A randomized controlled trial to assess the efficacy and cost-effectiveness of urinary catheters with silver alloy coating in spinal cord injured patients: trial protocol
A randomized controlled trial to assess the efficacy and cost-effectiveness of urinary catheters with silver alloy coating in spinal cord injured patients: trial protocol
Xavier Bonfill 0 1 2
David Rigau 0 1 2
Mara Luisa Juregui-Abrisqueta 2
Juana Mara Barrera Chacn 2
Sebastin Salvador de la Barrera 2
Carolina Mara Alemn-Snchez 2
Manuel Bea-Muoz 2
Susana Moraleda Prez 2
Albert Borau Duran 2
Juan Ramn Espinosa Quirs 2
Lus Ledesma Romano 2
Manuel Esteban Fuertes 2
Ignacio Araya 2
Ma Jos Martnez-Zapata 0 1 2
0 Institute of Biomedical Research (IIB Sant Pau) , Barcelona , Spain
1 Iberoamerican Cochrane Centre , Calle Sant Antoni M. Claret, 167, PO: 08025, Barcelona , Spain
2 Coordinating centre: Iberoamerican Cochrane Centre. Institute of Biomedical Research (IIB Sant Pau) , Barcelona
Background: Patients with non-acute spinal cord injury that carry indwelling urinary catheters have an increased risk of urinary tract infection (UTIs). Antiseptic Silver Alloy-Coated Silicone Urinary Catheters seems to be a promising intervention to reduce UTIs; however, actual evidence cannot be extrapolated to spinal cord injured patients. The aim of this trial is to make a comparison between the use of antiseptic silver alloy-coated silicone urinary catheters and the use of standard urinary catheters in spinal cord injured patients to prevent UTIs. Methods/Design: The study will consist in an open, randomized, multicentre, and parallel clinical trial with blinded assessment. The study will include 742 spinal cord injured patients who require at least seven days of urethral catheterization as a method of bladder voiding. Participants will be online centrally randomized and allocated to one of the two study arms (silver alloy-coated or standard catheters). Catheters will be used for a maximum period of 30 days or removed earlier if the clinician considers it necessary. The main outcome will be the incidence of UTIs by the time of catheter removal or at day 30 after catheterization, the event that occurs first. Intention-to-treat analysis will be performed, as well as a primary analysis of all patients. Discussion: The aim of this study is to assess whether silver alloy-coated silicone urinary catheters improve ITUs in spinal cord injured patients. ESCALE is intended to be the first study to evaluate the efficacy of the silver alloy-coated catheters in spinal cord injured patients. Trial registration: NCT01803919
Spinal cord injuries; Urinary tract infection; Urinary catheters; Protocol; Randomized clinical trial
Most patients with spinal cord injuries (SCI) suffer from
some type of neurogenic lower urinary tract dysfunction
which requires the use of different strategies for voiding,
including urinary catheters. Almost all patients with
indwelling urinary catheters develop bacteriuria and in
consequence urinary tract infections (UTI) occur
frequently. Frequent UTI are bothersome for the patients,
implies frequent antibiotic use and increase of resistant
strains, may cause septicemia and are therefore related
to a decreased health-related quality of life [1-3].
Several trials have evaluated the effectiveness of
different types of indwelling urinary catheters to prevent
urinary infections in hospitalized adults requiring short-term
catheterization. A systematic review of randomized
controlled trials revealed that silver-alloy but not silver-oxide
coated catheters, were associated with a significant
reduction in bacteriuria in comparison to standard
catheters . Another recent systematic review aimed to
determine which type of indwelling urinary catheter is
best to use for long-term bladder drainage in adults
found that all trials were small and with
methodological weaknesses. The evidence from this systematic
review was not sufficient as a reliable basis for
practical conclusions .
A large randomized clinical trial assessing three
different catheters (silver-alloy-coated, nitrofural-impregnated
and a PTFE-coated catheters) in hospitalized adults with
acute pathologies requiring short urinary catheterization
has been recently published. No clinically relevant
difference was noted between the three groups .
Few randomized clinical trial have evaluated the
effectiveness of different catheters in SCI population, most of
them assessing the use of intermittent catheterization,
but none using antiseptic-impregnated catheters [7-11].
