History of Changes for Study: NCT02901717

Version	Submitted Date	Changes
1	September 14, 2016	None (earliest Version on record)
2	July 21, 2017	Study Status, Oversight and Study Design
3	July 5, 2018	Recruitment Status, Study Status, Arms and Interventions, Study Design, Study Description, Contacts/Locations, Eligibility, Outcome Measures and Oversight
4	July 9, 2018	Recruitment Status, Study Status and Contacts/Locations
5	August 13, 2019	Contacts/Locations and Study Status
6	October 21, 2019	Contacts/Locations, Outcome Measures, Study Status, Study Description, Eligibility, Arms and Interventions and Study Design
7	October 23, 2019	Outcome Measures and Study Status
8	September 2, 2020	Study Status
9	April 6, 2021	Contacts/Locations and Study Status
10	July 1, 2021	Study Status and Contacts/Locations
11	April 18, 2022	Recruitment Status, Study Status and Contacts/Locations

Brief Summary:

This is a Phase 3, multi-center, randomized, double-blind study to determine the efficacy and safety of MLT, a novel antibiotic lock therapy that combines minocycline with edetate disodium in 25% ethanol solution.

Approximately 700 subjects who have been diagnosed with CRBSI/CLABSI and who meet all necessary criteria for the study will be randomized in a 1:1 ratio to 1 of 2 treatment arms:

MLT Arm: MLT + SOC intravenous (IV) antibiotic therapy; or
Control Arm (subjects randomized to the Control Arm will receive treatment based on the type and virulence of the infecting organism as documented by the Investigator prior to randomization)

Detailed Description:

Mino-Lok Therapy is being developed as an adjunctive therapy for the treatment of catheter-related or central line associated bloodstream infection (CRBSI/CLABSI) in combination with appropriate systemic antibiotic(s), to preserve central venous access and to avoid the complications and morbidities associated with catheter removal and reinsertion.

Approximately 700 subjects who have been diagnosed with CRBSI/CLABSI and who meet all necessary criteria for the study will be randomized in a 1:1 ratio to 1 of 2 treatment arms:

MLT Arm: MLT + SOC intravenous (IV) antibiotic therapy; or
Control Arm (subjects randomized to the Control Arm will receive treatment based on the type and virulence of the infecting organism as documented by the Investigator prior to randomization):
1. Saline-heparin (placebo) lock + SOC IV antibiotics. (NOTE: The saline lock arm is reserved for coagulase-negative staphylococci, enterococci, or other organisms deemed to be of low virulence per the Investigator); or
2. Antibiotic lock + SOC IV antibiotics. The antibiotic lock will be comprised of heparin and the same antibiotic delivered systemically. (NOTE: The antibiotic lock arm may include subjects with S. aureus, including methicillin-resistant S. aureus, vancomycin intermediate S. aureus, or vancomycin-resistant S. aureus; vancomycin resistant enterococci; Candida, Pseudomonas; other Gram negative organisms; or other organisms deemed to be of high virulence per the Investigator). At least 50 subjects will be randomized to this arm. In the event that more than 1 organism is isolated, the Investigator will specify which single antibiotic should be used for the lock.

Randomization will be stratified by type of CVC, presence of neutropenia, and by type and virulence of the infecting organism.

The first 5 doses of lock therapy should be administered within the first 7 days following randomization (Visit T1 through Visit T5), with the first 3 doses administered consecutively once daily (QD) for the first 3 days following randomization (Visit T1 through Visit T3). The next 2 doses should be administered within the next 4 days. Subsequent doses will occur once weekly over the following 2 weeks (Visit T6 and Visit T7 [EOT]) for a total of 7 doses.

All lock treatments will be administered for a dwell time of 2 hours QD on each day of treatment.

All efforts will be made to ensure that lock therapy is performed between antibiotic doses and is scheduled to maximize the time between the lock therapy and administration of IV antibiotics.

The primary endpoint is the proportion of subjects in the ITT Population who have Overall Success at TOC (Week 8). Success is defined as any subject who demonstrates eradication of the pathogen, stabilization or improvement in signs and symptoms of the infection, catheter salvage, AND survival at termination of the study. Analysis for the primary endpoint will compare the overall success rate between the MLT Arm and the Control Arm.

Arms

Assigned Interventions

Active Comparator: Standard of Care

Saline-heparin (placebo) lock + standard of care antibiotics; or antibiotic lock + standard of care antibiotics. The standard of care antibiotic will be chosen by the investigator at the time of the infection.

Drug: Standard of care with placebo lock (saline and heparin)

Standard of Care antibiotics appropriate for the infecting organism with a placebo lock solution of saline and heparin. The saline lock arm is reserved for coagulase-negative staphylococci, enterococci, or other organisms deemed to be of low virulence per the Investigator.

Other Names:

Standard of Care antibiotics without antibiotic lock

Drug: Standard of Care with an antibiotic lock

Standard of Care antibiotics appropriate for the infecting organism with an antibiotic lock solution using the same standard of care antibiotic delivered systemically. The antibiotic lock arm may include subjects with S. aureus, including methicillin-resistant S. aureus, vancomycin intermediate S. aureus, or vancomycin-resistant S. aureus; vancomycin resistant enterococci; Candida, Pseudomonas; other Gram negative organisms; or other organisms deemed to be of high virulence per the Investigator. The standard of care antibiotic will be determined by the investigator at the start of treatment.

Other Names:

Standard of Care antibiotics with standard of care antibiotic lock

Experimental: Mino-Lok Therapy (MLT)

Standard of care plus MLT. MLT contains minocycline with EDTA and ethanol.

