Community Central Line Infection Prevention Trial

Study Design and Population: The proposed study will use a cluster-randomized, 2 period
crossover design, clinical trial to evaluate a promising new intervention, namely 70%
isopropyl alcohol embedded protective caps, to reduce CLABSIs, 2ndry BSI, and SPBC at home
for chronic central lines in pediatric hematology/oncology patients. The Control Arm will
involve "usual care" for ambulatory central lines per institutional policy and the
Intervention Arm will add use of 70% isopropyl alcohol embedded protective caps to "usual
care. Each participating institution will be randomly assigned to either the intervention or
control phase of the design for the first 12 months of the study. There will then be a 3
month wash out period, followed by each institution then implementing either the control or
intervention phase for another 12 months such that each institution will complete 12 months
each in the intervention arm and the control arms of the study.

Sixteen pediatric hematology/oncology institutions will serve as the core population for this
proposal and unit of randomization. All ambulatory patients taken care of by these pediatric
hematology/oncology clinics at these institutions will be eligible for this study. The only
inclusion criteria will be presence of an external central line. Given the intervention is a
protective cap for central line access ports, patients who only have a totally implanted port
as their central venous access will not be eligible for this study as the intervention is not
physically applicable to such central lines.

The intervention the investigators will deploy is the CUROS® brand of 70% isopropyl alcohol
embedded protective caps for central lines. These caps are manufactured by Ivera Medical
Corporation. As in kind contribution to this proposed study, Ivera Medical Corporation has
agreed to donate and distribute all needed CUROS® caps to the participating institutions for
the duration of this study. If any of the participating teams wishes to instead use a
comparable brand of 70% isopropyl alcohol embedded protective caps for central lines that
will be permitted.

Distribution of the CUROS® caps will be accomplished within the clinics of each participating
institution and compliance with the intervention at homes will be monitored by clinic staff
via tracking counts of CUROS® caps dispensed to families. Children with chronic
hematologic/oncologic conditions are seen frequently in clinic, often up to every week.
Clinic staff can distribute and track volume of CUROS® caps dispensed to each family/patient,
with the family/patient can report back each visit on the volume of CUROS® caps utilized.
This will ensure reliable distribution to the families/patients, provide a face to face
educational opportunity to ensure proper application of the CUROS® cap, and provide
compliance opportunities via counts of CUROS® caps utilized.

This proposal will involve a cluster-randomized, 2 period crossover design, clinical trial.
Given this proposal's focus on reducing central line infections at home, the main
facilitators of best practice use of these caps at home will be the families and patients
themselves. The research team will spread the needed additional education, tools, data,
analyses, and support for this proposal.

Study Organization and Timeline: The work will build on the partnership between the pediatric
quality improvement research group at Johns Hopkins University and the vendor Ivera Medical
Corporation, maker of the CUROS® brand 70% isopropyl alcohol embedded protective caps for
central lines. Dr. Miller is Principal Investigator and serves as Vice Chair of Quality and
Safety, Director of Division of Quality and Safety at the Johns Hopkins Children's Center.
Dr. Miller had led and continues to lead efforts to transform the quality and safety of the
delivery system at Johns Hopkins University and is a formally trained in Lean Six Sigma
quality improvement as well as having her Masters of Science degree in clinical research. In
addition, Dr. Aaron Milstone at Johns Hopkins University, director of pediatric hospital
epidemiology and infection control and an accomplished researcher in pediatric infection
prevention, will be a Co-Investigator on this proposal. Dr. Milstone led the recently
published clinical trial work in Lancet describing the impact of chlorhexidine bathing on
CLABSI and positive blood cultures in children in 10 PICUs. Dr. Elizabeth Colantuoni is a
Biostatistician and Assistant Scientist in the Johns Hopkins Bloomberg School of Public
Health.

The work will span four years. Year 1 Preparatory work will include establishing
Institutional Review Board approval at each of the participating institutions, setting up
data collection and submission processes, setting up distribution mechanisms for the
intervention both to the clinics and then within each clinic to the homes, and educating
providers, patients, and families on how to apply the CUROS® cap across all the participating
institutions. Years 2, 3, and 4 will include two 12 month trial periods with a 3 month wash
out period in between. The last 9 months of Year 4 will be used for data analysis and
manuscript preparation.

