Phase IIa Clinical Study of N-Rephasin® SAL200

A Randomized, Double-blind, Placebo-controlled, Multicenter Phase IIa Clinical Study to Evaluate Safety and to Explore Efficacy of N-Rephasin® SAL200, in Patients With Persistent Staphylococcus Aureus Bacteremia

This study is performed to evaluate safety and to explore the efficacy of a single intravenous dose of N-Rephasin® SAL200 (3 mg/kg) in addition to the conventional standard treatment, for persistent Staphylococcus aureus bacteremia in patients, for more than 48 hours even after antibiotic treatment to which Staphylococcus aureus is susceptible.

Study Overview

• Status: Terminated
• Conditions: Anti-Bacterial Agents; Staphylococcus Aureus Bacteremia
• Intervention / Treatment: Biological: N-Rephasin® SAL200; Other: Placebo

Detailed Description

Subjects:

Patients with persistent Staphylococcus aureus bacteremia for more than 48 hours from the beginning of antibiotics treatment to which Staphylococcus aureus is susceptible.

Study Method:

1. Selection of patients with persistent S.aureus bacteremia for more than 48 hours even after application of the standard treatment for S. aureus bacteremia
2. Randomization according to the trial institutions
3. The control group receives a single intravenous dose of the placebo in addition to the standard treatment for persistent Staphylococcus aureus bacteremia
4. The study group receives a single intravenous dose of the N-Rephasin® SAL200 (3 mg/kg) in addition to the standard treatment for persistent Staphylococcus aureus bacteremia
5. A blood culture is performed 18 hours (±6 hours) after the administration of N-Rephasin® SAL200
6. Blood cultures continue to be performed every 24 hours (±6 hours) or 48 hours (±6 hours) after the previous blood culture, until two consecutive results of 'no growth (negative conversion)' are obtained
7. Adverse events are monitored at the time of the first blood culture following the administration of N-Rephasin® SAL200 or placebo, and at the subsequent intervals of 24 hours or 48 hours

Statistical Analysis:

1. Primary endpoints

   • Safety analysis is conducted in the Safety group. A distribution table of patients who experience at least one adverse event (incidence), and distribution tables of the relationship of the reported adverse events with the investigational product (distribution tables for severity and the relationship with the drug) are presented with respect to the groups (study group, control group), to determine safety of the investigational product.
   • The results of the laboratory tests, anaphylaxis test, inflammatory cytokine test and vital signs at baseline and the last visit are summarized as mean values and standard deviations, to determine the change before and after the treatment within each group.
   • Categorical data are divided into normal and abnormal, and summarized as the frequency and percentage to determine the difference before and after treatment within each group.

2. Secondary endpoints

   • Proportion of patients who are negative for bacterial growth in the first blood culture after administration of the investigational drug. The descriptive statistics for the proportion of patients who are negative for bacterial growth in the first blood culture (the rate of no growth) after the first treatment are presented by treatment group. Whether the rate of no growth is superior in the study group compared to the control group, is evaluated by a descriptive statistical method.
   • Proportion of patients who die due to S. aureus bacteremia by Day14 after the incidence of bacteremia. The descriptive statistics for the proportion of patients who die due to S. aureus bacteremia by Day14 are presented by treatment group and evaluated.
   • Proportion of treatment failure for S. aureus bacteremia by Day 14 (if two consecutive results of 'no growth' are not achieved in the blood cultures which are performed until Day 14. The descriptive statistics for the proportion of treatment failure for S. aureus bacteremia by Day 14 are presented and evaluated.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, Korea, Republic of, 13620
      • Seoul National University Bundang Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with MSSA/MRSA bacteremia who are confirmed to have more than a pair of Gram positive bacteria in a blood culture conducted at 48~96 hours after the start of antibiotic treatment to which S. aureus is susceptible.
2. Males or females aged 19 years or older
3. Those who understand the explanatory notes for subjects, and sign the informed consent.

Exclusion Criteria:

1. Those who do not receive appropriate antibiotics within 48 hours after the occurrence of bacteremia (the time point of reporting it to the department of laboratory medicine)
2. The Gram positive strain, identified in a blood culture conducted at 48~96 hours after the start of antibiotic treatment to which S. aureus is susceptible, is not the same strain of S. aureus which was cultured when the definite diagnosis of S. aureus bacteremia was made
3. Those who pass 48 hours after confirmation of persistent S. aureus bacteremia through a blood culture conducted at 48~96 hours after the start of antibiotic treatment to which S. aureus is susceptible

