Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03942861 |
| Other study ID # |
CopenhagenUHH |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 21, 2019 |
| Est. completion date |
February 21, 2022 |
Study information
| Verified date |
January 2021 |
| Source |
Copenhagen University Hospital at Herlev |
| Contact |
Johan F.K. Fremberg Ilvemark, MD |
| Phone |
0045 38686678 |
| Email |
jfre0079[@]regionh.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Introduction Acute severe ulcerative colitis (ASUC) occurs in 15-25 % of all ulcerative
colitis (UC) patients. Initial treatment with intravenous corticosteroids fails in 30-50 % of
patients, for whom the next line of treatment is biological therapy or colectomy. Acute
colectomy has a higher risk of morbidity and mortality than a scheduled colectomy. Data
suggest that an accelerated administration of biological treatment in corticosteroid
non-responders compared to clinical practice, 5-7 days with intravenous corticosteroids, may
be superior in inducing disease remission, thus potentially avoiding acute colectomy.
However, there are currently no patient friendly and objective diagnostic tool to preselect
patients for such a treatment. The aim of this study is to examine if gastrointestinal
ultrasound (GIUS) could preselect corticosteroid non-responders to biological treatment after
48 hours to increase effectiveness of the second line therapy and thereby reduce the
morbidity and mortality of ASUC.
Methods and analysis The study is a clinician blinded observational multi-center study
derived from the Department of Gastroenterology, Herlev Hospital, Denmark. Fifty ASUC
patients will be included at the time of hospitalization and followed for 12 months. Baseline
clinical activity scores, endoscopic scores, blood samples, fecal-calprotectin, vital
parameters and GIUS measurements will be obtained prior to administration of intravenous
corticosteroids. All examinations except fecal-calprotectin and endoscopy will be repeated at
48 ± 24 hours, 5-7 days and 3 months after treatment start. Endoscopic scores and
fecal-calprotectin will be obtained after 3 months and an additional fecal-calprotectin after
6 ± 1 days. Treatment outcome will be registered at each event and after 12 months. Patients
will be divided into corticosteroid responders and non-responders and compared to GIUS
measurements at each event using non-parametric statistics (Mann-Whitney and Wilcoxon test)
and time to endpoints by survival statistics (Kaplan Meier). ROC statistics will determine
the best cutoff values for GIUS parameters for optimal sensitivity, specificity and accuracy.
Ethics and dissemination The study is approved by the National committee on health research
ethics (H-18031264). Results will be published in relevant scientific journals and presented
at international conferences. Fully anonymized data will be accessible from authors upon
request.
Description:
Introduction
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), typically diagnosed
between the age of 15 and 40 and characterized by colonic mucosal inflammation and
ulcerations. These mucosal changes lead to bloody diarrhea and in severe cases, fever,
anemia, weight loss and death if not treated appropriately. The condition requires prompt
immunosuppressive treatment and monitoring. To characterize disease severity and guide
treatment decisions, clinicians typically use a combination of clinical scores based on
patients symptoms, endoscopic scoring systems based on mucosal appearance endoscopic
assessments of disease extent and blood and stool markers of inflammation.
Most patients experience a mild to moderate disease course with varying periods of activity
and remission. However, 15-25 % will experience a flare of acute severe UC (ASUC), a
condition characterized by extensive and deep ulcerations on endoscopy combined with a high
clinical score of severity. Due to the risk of bowel wall perforation, these patients are
usually admitted to the hospital ward for intensive monitoring and medical therapy. The
medical therapy ultimately aims at avoiding acute colectomy, a procedure that still carries a
30-day mortality rate of 5 %, which is higher compared to elective surgery (OR 1.82; CI 95 %
1.19 - 2.62). Initial therapy is well established and consists of intravenous
corticosteroids, which in early clinical trials dramatically improved the disease outcome by
reducing the mortality rate from 24 to 7 %. Unfortunately, even today 30 - 50 % of patients
with ASUC fails to respond to initial corticosteroid treatment and are therefore eligible for
medical rescue treatment if surgery is not imminent.
