Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03857464 |
| Other study ID # |
REB 18 0397 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 15, 2019 |
| Est. completion date |
May 31, 2020 |
Study information
| Verified date |
May 2023 |
| Source |
University of Calgary |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The investigators will conduct a two-period, two-intervention, cluster randomized crossover
(CRXO) designed study at Foothills Hospital in Calgary, Alberta. Each cluster (hospital ward)
will receive each of the two interventions in a separate approximately 6-month period of time
leading to two "cluster-periods" with associated "wash-in" and "wash-out" periods attached.
The two interventions are: 1) a rapid diagnostic test (RDT) using near-patient testing (NPT)
for C. difficile infections (CDI); 2) testing for CDI using centralized testing facilities
(standard operating procedure, 2 step algorithm).
The investigators hypothesize that NPT for CDI will result in reduced patient isolation days
in the hospital, decreased morbidity and mortality, reduced unnecessary antibiotic use and
overall reduced costs to the health care system, including both hospital and laboratory.
Our primary endpoint is to examine the differential effect of NPT on the duration of contact
precautions (i.e. patient isolation days). Secondary outcomes will compare turn-around times
from specimen submission to result, days of hospitalization, the number of days of antibiotic
therapy, the incidence of CDI, severe CDI, and in-hospital mortality. A comprehensive
economic evaluation will be performed to determine the cost of testing, patient isolation,
and hospitalization for all patients in the control and treatment arms.
Description:
Antimicrobial resistance (AMR) has been designated as a major priority by the World Health
Organization (WHO), Centers for Disease Control and Prevention (CDC) and the Public Health
Agency of Canada (PHAC). PHAC has identified Clostridium difficile infection (CDI) as a Tier
1 AMR priority pathogen. CDI occurs directly as a consequence of antibiotic use and falls
under the clinical syndrome of antibiotic-associated diarrhea (AAD). It is the most common
cause of infectious diarrhea among hospitalized patients in developed countries like Canada
(Skidmore, 1993). The economic cost of CDI in the United States is estimated at USD 5.4
billion, close to 87% of which occurs in healthcare settings (Desai et al., 2016).
Clinical microbiologists have developed a two-step algorithm in which an EIA or an RDT is
first used to screen stools for the presence of glutamate dehydrogenase (GDH) antigen derived
from C. difficile. The GDH antigen test is very specific (> 95%) and negatives can be
reported right away, only requiring GDH-positive or toxin-positive specimens (by EIA or RDT)
to be confirmed by NAAT. In Calgary, the two-step algorithm is performed for a population of
close to 1.5 million people at an offsite Diagnostic and Scientific Centre (DSC). The use of
a testing centre undermines some of the advantages of the rapid testing methodologies
developed in recent years, because of increased transportation and processing time.
A key issue in many settings is that testing falls into a separate budget from the treatment
of patients with CDI infections. This has the potential to distort the decision of whether to
run a test and, if so, what sort of test. The distortions are of two types. First, the
hospital may decide to order more tests than is optimal, since the tests are perceived as
"free" from the perspective of decision-makers. At the same time, the diagnostic facility may
choose low-cost, slow diagnostics, because the costs associated with delays in test results
are borne by the hospital. This is a classic case of silos in health care costs inefficiently
distorting policy decisions, with potentially negative results for both patient health and
costs.
Many institutions follow the clinical practice guidelines provided by the Infectious Diseases
Society of America for the management of C. difficile (Cohen et al., 2010). As part of
routine Infection Prevention and Control (IPC) management, patients with acute diarrhea of
unknown cause are pre-emptively placed in private rooms with additional contact precautions,
which mandate the use of gowns and gloves for healthcare workers. This is also known as
patient isolation. Investigation for gastrointestinal pathogens is typically initiated and
the duration of patient isolation depends largely on the result of microbiological testing.
When severe or complicated CDI is suspected, patients are initiated on empiric treatment as
soon as the diagnosis is suspected. Generally, oral metronidazole is used for
mild-to-moderate CDI and oral vancomycin for severe CDI. Among hospitalized patients with
acute diarrhea, initiation of pre-emptive management for CDI is common.
The intervention of interest is implementing a new RDT to Near Patient Testing (NPT); initial
screening for CDI to be performed at the on site hospital rapid response laboratory (RRL)
instead of the DSC. Techlab Inc. offers a lateral flow assay (C. DIFF QUIK CHEK COMPLETE®
test) that detects both GDH and Toxin simultaneously and further simplifies the testing
algorithm. As prescribed in the two-step algorithm, GDH and Toxin negatives will be reported
out immediately as negative for CDI, while positive or discrepant results will be confirmed
at the DSC using NAAT. The vast majority of requests for CDI testing are negative thus
allowing a majority of results to be reported immediately without confirmation at the DSC.
The Investigators will conduct a two-period, two-intervention, cluster randomized crossover
(CRXO) design study at Foothills Hospital. Each cluster (ward) will receive each of the two
interventions in a separate 6-month period of time leading to two "cluster-periods" with
associated "wash-in" and "wash-out" periods attached. The interventions are RDT using NPT for
CDI, and testing for CDI using our centralized testing facility.
This study is cross-sectional CRXO in that, each cluster-period consists of different
individuals (patients). The order in which the interventions are delivered to each cluster
(ward) is randomized to control for potential period effects. Within Foothills Hospital there
are 40 wards which will be observed over a 12-month period. Each ward is randomly assigned to
administer one of the two interventions for the first 6-month period (Period 1). In the
second 6-month period (Period 2), the ward will administer the other intervention. Within
each ward (cluster) there are two cluster-periods. Study outcomes during Period 1 and Period
2 intervention will be compared in both arms (NPT and centralized laboratory testing).
