A Phase 2a Study, Effect of Vancomycin With vs Without Delpazolid (LCB01-0371) in Patients With MRSA Bacteremia

Study Overview
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Brief Summary
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The objectives of this study is to exploratory whether vancomycin + delpazolid is more effective to the standard of treatment (vancomycin)/ for hospitalised adults with MRSA bacteraemia.

Detailed Description
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The mortality from S aureus bacteremia is higher for MRSA than for methicillin-susceptible S aureus (MSSA), typically at 20% to 25%. The current standard therapy for MRSA bacteremia is vancomycin. Vancomycin has many shortcomings, including poor tissue penetration and slow killing time. Vancomycin has reduced efficacy against MRSA and tended to increase the MIC level (called MIC creep). Addition of Delpazolid to Vancomycin could improve the known drawbacks of Vancomycin alone.

Official Title
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A Multicenter, Double-blinded, Randomized, Parallel Design, Phase IIa Clinical Trial to Evaluate the Efficacy, Safety and PK of LCB01-0371 With Vancomycin Versus Vancomycin Monotherapy in Patients With MRSA Bacteremia

Conditions
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MRSA Bacteremia

Intervention / Treatment
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* Drug: Delpazolid
* Drug: Vancomycin
* Drug: Placebo of Delpazolid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥19 years of age on the date of written consent Subject who has confirmed positive MRSA at least one set of blood cultures within 72 hours prior to randomization OR, Subject who has confirmed positive MRSA at least one set of blood culture whthin 96 hours prior to randomization and treated with vancomycin at least 72 hours prior to randomization Subject who has clinical symptoms or signs of MRSA bacteremia according to the judgment of the investigator Subject who voluntarily decides to participate in this clinical trial after being explained fully, and agrees in writing to implement the clinical trial compliance matters Exclusion Criteria: Subject with polymicrobial bacteremia or infections including Gram-negative strain Subject undergoing or in need of treatment with antiviral or antifungal drugs Subject who has received treatment for MRSA bacteremia within 3 months of screening (Subjects who have re-infection by investigator's judgement may participant in the study.) Subject who has been administered effective antibiotics against MRSA (Vancomycin, etc.) for more than 96 hours prior to the first investigational product administration. (However, antibiotics effective for MRSA such as vancomycin are allowed to be administered for less than 72 hours.) Septic shock patients Subject who has hypersensitivity to vancomycin or linezolid Subject who has a history of hypersensitivity to peptide-based antibiotics and aminoglycoside-based antibiotics Subject who is receiving a MAO inhibitor(MAOI) or has received MAOI within 14 days of the first investigational drug administration Subject taking serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptan), meperidine, or buspirone Subject with severely decreased immunity (Severe neutropenia (ANC <0.5×10^9/L) etc.) Subject who is expected to die within 2 days due to serious complications of MRSA bacteremia based on the judgment of the investigator Body Mass Index (BMI) ≥35 kg/m2 Subject who is unable to administer drugs orally Pregnant or lactating female, female or male with childbearing potential who disagrees with the use of appropriate contraceptive methods during the study and up to 14 days after the last dose of the investigator product Subject who has received other clinical trial drugs within 30 days of screening Subject who is not suitable for participation in this clinical trial according to the medical findings of investigators

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo-controlled
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination therapy - Vancomycin IV plus Delpazolid 800 mg, PO, BID<br>Intravenous vancomycin dosed as per 2020 IDSA guideline Doses of 15 to 20 mg/kg (based on actual body weight) administered every 8 to 12 hours as an intermittent infusion are recommended for most patients with normal renal function when assuming a MICBMD of 1 mg/L. Depending on the investigator's judgment, it is allowed to change to daptomycin after at least one week of administration of vancomycin, and also it is allowed to change to oral antibiotics other than oxazolidinones after two weeks of administration of vancomycin (including daptomycin). | Drug: Delpazolid<br>* BID, PO<br>* Other names: LCB01-0371;Drug: Vancomycin<br>* IV infusion per 2020 IDSA guideline<br>|
| Placebo Comparator: Monotherapy - Vancomycin IV plus Placebo of Delpazolid<br>Intravenous vancomycin dosed as per 2020 IDSA guideline Doses of 15 to 20 mg/kg (based on actual body weight) administered every 8 to 12 hours as an intermittent infusion are recommended for most patients with normal renal function when assuming a MICBMD of 1 mg/L. Depending on the investigator's judgment, it is allowed to change to daptomycin after at least one week of administration of vancomycin, and also it is allowed to change to oral antibiotics other than oxazolidinones after two weeks of administration of vancomycin (including daptomycin). | Drug: Vancomycin<br>* IV infusion per 2020 IDSA guideline<br>Drug: Placebo of Delpazolid<br>* BID, PO<br>* Other names: Placebo of LCB01-0371;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall cure rate by Day 14 (composite response rate: clinical improvement plus clearance of bacteremia) | 'Overall cure' means that there are no symptoms of infection that existed when enrolled in the clinical trial, there are no new metastatic infection due to MRSA and no new infection (clinical improvement), and MRSA negative is confirmed twice in a row as a result of blood culture tests ( clearance of bacteremia). a. If negative in the blood culture test is confirmed for the first time, additional test will be performed the next day, and if it results negative for a total of two times in a row, it is judged as 'clearance of bacteremia'. | by Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall cure rate by End of Treatment (EOT) | composite response rate: clinical improvement plus clearance of bacteremia | by EOT visit (up to 6 weeks) | 
| Mortality due to MRSA bacteremia | Proportion of subjects who died due to MRSA bacteremia | by Test of Cure (TOC) (=4 weeks after EOT (up to 6 weeks)) | 
| Microbiological relapse rate | Defined as a positive blood culture to MRSA when previous ones were negative | by TOC (=4 weeks after EOT) | 
| Clearance of MRSA bacteremia rate | Proportion of subjects who confirmed MRSA negative two consecutive set in the blood culture test | Day 3, Day 5, Day 7, Day 14, EOT (up to 6 weeks) | 
| Persistent MRSA bacteremia rate | Proportion of subjects who have positive results on blood culture tests | Day 3, Day 5, Day 7, Day 14 | 
| Time to clearance of MRSA bacteremia | If negative in the blood culture test is confirmed for the first time, additional test will be performed the next day, and if it results negative for a total of two times in a row, it is judged as clearance of bacteremia. The period until the clearance of bacteremia is defined as the period (day) from the date of the first blood culture test within 72 hours prior to randomization with MRSA positive (index blood culture) to the date of the blood culture test with the first negative result confirmed. | by EOT (up to 6 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRSA, Staphylococcus aureus bacteremia, SAB, bloodstream infection, BSI, Bacteremia