Ethanol Lock Therapy for Treatment and Secondary Prophylaxis of Central Line-Associated Bloodstream Infection

A Double-Blind, Randomized, Placebo-Controlled, Trial of Ethanol Lock Therapy for Treatment and Secondary Prophylaxis of Central Line Associated Bloodstream Infection (CLABSI) in Children and Adolescents

Use of long-term central venous access devices (including tunneled lines and ports) can be associated with development of bloodstream infection caused by build-up of bacteria or fungus on the inside of the device, called central line associated bloodstream infection (CLABSI). This infection generally requires hospital admission and antibiotic therapy. This treatment usually helps eradicate the infection but sometimes it is not possible to clear or it comes back after treatment. Also, once someone has had one line infection the chance of getting another one is higher. This study will test whether treatment and secondary prophylaxis of CLABSI with ethanol lock therapy (ELT) can significantly reduce the risk of treatment failure (comprising failure to clear initial infection, relapse or reinfection) in children and adolescents treated for cancer or hematologic disorders or undergoing hematopoietic stem cell transplantation (HSCT). ELT involves injecting a solution of ethanol and water into the line or port, allowing it to dwell for 2 hours, and then withdrawing the solution.

Study Overview

• Status: Completed
• Conditions: Central Line-Associated Bloodstream Infection
• Intervention / Treatment: Drug: ethanol; Drug: heparin-saline placebo

Detailed Description

Eligible patients with CLABSI will be enrolled within 96 hours of collection of positive blood culture and randomized to blinded treatment with 70% ethanol or heparin-saline placebo catheter lock therapy.

After enrollment, all subjects will receive catheter lock therapy for a 5 day Treatment Phase, followed by a 24 week Prophylaxis Phase. Participants in the active treatment arm will receive 70% ethanol locks and those in the placebo arm will receive heparin-saline placebo locks in identical fashion.

In addition to the study intervention, participants in both arms will receive standard systemic antibiotic therapy according to the preference of the ward clinician.

The intervention will continue for 24 weeks unless off-therapy criteria are met or the catheter is removed.

After the intervention is discontinued, participants will be monitored for 90 days, or 30 days after line removal, whichever is shorter. If the intervention is discontinued prior to 24 weeks due to adverse event or physician request, participants will be monitored for the remainder of the 24 week period.

Primary Objective:

• To compare the proportion of therapeutic failures in children and adolescents with CLABSI during treatment with standard care plus Ethanol Lock Therapy (ELT) versus standard care alone.

Secondary Objectives:

• To estimate and compare the cumulative incidence of CLABSI treatment failure, relapse or reinfection in children and adolescents receiving ELT plus standard care versus those receiving standard care alone.
• To estimate the risk of central venous access device (CVAD) occlusion associated with the use of ELT plus standard care, compared with standard care alone, in children and adolescents.
• To estimate the risk of adverse events possibly attributable to ELT associated with the use of ELT plus standard care, compared with standard care alone, in children and adolescents.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital Melbourne
• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects ≥6 months to < 25 years of age who are ≥5kg
• New diagnosis (within 96 hours of collection of first positive blood culture) of CLABSI (participants with previous CLABSI will be eligible if not previously enrolled in the study)
• Silicone CVAD in situ (ports, Hickman and Broviac lines will all be eligible)
• Treating clinician plans to attempt salvage of CVAD
• Participant is receiving treatment for cancer or any hematologic disorder or is receiving hematopoietic stem cell transplantation (HSCT) at a participating institution.

Exclusion Criteria:

• Allergy to ethanol or components of placebo lock
• Concomitant use of metronidazole, disulfiram or trabectedin
• Plan to remove CVAD within 6 days
• Continuous use of all lumens of CVAD leading to anticipated inability to lock each lumen for at least 2 hours per day
• Known CVAD obstruction
• Subjects who are capable of becoming pregnant will require an negative pregnancy test before entry to study
• Use of ELT in the preceding 2 weeks
• Expected survival <6 days
• Proven alternative source of bloodstream infection (BSI), or clinical evidence of CVAD track or port-pocket infection
• Multiple long-term CVADs in situ