Methods SPECIFIC AIM 1 and SPECIFIC AIM 2:

Specific Aim #1: Evaluate whether use of 70% isopropyl alcohol embedded protective caps on
central lines reduces the rate of CLABSI in ambulatory pediatric hematology/oncology
patients.

Hypothesis: Use of 70% isopropyl alcohol embedded protective caps on central lines will be
associated with at least a 25% reduction in the ambulatory CLABSI rate for pediatric
hematology/oncology patients.

Specific Aim #2: Evaluate whether use of 70% isopropyl alcohol embedded protective caps on
central lines reduces the rate of all positive blood cultures in ambulatory pediatric
hematology/oncology patients.

Hypothesis: Use of 70% isopropyl alcohol embedded protective caps on central lines will be
associated with at least a 25% reduction in the positive blood culture rate at home for
pediatric hematology/oncology patients.

Independent variables: The primary independent variable will be CLABSI rates for Specific Aim
#1 and all positive blood culture rates, defined as CLABSI rates + 2ndry BSI rates + SPBC
rates, for Specific Aim #2. All of the participating units already devote Hospital Infection
Control staff to identify and track all 3 of these types of ambulatory central line
infections.

Dependent variable: The dependent variable for these Specific Aims will be the dichotomous
assignment to either control or intervention arms where unit will receive both arms.

Data collection method: All Hematology/Oncology units will submit monthly aggregate clinic
data on CLABSI, 2ndry BSI and SPBC (numerators and denominators) via a web-based data entry
tool.

Exploratory analyses: Descriptive statistics at the unit level will be calculated to
summarize rates of infections (CLABSI and all infections) over time when the unit receives
both the control and treatment arm. Scatterplots and line plots will be used to describe the
trends in infection rates during the course of the study separately by treatment arm. In case
missing data occurs in our analysis we will explore the relationship between missing data and
the unit's observed data in months prior and our analysis methods will be valid under the
assumptions that the missing data are generated completely at random or depend on the prior
observed rates (missing at random). Our data integrity efforts and frequent contacts with
this team will work to minimize any instances of missing data.

Multivariate analyses: Generalized linear mixed Poisson regression models will be used to
test for a treatment effect. Specifically, the monthly number of CLABSI (Specific Aim #1) or
the monthly number of all infections (Specific Aim #2) will be modeled as a function of the
dichotomous treatment assignment and an indicator for when the treatment arm was received
(first or second 12 month period) with inclusion of an offset representing the monthly number
of central line days and a random intercept for unit to account for the correlation of
monthly rates of infections over time within the same unit. The models rely on two key
assumptions: i) the infection rates follow a Poisson distribution where the mean rate is the
same as the variance in the rate and ii) the correlation of the rates within a unit over time
is exchangeable. These assumptions will be assessed via descriptive analyses and by adding a
robust variance estimate clustering on the unit.

Methods, Specific Aim #3: To evaluate whether the use of 70% isopropyl alcohol embedded
protective caps on central lines changes the distribution of bacteria isolated from blood
cultures of ambulatory pediatric hematology/oncology patients.

Hypothesis: Use of 70% isopropyl alcohol embedded protective caps on central lines will be
associated with altered microbial epidemiology for CLABSI, secondary blood steam infections,
and single positive blood cultures at home for pediatric hematology/oncology patients.

Independent variables: Organisms isolated for all blood cultures (CLABSI + 2ndry BSI + SPBC)
in patients involved in this study will be collected from participating teams during both the
Control and Intervention arms of the clinical trial and sorted into Gram Positive versus Gram
Negative organisms.

Dependent variable: The dependent variable for this Specific Aim will be the dichotomous
assignment to either control or intervention arms.

Data collection method: All Hematology/Oncology ambulatory care teams will submit the
microbial pattern data for each CLABSI, 2ndry BSI and SPBC.

Analyses: The analysis would be a comparison of proportions of Gram positive organisms
causing CLABSI, 2ndry BSI and SPBC between the control and intervention study arms. Given
that Gram positive organisms are the most common organisms causing CLABSI and SPBC in
children, achieving a reduction in Gram positive organisms would be an important additional
finding of this clinical trial.

Inclusion Criteria:

- pediatric outpatients with either hematologic or oncologic diagnosis who have an
external central line

Exclusion Criteria: