe HE, Felkins K, Cooper SD, et al. Transfer of Linezolid into Breast Milk. Journal of Human Lactation 
2014;30(4):410-12. doi: 10.1177/0890334414546045 
97. Lim FH, Lovering AM, Currie A, et al. Linezolid and lactation: measurement of drug levels in breast milk and the 
nursing infant. Journal of Antimicrobial Chemotherapy 2017;72(9):2677-78. doi: 10.1093/jac/dkx159 
98. Holland TL, Chambers HF, Boucher HW, et al. Considerations for Clinical Trials of Staphylococcus aureus 
Bloodstream Infection in Adults. Clin Infect Dis 2019;68(5):865-72. doi: 10.1093/cid/ciy774 
99. Ong SWX, Petersiel N, Loewenthal MR, et al. Unlocking the DOOR-how to design, apply, analyse, and interpret 
desirability of outcome ranking endpoints in infectious diseases clinical trials. Clin Microbiol Infect 
2023;29(8):1024-30. doi: 10.1016/j.cmi.2023.05.003 [published Online First: 20230512] 
100. Doernberg SB, Tran TTT, Tong SYC, et al. Good Studies Evaluate the Disease While Great Studies Evaluate 
the Patient: Development and Application of a Desirability of Outcome Ranking Endpoint for 
Staphylococcus 
aureus 
Bloodstream 
Infection. 
Clin 
Infect 
Dis 
2019;68(10):1691-98. 
doi: 
10.1093/cid/ciy766 
101. Evans SR, Follmann D. Using Outcomes to Analyze Patients Rather than Patients to Analyze Outcomes: A 
Step toward Pragmatism in Benefit:risk Evaluation. Stat Biopharm Res 2016;8(4):386-93. doi: 
10.1080/19466315.2016.1207561 [published Online First: 20161206] 
102. Hemkens LG, Contopoulos-Ioannidis DG, Ioannidis JP. Concordance of effects of medical interventions on 
hospital admission and readmission rates with effects on mortality. CMAJ 2013;185(18):E827-37. doi: 
10.1503/cmaj.130430 [published Online First: 20131021] 
103. trial S-SaNAP. Core Protocol, 2021. 
104. McNamara JF, Harris PNA, Chatfield MD, et al. Measuring patient-centred long-term outcome following a 
bloodstream infection: a pilot study. Clin Microbiol Infect 2020;26(2):257 e1-57 e4. doi: 
10.1016/j.cmi.2019.10.011 [published Online First: 20191023] 
105. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework 
and item selection. Med Care 1992;30(6):473-83. 
106. Lins L, Carvalho FM. SF-36 total score as a single measure of health-related quality of life: Scoping review. 
SAGE Open Med 2016;4:2050312116671725. doi: 10.1177/2050312116671725 [published Online First: 
20161004] 
107. Chitra S, Hinahara J, Goss TF, et al. Health-Related Quality of Life as Measured by the 36-Item Short Form 
Survey Among Adults With Acute Bacterial Skin and Skin Structure Infections who Received Either 
Omadacycline or Linezolid in a Phase 3 Double-Blind, Double-Dummy Clinical Trial. Open Forum Infect 
Dis 2021;8(10):ofab459. doi: 10.1093/ofid/ofab459 [published Online First: 20210908] 
108. Opota O, Croxatto A, Prod'hom G, et al. Blood culture-based diagnosis of bacteraemia: state of the art. Clin 
Microbiol Infect 2015;21(4):313-22. doi: 10.1016/j.cmi.2015.01.003 [published Online First: 20150116] 

 
 