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment; Eligible patients with CLABSI will be enrolled within 96 hours of collection of positive blood culture and randomized to blinded treatment with 70% ethanol catheter lock therapy.	Drug: ethanol; 70% ethanol catheter lock therapy; Other Names: 70% ethanol
Placebo Comparator: Control; Eligible patients with CLABSI will be enrolled within 96 hours of collection of positive blood culture and randomized to blinded treatment with heparin-saline placebo catheter lock therapy.	Drug: heparin-saline placebo; heparin-saline placebo catheter lock therapy; Other Names: heparin-saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Therapeutic Failures (Early or Late Failure) in Children and Adolescents With CLABSI Receiving Standard Care Plus Ethanol Lock Therapy (ELT) vs. Standard Care Alone	Therapeutic failure was a pre-defined composite outcome comprising either 'early failure': central line removal, death, persistent positive blood cultures for >72 hours, development of new CLABSI, or initiation of other ALT) during the 5 day treatment phase, or 'late failure': relapse (new CLABSI with an identical organism), or reinfection (new CLABSI with a different organism) during the 24 week prophylaxis phase. The percentage of evaluable participants with therapeutic failure is reported.	Up to 25 weeks after the start of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Incidence of Therapeutic Failure in Participants Receiving Standard Care Plus ELT vs. Standard Care Alone	Therapeutic failure was a pre-defined composite outcome comprising either 'early failure': central line removal, death, persistent positive blood cultures for >72 hours, development of new CLABSI, or initiation of other ALT) during the 5 day treatment phase, or 'late failure': relapse (new CLABSI with an identical organism), or reinfection (new CLABSI with a different organism) during the 24 week prophylaxis phase. The cumulative incidence of therapeutic failure is reported.	Up to 25 weeks after the start of treatment
Cumulative Incidence of Relapse in Participants Receiving Standard Care Plus ELT vs. Standard Care Alone	Relapse was defined as new CLABSI with an identical organism occurring during the 24 week prophylaxis phase. The percentage of evaluable participants with relapse is reported.	Up to 25 weeks after the start of treatment
Cumulative Incidence of Reinfection in Participants Receiving Standard Care Plus ELT vs. Standard Care Alone	Reinfection was defined as new CLABSI with a different organism occurring during the 24 week prophylaxis phase. The percentage of evaluable participants with reinfection is reported.	Up to 25 weeks after the start of treatment.
Rate of Central Venous Access Device (CVAD) Occlusion Events in Participants Receiving Standard Care Plus ELT vs. Standard Care Alone	Occlusion was defined as central line occlusion or dysfunction requiring thrombolytic therapy. The percentage of evaluable participants requiring thrombolytic therapy for central line occlusion is reported.	Up to 26 weeks after the start of treatment.
Adverse Events in Participants Receiving Standard Care Plus ELT vs. Standard Care Alone	Adverse events attributable to lock therapy or related to the central venous access device (CVAD) were elicited from direct questioning at study visits and from the medical record. The percentage of evaluable participants with any potentially attributable adverse effect is reported.	Up to 37.5 weeks after the start of treatment.

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Investigators: Principal Investigator: Joshua Wolf, MBBS, BA, St. Jude Children's Research Hospital

Publications and helpful links

General Publications

• Wolf J, Connell TG, Allison KJ, Tang L, Richardson J, Branum K, Borello E, Rubnitz JE, Gaur AH, Hakim H, Su Y, Federico SM, Mechinaud F, Hayden RT, Monagle P, Worth LJ, Curtis N, Flynn PM. Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial. Lancet Infect Dis. 2018 Aug;18(8):854-863. doi: 10.1016/S1473-3099(18)30224-X. Epub 2018 Jun 5.

Helpful Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2011
• Primary Completion (Actual): November 11, 2016
• Study Completion (Actual): November 11, 2016

Study Registration Dates

• First Submitted: November 14, 2011
• First Submitted That Met QC Criteria: November 16, 2011
• First Posted (Estimate): November 17, 2011

Study Record Updates

• Last Update Posted (Actual): November 13, 2017
• Last Update Submitted That Met QC Criteria: October 12, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: children; adolescents; bloodstream infection; central line; antibiotic lock therapy; catheter lock therapy; ethanol lock therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Sepsis; Infections; Communicable Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Local; Anti-Infective Agents; Central Nervous System Depressants; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Ethanol; Heparin; Calcium heparin
• Other Study ID Numbers: ETHEL

Drug and device information, study documents

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