We propose a clinical trial in SCI patients needing an
indwelling urethral catheter to assess the effectiveness of
urinary catheters with antiseptic, silver-alloy coating.
The study hypothesis is that the use of these urinary
catheters reduces the risk of UTI compared to the use of
conventional urinary catheters.
Seven-hundred and forty-two participants in this study
are being recruited from rehabilitation or spinal units at
specialized hospitals and outpatient centres across Spain
(Table 1 and ESCALE group in Additional file 1). The
inclusion period is from November 2012 to December 2014.
This yields the inclusion of patients with first-ever
urethral catheterization and also patients with indwelling
urethral catheterization as a method of voiding.
The criteria for inclusion in this study are:
1. Male or female patients with traumatic or medical spinal cord injury.
2. Age of 18 years or above.
3. Patients who need an indwelling urinary catheter as a method of bladder drainage for at least 7 days.
4. Patients who are willing to participate in the
study and give their written informed consent
(If a patient is unable to give written consent
because of physical or mental disability, an
affirmation of consent will be taken in his presence
from his relative or legal guardian).
Table 1 Participating centers
Complexo Hospitalario Universitario A Corua
Hospital Universitario Central de Asturias
Hospital Universitario Cruces, Barakaldo.
Hospital Universitario Miguel Servet, Zaragoza
Hospital Universitario La Paz, Madrid
Hospital Nacional de Parapljicos de Toledo
Hospital Universitario Virgen del Roco, Sevilla
Hospital de Neurorrehabilitacin - Instituto Guttmann, Badalona
Hospital Universitario Puerta del Mar, Cadiz
1. Patients who can benefit from other method of
bladder drainage such as intermittent
catheterization, suprapubic drainage or reflex
voiding; as well as those using an external collector.
2. Patients with urinary tract infection at the moment of inclusion.
3. Current antibiotic use or use within 7 days prior to inclusion.
4. Outpatients with sporadic medical examinations (less than one per month).
5. Known allergy to latex, silver salts or hydrogels.
6. Patients with surgical interventions in the urinary tract that may interfere, at the investigator criteria, with the study results.
7. Pregnant or breastfeeding woman.
Subjects eligible for the study are contacted through
medical staff and are provided with information about
the study (verbal and written information). Consent is
then obtained for participation in the study.
Participants are randomly allocated to intervention or
The intervention arm receives urinary catheters with
antiseptic silver alloy coating (BIP Foley catheter Silicone,
Bactiguard Infection Protection). Bactiguard Infection
Protection coating consists of noble metals such as gold,
palladium and silver and its mechanism of action is to
avoid the adhesion of bacteria to the inner catheter surface.
All are made of full silicone.
The control arm receive standard urinary catheters
commonly used in each hospital, most of them made of
silicone or silicone-latex.
Trained health staff performs urethral catheterization
procedure and select the most adequate catheter size.
To ensure aseptic conditions they are asked to strictly
follow the current protocol in their respective centres.
Indwelling urethral catheters are periodically replaced
about 30 days of use; to not interfere with current
clinical practice, the policy of each centre (or the
investigator criteria) for catheter replacement and removal is
considered valid for this study.
Blinding This study is not blinded and the patient and
health staff will know whether the patient is allocated to
intervention or control arms. Differences in the shape
and color of urinary catheters made study blinding too
complex. To prevent bias the primary outcome will be
evaluated by a data adjudication committee blinded to
Randomization The random sequence for the two
comparison groups is computer generated ensuring equal
allocation ratio. Blocked stratification for study centre is
used to ensure that the two groups do not differ between
centres. On-line central randomization ensures that
intervention allocation is properly concealed.
Due to the characteristics of the included patients,
it would be possible that they still require the use of
an indwelling urinary catheter after their participation
in the study. The study allows the participants to be
randomized more than once if all the inclusion and
exclusion criteria are still valid. Between first and
subsequent participation in the study, patients should use
Data collection All data is collected through an on-line
electronic data capture system (http://ensayoescale.com).
Secure access to this on-line platform is restricted to
each centre investigator and designed collaborators and
ensured by individual passwords.
The study on-line platform collects from each
participant the inclusion and exclusion criteria, baseline
clinical and demographic data, the allocated intervention
(size, reference number, and whether the aseptic
conditions are observed), any sign and symptom which may
be suggestive of acute UTI, results from urine and/or
blood analysis (if performed), antimicrobial susceptibility
test (if performed), any treatment given, adverse events
as well as the data and reason for urinary catheter
replacement or removal.
See Figure 1 for the study flow diagram.
Socio-demographic and baseline clinical data The
following data are registered: date of birth, gender, level of
spinal cord injury, traumatic or medical causes of spinal
cord injury, ASIA scale , time with indwelling urethral
catheter or first-ever urethral catheterization, presence of
diabetes mellitus and medical treatments history (including
treatments that may increase risk of infection).
Primary outcome The primary outcome is the
development of a UTI related to urinary catheterization.
The patient must have at least one sign or symptom
suggestive of UTI (see Table 2) with no other recognized
cause and a positive urine culture with no more than 2
species of microorganisms. The study does not establish
a specific threshold of uropathogen colony count criteria
for the diagnosis of UTI and use each centre criteria.
An UTI is considered associated with the use of study
catheter if the specimen collection is performed at any
time from catheterization procedure and 30th day, catheter
removal or catheter replacement (whichever occurs first).
It was considered that knowing if one type of urinary
catheter or another may reduce symptomatic UTI is
critical for clinical decisions. Many other studies considered
asymptomatic bacteriuria (ASB) as primary outcome but
ASB is very common in SCI patients, especially in those
using indwelling catheters, and it appears to have no
long-term squeals .
Secondary outcomes Asymptomatic UTI, bacteremic
UTI, and adverse events related to catheterization
procedure are considered secondary outcomes.
Patients with an asymptomatic UTI are those with no
signs or symptoms but with a positive urine culture with
no more than 2 species of microorganisms in an specimen
collected at any time from catheterization procedure and
30th day, catheter removal or catheter replacement
(whichever occurs first).
Patients with bacteremic UTI are those fulfilling the
primary outcome and with a positive blood culture with
at least 1 matching uropathogen microorganism to the
The study measures the direct costs attributable to the
use of intervention or control urinary catheters and their
Any untoward medical occurrence in a patient using
catheters with antiseptic silver alloy coating or standard
catheters under study are also recollected.
Primary efficacy analysis will be performed on the intent
to treat population set, including those participants
correctly randomized and willing to participate in the study.
Per protocol analysis will also be performed including
Patients admitted / referred to:
Rehabilitation or spinal units
or outpatient centres
Inclusion / exclusion criteria
Information sheet and consent
RANDOMIZATION 1:1 allocation , stratified by centre Silver alloy coating CATHETERS
Figure 1 Study flow diagram.
those participants correctly randomized, willing to
participate and with no major protocol violations. A further
exploration of the sensitivity will be performed with
these two sets of population to check they lead to the
same conclusions. Primary and secondary outcome
analyses including dichotomous data will be analyzed using
Chi-squared test (or Fishers exact test if analysis sample
size is small). Socio-demographic and baseline clinical
data will be described providing mean and standard
Costovertebral pain or tenderness
Fever (body temperature > 38C)
Abdominal pain or tenderness
Change in urine colour
Change in voiding patterns
deviation (or median and range) and compared using
ANOVA test (or Kruskall-Wallis test) depending whether
the data fulfil the application requirements.
In addition a regression analysis depending on
gender, lesion level, re-inclusion and indwelling urethral
catheterization carriers, first-ever catheter or another
significant or clinical relevant outcome will be considered. No
interim analysis is planned.
The level of significance will be the usual 5% (alpha =
0.05), two-sided. All the analysis will be performed with
Power calculation: The sample size was calculated on
the assumption that 24% of patients will suffer from an
UTI related to urinary catheterization, and a relative
reduction of 35% with the use of catheters with antiseptic silver
alloy coating, which is considered clinically relevant. A
total sample size of 742, 371 in each group (allowing for
5% attrition) have a minimum of 80% power to detect
these differences between intervention groups.
There is very limited information on the overall
incidence of UTI in SCI patients using indwelling catheters,
most coming from observational studies that included
patients using different voiding methods, with a variety
of risk factors, using heterogeneous definitions of UTI.
In addition follow-up periods and incidence measures
used varied broadly. We thus considered, conservatively,
that almost one quarter of participants will suffer from
an UTI [14,15].