LIPS Trial, Version 1.2 of 30/07/2025 
 
Page 63 of 64 
109. Rieg S, Peyerl-Hoffmann G, de With K, et al. Mortality of S. aureus bacteremia and infectious diseases 
specialist consultation--a study of 521 patients in Germany. J Infect 2009;59(4):232-9. doi: 
10.1016/j.jinf.2009.07.015 [published Online First: 20090803] 
110. Honda H, Krauss MJ, Jones JC, et al. The value of infectious diseases consultation in Staphylococcus aureus 
bacteremia. Am J Med 2010;123(7):631-7. doi: 10.1016/j.amjmed.2010.01.015 [published Online First: 
20100520] 
111. Arensman K, Dela-Pena J, Miller JL, et al. Impact of Mandatory Infectious Diseases Consultation and Real-
time Antimicrobial Stewardship Pharmacist Intervention on Staphylococcus aureus Bacteremia Bundle 
Adherence. Open Forum Infect Dis 2020;7(6):ofaa184. doi: 10.1093/ofid/ofaa184 [published Online First: 
20200521] 
112. Goto M, Jones MP, Schweizer ML, et al. Association of Infectious Diseases Consultation With Long-term 
Postdischarge Outcomes Among Patients With Staphylococcus aureus Bacteremia. JAMA Netw Open 
2020;3(2):e1921048. doi: 10.1001/jamanetworkopen.2019.21048 [published Online First: 20200205] 
113. Swissethics. Forschung in Notfallsituationen  [Available from: https://swissethics.ch/templates/forschung-in-
notfallsituationen. 
114. Doern CD, Park JY, Gallegos M, et al. Investigation of Linezolid Resistance in Staphylococci and Enterococci. 
Journal of Clinical Microbiology 2016;54(5):1289-94. doi: doi:10.1128/jcm.01929-15 
115. Human UDoHa, Services NIoH, National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE): US Department of Health and Human 
Services, National Institutes of Health, National Cancer Institute., 2017. 
116. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, National Institutes of Health, National Cancer 
Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0 ed, 2017. 
117. Pocock SJ, Ariti CA, Collier TJ, et al. The win ratio: a new approach to the analysis of composite endpoints in 
clinical trials based on clinical priorities. Eur Heart J 2012;33(2):176-82. doi: 10.1093/eurheartj/ehr352 
[published Online First: 20110906] 
118. Soe YM, Bedoui S, Stinear TP, et al. Intracellular and host cell death pathways. Cellular Microbiology 
2021;23(5):e13317. doi: https://doi.org/10.1111/cmi.13317 
119. Thwaites GE, Gant V. Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus 
aureus? Nature Reviews Microbiology 2011;9(3):215-22. doi: 10.1038/nrmicro2508 
120. Jantarug K, Tripathi V, Morin B, et al. A Far-Red Fluorescent Probe to Visualize Gram-Positive Bacteria in 
Patient Samples. ACS Infectious Diseases 2024;10(5):1545-51. doi: 10.1021/acsinfecdis.4c00060 
121. Scotton WJ, Hill LJ, Williams AC, et al. Serotonin Syndrome: Pathophysiology, Clinical Features, Management, 
and 
Potential 
Future 
Directions. 
International 
Journal 
of 
Tryptophan 
Research 
2019;12:1178646919873925. doi: 10.1177/1178646919873925 
 
 
 

 
 
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Page 64 of 64 
18. APPENDICES 
Documents that are periodically updated and may be updated during the course of the study, are listed here and 
provided separately. 
 
18.1 Linezolid Stada® Summary of Product Characteristics 
Provided separately. 
 
18.2 The Hunter Serotonin Toxicity Criteria: for diagnosing serotonin 
syndrome 
 
 
 
Figure 2: The Hunter Serotonin Toxicity Criteria  
Note the requirement for the presence of some form of neuromuscular excitation, the sine qua non for a diagnosis 
of serotonin syndrome. *The presence of temperature ⩾38.5°C and/or marked hypertonia or rigidity (especially 
truncal) indicates severe SS with a risk of progression with respiratory compromise. 
Taken from: Scotton, William J et al. 2019121 

 
 
List of LIPS Trial Sites, Version 1.0 of 27/03/2025 
 
 
List of LIPS Trial Sites 
 
 
1. Universitätsspital Basel (USB), Petersgraben 4, 4031 Basel 
2. Kantonsspital Aarau (KSA), Tellstrasse 25, 5001 Aarau 
3. Claraspital Basel, Kleinriehenstrasse 30, 4058 Basel 
4. Inselspital Bern, Freiburgstrasse 20, 3010 Bern 
5. Hôpitaux Universitaires de Genève (HUG), Rue Gabrielle-Perret-Gentil 4, 1205 Genève 
6. Hôpital du Jura, Fbg des Capucins 30, 2800 Delémont 
7. Centre hospitalier universitaire vaudois (CHUV), Rue du Bugnon 46, 1005 Lausanne 
8. Ospedale Regionale di Lugano (EOC), Via Tesserete 46, 6900 Lugano 
9. HOCH Health Ostschweiz, Kantonsspital St. Gallen, Rorschacher Str. 95, 9000 St. Gallen 
10. Kantonsspital Winterthur, Brauerstrasse 15, 8400 Winterthur 
11. Stadtspital Zürich Triemli, Birmensdorferstrasse 497, 8063 Zürich 
12. Universitätsspital Zürich (USZ), Rämistrasse 100, 8091 Zürich 
 

 
 
