Mino-Lok Therapy for Treatment of Catheter Related Blood Stream Infections.
Scientific Title of Study
A Phase 3, Multi-Center, Randomized, Open-Label, Assessor-Blind Study to Evaluate the Efficacy and Safety of Mino-Lok Therapy (MLT) in Combination with Systemic Antibiotics in the Treatment of Catheter-Related or Central Line Associated Bloodstream Infection
Department of Infectious Diseases, Dabwali Road, Lal Singh Nagar, Bathinda, PIN 151001, India Bathinda
9878943178
Saurabhnayak2012@gmail.com
Dr Vinay Rathore
All India institute of medical sciences Raipur
Department of Nephrology, Gate No, 1, Great Eastern Road, opposite Gurudwara, AIIMS Campus, Tatibandh, Raipur, Chhattisgarh 492099 India Raipur
9408388382
vinayrathoredm@aiimsraipur.edu.in
Dr Abdul Ghafur
Apollo Cancer Centre
Department of Infectious Diseases, A block 2nd floor, No: 320, Padma Complex Anna Salai Teynampet, Chennai, Tamil Nadu, 600035 India Chennai
9841700827
drghafur@hotmail.com
Dr Shweta Ram Chandankhede
CARE Hospitals
1st Floor, Department of Critical Care Medicine, Care Hospital, Road Number 1, Prem Nagar, Banjara Hills, Hyderabad, Telangana 500034 India Hyderabad
9963431945
shwets0106@gmail.com
Dr Santosh Varughese
Christian Medical College Vellore
Christian Medical College Vellore Ranipet Campus
Department of Nephrology, 6th Floor,
Kilminnal Village
Ranipet District,
Tamil Nadu
pin code 632517 India
Vellore
9843139601
santosh.vellore@gmail.com
Dr Gaurav Jain
Dharamshila Narayana Superspeciality Hospital
Ground Floor OPD, Dharamshila Narayana Superspeciality Hospital Marg,Vasundhara Enclave , Near New Ashok Nagar Metro Station Dallupura, New Delhi – 110096 India New Delhi
7838582169
gaurav.jayn@gmail.com
Dr Neha Rastogi
Fortis Memorial Research Institute
Department of Infectious Disease, Fortis Memorial Research Institute, Sector 44,Opposite Huda City Metro station, Gurugram, India-122002 Gurgaon
8588969347
neha.rastogi@fortishealthcare.com
Dr Kapil Zirpe
Grant Medical Foundation, Ruby Hall Clinic
Department of Neuro Critical Care, 1st Floor, No. 40 Sassoon Road, Pune, 411001 Maharashtra India Pune
9762755733
kapilzirpe@gmail.com
Dr Rajnish Nagarkar
HCG Manavata Cancer Centre, Nashik
Ground Floor OPD, HCG Manavata Cancer Centre, Behind Shivang Auto Mumbai Naka, Nashik‑422002, Maharashtra, India Nashik
9822574157
drraj@manavatacancercentre.com
Dr Viny Kantroo
Indraprastha Apollo Hospitals, Delhi
Department of Respiratory Critical Care and Sleep Medicine. Indraprastha Apollo Hospitals, Sarita Vihar, Mathura Road, New Delhi, Delhi – 110076 India New Delhi
8077761037
vinykantroo@gmail.com
Dr Ajay Jhaveri
Jaslok Hospital And Research Centre
15, Dr. G. Deshmukh Marg Mumbai Mumbai City Mumbai
02223516661
drajayjhaveri@gmail.com
Dr Piyush Chaudhari
Jehangir Clinical Development Centre Pvt. Ltd
Department of Infectious Disease, Jehangir Clinical Development Centre Pvt. Ltd. Jehangir Hospital Premises 32, Sassoon Road, Pune-411001 Maharashtra India Pune
7756001550
drpiyushchaudhari85@gmail.com
Dr Muralidhar Varma
Kasturba Medical College of Manipal
Department of Infectious disease, Kasturba Medical College, Udupi - Hebri Road, Madhav Nagar, Manipal, Karnataka 576104, India Udupi
0448202923874
muralidhar.varma@manipal.edu
Dr Vipul Chakurkar
KEM Hospital, Pune
Renal Unit, 2nd Floor, Diamond Jubilee Building,KEM Hospital, Sardar Moodliar Road, Rasta Peth, Pune-411011
Pune
919403207328
chakurkarvipul@gmail.com
Dr Ritesh Aggarwal
Max Smart Super Speciality Hospital