This study is a randomized controlled trial to assess the
incidence of symptomatic UTI in patients with SCI and
needing an indwelling urinary catheter. The trial is
designed to provide an adequate answer whether patients
requiring long periods of catheterization might benefit
from antiseptic-impregnated catheters (silver and other
noble metals coating). Patients will be assessed during
30 days or until catheter removal. Signs and symptoms
suggestive of UTI and urine cultures will be collected for
the definition of a clinically relevant primary outcome.
Other outcomes such as bacteremic UTI, adverse events
and costs will be also accounted.
Coating urinary catheters with silver alloy and other
noble metals as well as with antibiotics seem to be a
promising intervention to reduce hospital-acquired
infections, as described in a systematic review of
randomized clinical trials . This review included studies using
short-term catheterization and pooled the results of a
surrogate outcome such as bacteriuria. One recent
clinical trial did not show clinically relevant differences
between antiseptic-impregnated catheters (silver alloy or
antimicrobial) to standard ones in 7102 adults with acute
pathologies requiring a short-term urinary catheterization
. This large and pragmatic clinical trial defined
catheterassociated UTI as the presence of participant-reported
suggestive symptoms and clinician prescription of
antibiotic for a UTI at any time up to 6 weeks after
randomization. Even though this unusual definition, in
patients carrying a catheter for an average of two days
the results did not support the routine use of
antisepticimpregnated catheters. However, these evidences are not
directly applicable to SCI patients.
Our study has several methodological strengths such
as an accurate method of randomization, concealment
allocation and a data adjudication committee blinded to
the intervention. It also needs to be emphasized that the
primary objective of our study has not been previously
evaluated in SCI population and is based in a sound
primary outcome which is critical for decision-making. In
addition, the study is designed to find a clinically
meaningful reduction in the relative incidence of UTI of 35%.
This figure is translated to an absolute reduction of 84
fewer UTI per 1000 patients using indwelling catheters.
Conversely, if the study does not rule out irrelevant or
no benefit from the use of silver-alloy coating urinary
catheters, most SCI patients requiring indwelling urethral
catheterization would use the standard catheters which
cost is 10 times less as compared to silver-alloy ones.
There are also several potential limitations of the trial.
The most important one is its blinded nature. Patients
and health staff will know the allocated intervention,
thus they might become more prone to report sign,
symptoms as well as to ask for urine or blood tests if
they know that a standard catheter is used. This source
of bias would be mitigated with the data adjudication
committee blinded to the intervention. Another
limitation is the UTI definition. Even though the Centers for
Disease Control and Prevention  recognizes that
subjects with at least one of the following signs or symptoms
(fever (>38C), suprapubic tenderness, or costovertebral
angle pain or tenderness) and a positive culture suffer from
a symptomatic UTI, the sensitivity and specificity of
urinary symptoms in SCI patients is very poor [13,17]. The
diagnosis of UTI in SCI patients is based on the
combination of symptoms and signs, which are often non-specific.
The signs and symptoms criteria for UTI in this study are
adapted from the National Institute on Disability and
Rehabilitation Consensus Statement , which together with
other clinical and laboratory data will be the basis for data
adjudication committee to decide if a patient suffered from
We present the protocol of an open label, randomized
controlled clinical trial to determine the effectiveness of
urinary catheters with antiseptic silver alloy coating on
the reduction of symptomatic UTI in SCI patients with
indwelling urethral catheter. The urinary catheters with
antiseptic silver alloy coating are compared to standard
urinary catheters (with no antiseptic coating) during a
period up to 30 days. This study will provide clear
information about the clinical effectiveness of silver-alloy
catheters to guide its use in a population requiring
Additional file 1: Table S1. ESCALE Group.
Manuel Bea-Muoz received funding from Coloplast and Hollister for his
participation in conferences and courses. He received fees from Wellspect
Halthcare for conferences talks. The rest of authors declare that they have no
XB, DR, MJM conceived of the study, participated in its design and coordination
and drafted the manuscript. MLJ, JMB, SSB, CMA, MB, SM, AB, JRE, LL, ME and IA
made substantial contributions to design, revised the manuscript critically for
intellectual content and have given final approval of the version to be published.
All authors read and approved the final manuscript.
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