 
List of LIPS trial team, Version 1.2 of 04/08/2025 
 
List of project leaders and other key persons 
involved in the trial 
 
Title 
Name 
Institution 
Position 
Role and Function/Responsibility in the 
project 
PD 
Dr. 
Richard Kühl 
University 
Hospital Basel 
Senior 
physician 
Sponsor-investigator and Co-Principal 
Investigator; Responsible for the overall 
trial implementation; Local Investigator 
University Hospital Basel 
PD, 
PhD 
Benjamin Speich 
University 
Hospital Basel 
Senior 
Researcher 
Co-Principal Investigator; Responsible for 
the overall trial implementation 
Prof. 
Dr. 
Nina Khanna 
University 
Hospital Basel 
Chief 
physician 
Co-Principal Investigator; Responsible for 
the overall trial implementation 
PhD 
Natalie Rose 
University 
Hospital Basel 
Trial Manager 
Clinical Trial Project Manager: Coordinating 
all aspects of the trial  
Dr. 
Nadine 
Bernasconi 
University 
Hospital Basel 
Medical Study 
Coordinator 
Collaborator: Input on local site 
implementation procedures and responsible 
for local recruitment, Point of contact for 
medical questions from study sites 
Dr. 
Michaela 
Schumacher 
University 
Hospital Basel 
Medical Study 
Coordinator 
Collaborator: Input on local site 
implementation procedures and responsible 
for local recruitment, Point of contact for 
medical questions from study sites 
Dr. 
Severin Vogt 
University 
Hospital Basel 
Attending 
physician 
Collaborator; Support trial design, safety 
aspects, pharmacological surveillance 
Prof. 
Dr. 
Maja Weisser 
Rohacek 
University 
Hospital Basel 
Senior 
physician 
Collaborator; Support trial design, local 
implementation, analysis of the data 
PhD 
Laura Werlen 
University 
Hospital Basel 
Trial 
statistician 
Trial statistician; Statistical support and 
analysis 
Prof. 
Dr. 
Matthias Briel 
University 
Hospital Basel 
Unit head and 
research 
group leader 
Collaborator; Trial methodology 
Dr. 
Elisabeth 
Wehrle-Wieland 
Claraspital Basel 
Senior 
physician 
Local Investigator Claraspital Basel; 
Input on local site implementation 
procedures and responsible for local 
recruitment, follow-up and data quality 
PD 
Dr. 
Anna Conen 
Cantonal Hospital 
Aarau 
Senior 
physician 
Local Investigator Cantonal Hospital 
Aarau; Input on local site implementation 
procedures and responsible for local 
recruitment, follow-up and data quality 
PD 
Dr. 
Christine 
Thurnheer 
University 
Hospital Bern 
Senior 
physician 
Local Investigator University Hospital 
Bern; Input on local site implementation 
procedures and responsible for local 
recruitment, follow-up and data quality 
Dr. 
Yonas Martin 
University 
Hospital Bern 
Senior 
physician 
Collaborator; Trial methodology 
Prof. 
Dr. 
Stephan 
Harbarth 
University of 
Geneva Hospitals 
Chief 
physician 
Local Investigator University of Geneva 
Hospitals; Input on local site 
implementation procedures and responsible 

 
 
 
List of LIPS trial team, Version 1.2 of 04/08/2025 
 
for local recruitment, follow-up and data 
quality 
Dr. 
Michèle Birrer 
Hôpital du Jura 
Senior 
physician 
Local Investigator Hôpital du Jura; Input 
on local site implementation procedures and 
responsible for local recruitment, follow-up 
and data quality 
PD. 
Dr. 
Matthaios 
Papadimitriou-
Olivgeris 
University 
Hospital 
Lausanne 
Senior 
physician 
Local Investigator University Hospital 
Lausanne; Input on local site 
implementation procedures and responsible 
for local recruitment, follow-up and data 
quality 
PD 
Dr. 
Marco 
Bongiovanni 
Cantonal Hospital 
Lugano 
Senior 
physician 
Local Investigator Cantonal Hospital 
Lugano; Input on local site implementation 
procedures and responsible for local 
recruitment, follow-up and data quality 
Prof. 
Dr. 
Werner Albrich 
HOCH Health 
Ostschweiz, 
Cantonal Hospital 
St. Gallen 
Senior 
physician 
Local Investigator Cantonal Hospital St. 
Gallen; Input on local site implementation 
procedures and responsible for local 
recruitment, follow-up and data quality 
PD 
Dr. 
Urs Karrer 
Cantonal Hospital 
of Winterthur 
Chief 
physician 
Local Investigator Cantonal Hospital of 
Winterthur; Input on local site 
implementation procedures and responsible 
for local recruitment, follow-up and data 
quality 
Prof. 
Dr. 
Barbara Hasse 
University 
Hospital Zürich 
Senior 
physician 
Local Investigator University Hospital 
Zürich; Input on local site implementation 
procedures and responsible for local 
recruitment, follow-up and data quality 
Dr. 
Adrian Schibli 
Stadtspital Zürich 
Chief 
physician 
Local Investigator Stadtspital Zürich; 
Input on local site implementation 
procedures and responsible for local 
recruitment, follow-up and data quality 
PhD 
David Büchel 
University 
Hospital Basel 
Senior Data 
Manager 
Collaborator; Database set-up and data 
entry training, database maintenance, data 
export and archiving 
 
Roberta Renai 
University 
Hospital Basel 
Study 
Monitoring 
Project partner: Set up of risk-adapted 
monitoring, site initiation, routine and close 
out visits; drug accountability 
 
 
Renate Huber-
Wunderle 
University 
Hospital Basel 
Regulatory 
Affairs 
Manager 
Project partner: Supporting regulatory filings 
(ethics committee and Swissmedic), 
clinicaltrials.gov registration 
MSc 
Jeanne Lemant 
University 
Hospital Basel 
Data Scientist 
Project partner: Preparation and updating of 
data safety monitoring reports 
PhD 
Florian Peters 
University 
Hospital Basel 
Project 
manager 
Project partner: Study risk mitigation