1st Floor, Department of Critical Care, Max Smart Super Speciality Hospital, Mandir Marg, Press Enclave Marg, Saket District Centre, Saket, New Delhi, Delhi 110017 New Delhi
9310886779
ritesh.icu@gmail.com
Dr Deven Juneja
Max Super Specialty hospital
Second Floor ICU, Max Super Specialty hospital, 1 Press Enclave Road,
Saket, New Delhi, Delhi
110017, India New Delhi
9818290380
deven.juneja@maxhealthcare.com
Dr Deepak Govil
Medanta - The Medicity
2nd floor ICU, Medanta - The Medicity, Sector-38, Gurugram, Haryana-122001, India Gurgaon
01244141414
drdeepak_govil@yahoo.co.in
Dr Dilip Kr Dubey
Medanta Hospital
Lower ground floor, clinical research room, Medanta Hospital, Sector A, Pocket-1, Sushant Golf city, Amar saheed path , Lucknow Uttar Pradesh, 226030 Lucknow
9369047990
drdilipdubey2d@gmail.com
Dr Umang Agrawal
P. D. Hinduja Hospital and Medical Research Centre
1st floor, Department of General Medicine, P. D. Hinduja Hospital and Medical Research Centre, SVS Road, Mahim West, Shivaji Park, Mumbai, Maharashtra, 400016, India Mumbai
9004033919
drumangagrawal87@gmail.com
Dr Narayan Prasad
Sanjay Gandhi Post Graduate Institute of Medical Sciences
Nephrology Department, Ground Floor, Sanjay Gandhi Post Graduate Institute of medical sciences, Raibareli Road, lucknow, 226014 Lucknow
05222668700
narayan.nephro@gmail.com
Dr Chandrakala S
Seth GS Medical College and KEM Hospital
Department of Clinical Hematology, 10th Floor, New Building, Acharya Donde Marg, Parel, Mumbai, 400012, India Mumbai
For subjects receiving control lock therapy, the pharmacist will prepare a syringe of the antibiotic that will be used for the antibiotic lock based on standard institutional practices or recommendations from the IDSA guidelines. At each administration, a sufficient volume of lock solution will be instilled to fill each catheter lumen
Intervention
Mino-Lok Therapy
MLT-01: Minocyclin (Lyophilised Minocycline Powder - 5mg/Vial),
MLT-02: EDTA (Sodium ethylenediaminetetraacetate (EDTA) in 25% v/v ethanol (19.5% w/v) )
Dose: After re-constitution of MLT01 & MLT-02, resulting solution (Mino-Lok Solution) will be 1 mg/mL minocycline, 30 mg/mL Na-EDTA, and 25% ethanol. Each dose is to be prepared for single use by a single subject. At each administration, a sufficient volume of lock solution will be instilled to fill each catheter lumen.
Frequency: A total of 7 doses may be administered once daily (QD) for 7 consecutive days (Visit T1 through Visit T7 [EOT]), OR
A total of 7 QD doses may be administered over a period of up to 15 days with a dwell time of 2-4 hours.
Route of Administration: The Sufficient volume of Mino-lok solution will be instilled to fill each catheter lumen. The Mino Lok solution will not be used for systemic treatment and will not reach patients blood stream. After dwell time of 2-4 hours, the Mino-Lok solution will be aspirated from the catheter using a sterile syringe
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
1. Subject or a legally authorized representative must provide a signed informed consent form;
2. Male or female 18 years of age;
3. Subject must have a bloodstream infection with no other apparent source other than the CVC that meets one of the following criteria:
o A recognized single pathogen cultured from 1 or more blood cultures; OR
o A common skin contaminant cultured from 2 or more blood cultures drawn on the same or consecutive calendar days from a subject with fever (>38.0ºC), chills, or hypotension (systolic blood pressure <90 mmHg);
NOTE: When possible, it is recommended to collect blood cultures from both the CVC and a peripheral venipuncture.