NPT testing can deliver results within several hours, while typically off-site testing takes
about one day. If NPT and the off-site testing deliver identical test results as our pilot
data suggest, the investigators can follow the clinical outcomes for each arm without the
confounder of differences in test performance. As a contingency, if variation in test
performance characteristics is found, analysis of patient outcomes will take this into
consideration.
For patients without CDI, the antibiotics, and in many cases, the isolation, is unnecessary.
NPT testing has the potential to avoid this unnecessary use of antibiotics and to avoid
costly isolation procedures for the day+ that standard testing requires. It also enables a
better-directed diagnostic process for the cause of diarrhea. For patients who are positive
for CDI, the earlier test result will influence downstream events such as initiation of
antibiotic therapy, resolution of disease, hospitalization days, and other clinical outcomes.
The investigators hypothesize that NPT for CDI will result in reduced patient isolation days
in the hospital, decreased morbidity and mortality, reduced unnecessary antibiotic use and
overall reduced costs to the health care system, including both hospital and laboratory.
Previous data at this facility has indicated that the mean number of patients per ward is
39/month (SD=43) for a total of 1578 patients in a 6-month period and the mean number of
negative patients is 33/month (SD=34) for a total of 1300 negative pts in a 6-month period.
The inclusion criteria will be diarrhea in adult patients admitted to Foothills Medical
Center in Calgary, Alberta being tested for CDI. Outpatients and patients in the emergency
room will be excluded.
Our primary endpoint is to examine the differential effect of NPT on the duration of contact
precautions (i.e. patient isolation days). Secondary outcomes will compare turn-around times
from specimen submission to result, days of hospitalization, the number of days of antibiotic
therapy, the incidence of CDI, severe CDI, and in-hospital mortality. A comprehensive
economic evaluation will be performed to determine the cost of testing, patient isolation,
and hospitalization for all patients in the control and treatment arms.
Contact precautions (i.e. patient isolation) due to CDI will be defined as an order by
healthcare workers for contact precautions within the 7-day infection window of a CDI
diagnosis. The length of time on contact precautions will be defined as the calendar date
contact precautions are completed or patient discharge date minus the calendar date contact
precautions are ordered. Data on contact precautions will be extracted from the clinical
patient management system in Calgary, known as Sunrise Clinical Manager (SCM). It is used
extensively in all Calgary acute care facilities and emergency departments. These data
include patient identifiers (e.g. patient health number, names, date of birth), start and
stop dates of isolation, facility, and patient care unit where isolation order was placed,
and the reason for isolation (e.g. CDI, diarrhea). These data will be linked to the specimen
results tested for CDI by the patient's Personal Health Number (PHN). Turn-around times from
specimen submission to result will be provided by Calgary Laboratory Services. Days of
hospitalization will be defined as the difference between the admission and discharge date.
The specimen results will be linked to the Discharge Abstract Database using the patient's
PHN to determine during which acute care encounter the specimen was collected and the
admission/discharge dates of that encounter. Antibiotic therapy will be defined as the
administration of antibiotics initiated on the day of and up to 48 hours after specimen
collection for CDI testing. Total days of antibiotic therapy during the acute care encounter
will be defined as the calendar date antibiotic therapy is completed minus the calendar date
antibiotic therapy is ordered. The data will be extracted from SCM.
The investigators will also account for the severity of CDI. The epidemiological definition
for severe CDI is that primarily proposed by Cohen et al. This definition has been used by
infectious disease specialists in Alberta to guide the management and treatment of patients
with CDI. Patients with severe CDI will have leukocytosis with a white blood cell (WBC) count
>15,000 cells/µL OR an elevated serum creatinine (i.e. 200 µmol/L or greater). The inpatient
laboratory results that will be considered to meet the definition for severe CDI will be
those collected within a 7-day infection window around the date the laboratory tested
positive for C. difficile. The presence of either measure meeting the criteria within the
defined infection window will qualify as meeting the definition of severe CDI. If either
criterion is measured more than once during the infection window, the highest value will be
used to represent the severity of CDI. The laboratory values will be provided by Calgary
Laboratory Services and linked to the positive C. difficile test results. In-hospital,
all-cause mortality will be defined as death occurring during the acute care encounter where
specimens were collected for C. difficile testing.
The investigators predict that, given the large number of patients and randomized study
design, matching of patients by age, gender, and co-morbidities is not required. Potential
hurdles in the study model are logistical challenges associated with building a testing and
reporting system for a hospital on 24hrs/7 days per week basis. The strength of the proposal
lies in the scale and nature of the study which seeks to establish the medical and economic
benefit of NPT versus centralized testing. The results could dramatically influence public
health policy in this country and seek to bridge traditional silos, namely the laboratory and
hospital budgets. Data on costs will be furnished by our partners at Calgary Laboratory
Services/Alberta Health Services (Infection Prevention and Control).
Beyond evaluating the relative merits of NPT versus centralized testing, studies will also
look at the microbiology of CDI in this study. Specifically, the investigators will conduct
several laboratory methods to examine antibiotic resistance and genetic variation in CDI. For
example, whole genome sequencing of cultured CDI isolates may inform us about the
transmission of specific strains in our setting. Indeed, certain strains and states of gut
dysbiosis may result in increased morbidity and mortality (Shahinas et al., 2012). The
investigators will look at the microbiome of patients in this study to determine if dysbiosis
contributes to adverse clinical outcomes. The investigators will also correlate the strain
types with the results of testing to determine if genetic variation affects test performance.
Cultured toxin-producing CDI isolates will serve as a gold standard to evaluate test
performance.