Drug: Standard of care with Mino-Lok Therapy (MLT)

Standard of Care antibiotics appropriate for the infecting organism plus Mino-Lok therapy to disinfect and save the catheter.

Other Names:

Standard of care antibiotics + Mino-Lok

Primary Outcome Measures:

Proportion of subjects deemed successfully treated at the end of the study period
[ Time Frame: 8 weeks ]

Success is defined as any subject who demonstrates eradication of the pathogen, stabilization or improvement in signs and symptoms of the infection, catheter salvage, AND survival at termination of the study.

Secondary Outcome Measures:

Proportion of subjects with a response of Clinical Cure at End of Treatment.
[ Time Frame: 8 weeks ]

Clinical Cure is defined as the absence of baseline CRBSI/CLABSI signs/symptoms or, in the Investigator's opinion, improvement of signs/symptoms such that no additional therapy is necessary.

Proportion of subjects in the MITT and CE Populations with a response of microbiological eradication.
[ Time Frame: 8 weeks ]

All-cause mortality
[ Time Frame: 14 Days ]

All-cause mortality
[ Time Frame: 28 Days ]

Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
[ Time Frame: 8 Weeks ]

Safety and tolerability profile of subjects as assessed by adverse events, serious adverse events (SAEs), vital signs, clinical laboratory evaluations, and physical examinations.

Eligibility


Minimum Age:	12 Years
Maximum Age:
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	Inclusion Criteria: Inpatient or outpatient with presence of indwelling CVC (eg, totally implantable port, tunneled or non-tunneled catheter, peripherally inserted central catheter, or hemodialysis catheter) that has been in place for 14 days before the onset of a bloodstream infection that has been documented within 96 hours prior to enrollment and demonstrates the protocol definition of CRBSI/CLABSI as defined below: a. For subjects with no mucosal barrier injury (MBI), neutropenia, graft versus host disease (GVHD) involving the gastrointestinal (GI) tract, or diarrhea, ONE of the following must be satisfied: i. A recognized single pathogen cultured from 1 or more blood cultures that is not related to an infection at another site; OR ii. A common skin contaminant cultured from 2 or more blood cultures drawn on the same or consecutive calendar days; b. For all other subjects (ie, subjects with MBI, neutropenia, GVHD involving the GI tract, or diarrhea) ONE of the following must be satisfied: i. A recognized single pathogen cultured from 1 or more blood cultures that is not related to an infection at another site; OR ii. A common skin contaminant cultured from 2 or more blood cultures drawn from the same or consecutive calendar days; AND ONE of the following should be present: Paired positive quantitative blood cultures, whereby quantitative blood cultures are drawn through the CVC and peripheral vein and the blood cultures from the CVC reveal at least 3-fold greater number of colonies of the same organism (species and antibiogram) than the peripherally drawn quantitative blood culture; OR A differential period of CVC culture versus peripheral blood culture time to positivity of at least 2 hours; Subject must demonstrate at least ONE of the following clinical criteria (a or b): a. Temperature 38.0°C or 36.0°C, with 1 of the following clinical signs and symptoms that are attributed to the CRBSI/CLABSI and not thought to be related to an infection at another site: i. White blood cell count 12,000/mm3 or 4000/mm3, or with a differential count showing 10% band forms; ii. Tachycardia: Heart rate 100 bpm; iii. Tachypnea: Respiratory rate 20 breaths/minute; or iv. Hypotension: Systolic blood pressure 90 mmHg; OR b. Neutropenic (ie, absolute neutrophil count 500/mm3); NOTE: A neutropenic subject without the above signs/symptoms may be considered for the study if they have at least 1 positive blood culture, no other apparent source of their bacteremia, and satisfy the protocol definition of CRBSI/CLABSI.); Subjects who refuse to have their catheter removed or subjects for whom, in the Investigator's opinion, catheter retention for the duration of the study is reasonable or required; Exclusion Criteria: Subjects with hypersensitivity or allergy to tetracycline antibiotics or edetate disodium; Subjects with septic shock that requires inotropic support or is unresponsive to fluid resuscitation; Subjects taking disulfiram or disulfiram-like drugs; Subjects with prosthetic cardiac valves; Subjects with the presence of a deep-seated intravascular source of infection (eg, endocarditis [as evidenced by vegetations on an echocardiogram or clinical suspicion] or septic thrombosis) or bacteremia with documented microbiological evidence of another source of infection (eg, osteomyelitis, pneumonia, skin infection, urinary tract infection, joint infection, or abdominal infection) known to be due to the same organism cultured from the blood; Subjects with polymicrobial CRBSI/CLABSI caused by pathogens that would require multiple antibiotics to be used for adequate lock therapy treatment. For example, a subject with MRSA and Escherichia coli requiring treatment with vancomycin and meropenem would be excluded from the study. A subject with S. aureus and S. epidermidis, where both are identified as pathogens and where both could be treated with vancomycin, would be eligible. NOTE: If 1 organism is isolated, the Investigator should decide which of the organisms are pathogens and require therapy; Subjects with the presence of a tunnel or catheter exit site infection or an infusion port pocket abscess as manifested by purulence at the exit site, or inflammation with erythema, or induration of 1 cm in diameter; Subjects with persistent bacteremia despite 72 hours of antibiotic therapy to which the infecting organism is susceptible; Subjects with short-term CVCs indwelling 14 days; Subjects with a central line-related mycobacterial infection; or Subjects who, in the opinion of the Investigator, have a high probability of death within 3 months of randomization due to a disease process other than the CRBSI/CLABSI.