4. Those who have symptoms of septic shock at the time of acquisition of the consent form

   • Systolic blood pressure lower than 90 mmHg, or blood pressure lower than usual by more than 40 mmHg, in spite of the application of appropriate fluid therapy
   • Requirement of hypertensor to maintain the systolic blood pressure at 90 mmHg or higher
5. Those who were infected with mixed bacterial species
6. Those who are hypersensitive to N-Rephasin® SAL200, who have a clinically significant hypersensitivity to it, or a past history there of
7. Pregnant or lactating women and women of child-bearing potential (who do not agree to take appropriate contraceptive measures during the trial period)
8. Those who participated in other clinical trial within 30 days prior to enrollment
9. Patients with any conditions that may interfere with study participation or accurate evaluation on investigator's judgment
10. Those who may die within 72 hours due to other serious complications (e.g., cerebral infarction, etc.), as per the investigator's judgment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: N-Rephasin® SAL200; To assign the study group, administer the conventional standard treatment (CST) (antibiotics) for MRSA/MSSA with N-Rephasin® SAL200 (3mg/kg); N-Rephasin® SAL 200 is given by intravenous only once at Day 1.	Biological: N-Rephasin® SAL200; A single dose of SAL200 (SAL-1, 3mg/kg) intravenous administration of the study drug, in addition to the conventional standard treatment (antibiotics) for MRSA/MSSA
Placebo Comparator: Placebo; To assign the control group, administer the conventional standard treatment (CST) (antibiotics) for MRSA/MSSA with Formulation buffer (placebo); Placebo (INT200) is given by intravenous only once at Day 1 (same way with Experimental group)	Other: Placebo; A single dose of the formulation buffer (placebo), excluding the main ingredient of the study drug in addition to the conventional standard treatment (antibiotics) for MRSA/MSSA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Endpoints - Summary of Treatment-emergent Adverse Events (Safety Set)	The safety analysis was conducted based on the data of all AEs, physical examinations, clinical laboratory tests, and vital signs (blood pressure, pulse rate, body temperature, and respiratory rate) collected from the subjects. All subjects who enrolled in this study (13 subjects in the placebo group and 12 subjects in the N RephasinⓇ SAL200 group) were defined as the Safety Set and included in the analysis.	up to 4 Week ± 5 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy Endpoints 1	Number of Participants With Negative Result in the First Blood Culture	by day 14
Efficacy Endpoint 2	The Proportion (Percentage) of Subjects who Died of Staphylococcus aureus Bacteremia Within 14 Days of Bacteremia Diagnosis	by day 14
Efficacy Endpoint 3	Proportion (Percentage) of Treatment Failure Against Staphylococcus aureus Bacteremia by Day 14	by day 14

Collaborators and Investigators

• Sponsor: Intron Biotechnology, Inc.
• Investigators: Principal Investigator: Hong-Bin Kim, M.D, PhD, Seoul National University Bundang Hospital; Principal Investigator: Wan Beom Park, M.D, PhD, Seoul National University Hospital

Publications and helpful links

General Publications

• Kundsin RB. Documentation of airborne infection during surgery. Ann N Y Acad Sci. 1980;353:255-61. doi: 10.1111/j.1749-6632.1980.tb18928.x. No abstract available.
• Etienne J, Fleurette J, Ninet JF, Favet P, Gruer LD. Staphylococcal endocarditis after dental extraction. Lancet. 1986 Aug 30;2(8505):511-2. doi: 10.1016/s0140-6736(86)90377-6. No abstract available.
• Lamy B, Dargere S, Arendrup MC, Parienti JJ, Tattevin P. How to Optimize the Use of Blood Cultures for the Diagnosis of Bloodstream Infections? A State-of-the Art. Front Microbiol. 2016 May 12;7:697. doi: 10.3389/fmicb.2016.00697. eCollection 2016.
• van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of mortality in Staphylococcus aureus Bacteremia. Clin Microbiol Rev. 2012 Apr;25(2):362-86. doi: 10.1128/CMR.05022-11.

Helpful Links

• Etiene J, Fleurette J, Ninet JF, Favet P, Gruer LD. Staphylococcus endocarditis after dental extraction. Lancet. 1986;2:511-512
• Frency J, Brun Y, Bes M, Meugnier H, Grimont F, Grimon PAD, Newi C, Fleurette J. Staphylococcus lugdunensis sp. and Staphylococcus schleiferi sp. novel two species from human clinical specimens. Int Syst Bacteriol. 1998;38:168-172
• Seung-Ho Han et al., Monitoring of Methicillin-Resistant Staphylococcus aureus in Nasal Swabs Obtained fron Dental Clinic Healthcare Providers and Medical Environments Nurses. Int J Oral Biology. 2010;35:7-12
• Hyuk Min Lee, Dong Eun Yong, Kyungwon Lee., Antimicrobial Resistance of Clinically Important Bacteria Isolated from 12 Hospitals in Korea in 2004 . Korean Journal of Clinical Microbiology 2005;8(1):66-73
• Siegel JD, Rhinehart E, Jackson M, Chiarello L. Management of multidrug-resistant organisms in health care settings, 2006. Am J Infect Control 2007;35(10 SUPPL. 2):S165-93.
• Woo J-H, Song J-H, Cheong H-S, Lee E-K, Chae S-M, Kim N-J. Analysis of Economic Outcomes of Methicillin-Resistant Staphylococcus Aureus(MRSA) Bacteremia Using Retrospective Case-Control Study. Korean J Clin Pharm 2007;17(2):59-64.
• Lee, H, Yong, D, Lee, K, Hong, S, Kim, E, Jung, S, Park, Y, Choi, T, Eo, Y, Shin, J et al. Antimicrobial Resistance of Clinically Important Bacteria Isolated from 12 Hospitals in Korea in 2004. Korean J Clinical Microbiology 2005;8(1):66-73

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2017
• Primary Completion (Actual): November 7, 2019
• Study Completion (Actual): November 7, 2019

Study Registration Dates

• First Submitted: February 23, 2017
• First Submitted That Met QC Criteria: March 23, 2017
• First Posted (Actual): March 24, 2017

Study Record Updates

• Last Update Posted (Actual): October 6, 2021
• Last Update Submitted That Met QC Criteria: September 12, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: N-Rephasin SAL200; Methicillin-Sensitive Staphylococcus aureus; Methicillin Resistant Staphylococcus Aureus
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Sepsis; Bacteremia; Staphylococcal Infections
• Other Study ID Numbers: ITB-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No