4. Inpatient or outpatient with presence of indwelling CVC (ie, totally implantable port, tunneled or non-tunneled CVC, hemodialysis catheter, or peripherally inserted CVC) that has been in place for 5 days;
5. A bloodstream infection documented within 96 hours prior to enrollment (and from which an isolate of the baseline pathogen(s) is still available for analysis at the central laboratory) and demonstrates the protocol definition of CRBSI or CLABSI;
NOTE: Subjects may be enrolled and randomized while awaiting results of standard blood cultures from the local laboratory:
o If an organism has been identified from blood specimen testing using an FDA-cleared rapid diagnostic test (eg, T2MR); or
o If a positive blood culture specimen shows an organism by 1 of the following:
Gram stain; or
An FDA-cleared molecular rapid diagnostic test (eg, FilmArray BCID or Verigene);
If the pending blood culture does not confirm a qualifying organism by standard methods and an isolate is not available for testing at the central laboratory, the subject will be withdrawn from study drug treatment and managed at the Investigator’s discretion.
NOTE: Subjects with a positive blood culture identified up to 120 hours prior to enrollment and in whom an isolate of the baseline pathogen is still available for analysis at the central laboratory may be considered on a case by-case basis with prior approval from the Medical Monitor.
6. Subjects for whom, in the Investigator’s opinion, catheter retention for the duration of the study (6 weeks) is reasonable or required;
7. Female subjects of childbearing potential must have a negative urine and/or serum pregnancy test within 5 days prior to randomization;
NOTE: The following are considered women who are NOT of childbearing potential:
o Postmenopausal (defined as no menses for at least 12 consecutive months); or
o Documented to be surgically sterile;
8. Female subjects of childbearing potential and male subjects who are sexually active must agree to use a highly effective method of contraception from the time of informed consent until 30 days post dose;
NOTE: Highly effective methods of contraception include hormonal contraceptives, intrauterine device, double-barrier method, partner sterility, or abstinence.
9. Male subjects must agree to refrain from sperm donation throughout the duration of the study and for 90 days following the last dose of study drug; and
10. Subject must be willing to comply with all study procedures, whether inpatient or outpatient, for the duration of the study.
ExclusionCriteria
Details
1. Subjects with hypersensitivity or allergy to tetracycline antibiotics or edetate disodium;
2. Subjects with septic shock that requires inotropic support or is unresponsive to fluid resuscitation;
3. Subjects taking disulfiram at the time of randomization or who are expected to take disulfiram at any time during treatment with study drug;
4. Subjects with prosthetic cardiac valves, vascular grafts, pacers, automatic implantable cardioverter-defibrillator, or other non-removable vascular foreign body, with the exception of coronary stents and peripheral stents. Subjects who underwent a coronary artery bypass graft >1 year prior to Screening AND with no known complications associated with the graft may be enrolled;
5. 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);
6. Subjects with 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;
7. 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 methicillin-resistant Staphylococcus aureus (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. Isolates of all organisms should be sent to the central laboratory. In the event that the subject is being treated with more than 1 systemic SOC anti- infective, the Investigator will specify a single antibiotic that should be used for the antibiotic lock. It is acceptable for the SOC antibiotic lock to differ from the SOC anti- infectives, as necessary per local SOC.
8. 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;
9. Subjects who have been previously randomized into the present study;
10. Subjects who are pregnant or breastfeeding;
11. Subjects with proven or suspected persistent bacteremia or fungemia despite 72 hours of both systemic anti-infective therapy and lock therapy to which the infecting organism is susceptible;
12. Subjects with short-term CVCs indwelling 5 days;
13. Subjects with a central line-related mycobacterial infection or fungi other than Candida; or
14. 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.
To evaluate the efficacy of MLT in salvaging the colonized central venous catheter (CVC) in subjects with catheter-related or central line-associated bloodstream infection (CRBSI/CLABSI); and
To evaluate the safety of MLT in subjects with catheters treated with MLT.
Visit T3, Visit T4 or Visit T5,at EOT(End of Treatment)(Visit T7)andTOC (test of cure)
Secondary Outcome
Outcome
TimePoints
Proportion of subjects who have Overall Success in the Modified Intent-to-Treat (MITT) and Clinically Evaluable (CE) Populations. Overall Success is defined as no catheter failure events by TOC (Week 6);
Time to catheter failure between randomization and TOC (Week 6) in the MITT and CE Populations;
Proportion of subjects with Microbiological Eradication at TOC (Week 6) in the MITT and CE Populations;
Proportion of subjects with Clinical Cure at TOC (Week 6) in the MITT and CE Populations. 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;
All-cause mortality at Week 6 in the MITT Population; and
Safety and tolerability profile as assessed by adverse events, SAEs, vital signs, clinical laboratory evaluations, and physical examinations.
Week 6
Target Sample Size
Total Sample Size="200" Sample Size from India="80"
Leonard-Meron Biosciences (LMB) is a late-stage specialty pharmaceutical company focusedonthedevelopmentandcommercializationofcriticalcareproductswithaconcentrationon anti-infective drugs. LMB is developing Mino-Lok™, an antibiotic lock solution used to treat patients with catheter-relatedbloodstreaminfectionsthatisenteringphase3trials. Leonard-Meron Biosciences (LMB), Inc. is a wholly owned subsidiary of Citius Pharmaceuticals, Inc.(Nasdaq:CTXR)referredasCitius,isalate-stagebiopharmaceuticalcompanyfocusedonthe development and commercialization of first-in-class critical care products, with a pipeline of anti-infectivesin oncology, adjunct cancer care, stem cell therapy and unique prescription products.
Ithasbeendemonstratedthatchelatorssuchasedetatedisodiumhavetheabilitytoenhancethe activity of tetracycline antibiotics (e.g., minocycline) against microbial organisms embedded in biofilm, and also serve as anti-clotting agents. The safety of a lock solution containing minocycline and edetate disodiumhasbeenwellestablishedthroughclinicalandnon-clinicalstudiesandbothareapproved for intravenoususe.However,thougheffective,theyrequireaprolongeddwelltimeofatleast24hours in order to demonstrate activity. In a clinical setting, this lengthy dwell time may prove clinically infeasible for patients whose indwelling catheter must be used for other purposes. Additional studies and preliminary data demonstrate that a highly effective antimicrobial lock solution, which adds 25% ethanol to the antibiotic lock therapy combination of minocycline and edetate disodium, is highly efficaciousineradicatingorganismsembeddedinbiofilmoncathetersurfacesandiswelltolerated by patients.Ethanolhasbroad-spectrumantimicrobialactivityagainstmicrobialorganismsembedded in biofilm after a dwell time of only 1 to 2 hours; however, to use ethanol alone as a lock therapy would requireaconcentrationhigherthan40%toinhibitbiofilmgrowth.Suchhighconcentrationsof ethanol as a catheter lock solution may be associated with side effects such as headache, dizziness, nausea, light-headedness, or dyspnea.
Theuseofonly25%ethanolincombinationwithminocyclineandedetatedisodium,however,has been shown to enhance the rapidity with which the lock solution works to eradicate microbial organisms embeddedinbiofilmwithouttheriskoftoxicitythatmayaccompanyahighconcentrationofethanol.
A recently concluded prospective pilot study investigated the safety and efficacy of Mino-Lok Therapy (MLT) as an instrument for CVC (Central Venous Catheter) salvage in cancer patients. Thirty patientswithCRBSI/CLABSI(Catheter-RelatedorCentralLine-AssociatedBloodstreamInfection) were enrolled and received MLT for 2 hours daily for the first 5 to 7 days in combination with standard antimicrobialtherapy.Thefirst5doseswereadministeredsequentiallyoncedaily(QD)forthefirst 5 days following enrollment, and the subsequent doses were administered over the following 2 weeks.Patientswerefollowedfor1-monthpost-therapy.In27patientswhoreceivedatleast5 doses of MLT, theCVCs(CentralVenousCatheter)wereretainedforameandurationof91daysfollowingstudy enrollment. Data demonstrates that MLT was safe and well tolerated, and that it was efficacious in achieving CVC salvage in the setting of CRBSI/CLABSI