Accordingly, primary non-responders to high dose intravenous corticosteroids are usually
switched to infliximab (or at certain centers ciclosporine) after 5-7 days, if an acute
colectomy is not needed. Infliximab is an anti-tumor necrosis factor (TNF) alpha antibody,
which blocks TNFα, a key inflammatory mediator in UC,and has been proven effective in
corticosteroid resistant UC reducing the risk of acute colectomy from 58 % to 29 %.
Despite advances in medical treatment ASUC still carries a 10 % risk of acute colectomy.
Further improvement in medical therapy and strategy is therefore highly warranted. A decrease
in serum albumin is associated with an increased clearance of infliximab, and it has been
suggested that postponement of infliximab treatment in ASUC could reduce the bioavailability
of the drug as a result of severe hypoalbuminemia. In addition, infliximab is lost in feces
in the setting of ASUC, suggesting that an accelerated infliximab induction regimen or an
increased starting dose compared to standard procedures could be beneficial. However, a
recent review of retrospective studies showed no difference in colectomy rates when comparing
an accelerated infliximab induction regimen with standard induction regimen (both induced
after 3-5 days of corticosteroid treatment), although confounding by disease severity cannot
be excluded. Hence it is currently unresolved if optimized timing and dosing of infliximab
rescue treatment could be of major importance to reduce the need of acute colectomies and
thereby the morbidity and mortality among ASUC patients. Therefore, data to support
clinician's recognition of corticosteroid non-responders early in the process are warranted.
Unfortunately, there are currently no patient friendly, effective or objective point-of-care
tool to identify corticosteroid non-responders early in the process. A high clinical score,
C-reactive protein (CRP) and a low albumin is correlated with an inferior response, but due
to poor positive and negative predictive values they are not routinely used to pre-select
patients for specific medical therapies. Endoscopic severity is predictive for the outcome of
ASUC, but the use of close monitoring with endoscopy is limited in this setting due to the
risk of perforation and the need for repeated bowel cleansing.
Transabdominal gastrointestinal ultrasound (GIUS) is potentially a relevant objective
point-of-care tool, which could be used for treatment outcome assessment in ASUC. A recent
study in ulcerative colitis patients using GIUS to monitor anti-TNFα treatment demonstrated a
high correlation between change in GIUS parameters, bowel wall thickness (BWT) and color
Doppler Signal (DS), compared to baseline with treatment response after 6 and 12 weeks. The
results are in accordance with other studies showing a correlation between endoscopic
activity, clinical symptom scores, CRP and GIUS parameters after 2-3 months of treatment. In
this setting, GIUS can also predict treatment outcome after 12-15 months. Ultrasound has
several advantages compared to other modalities as it is non-invasive and does not inflict
pain, is easily repeatable and available and does not expose the patient to radiation.
Although some studies suggest 4 hours of fasting to diminish peristalsis and intraluminal
air, fasting before examination is generally not necessary, making it preparation free.
Not all bowel segments can be easily visualized, which can be an issue when assessing disease
extent. Especially the rectum and the left colonic flexure can be difficult to visualize and
examine with the transabdominal approach. The combined reported sensitivity and specificity
for detection of colonic inflammation is 74 % and 93 % per segment, whereas the sigmoid colon
and the terminal ileum are easy to identify and measure, showing a higher diagnostic
performance (sensitivity 92 % and specificity 87 %) compared to endoscopy. There is no
significant difference in diagnostic accuracy per bowel segment compared to other radiologic
modalities and in the latest ECCO guidelines GIUS is recommended as a valid alternative to CT
or MR.
There are different signs of inflammation to look for when examining the bowel using GIUS;
the most reported and prominent one being BWT. BWT in healthy subjects ranges between 0.5-3.0
mm depending on anatomical location. Studies on UC patients use different cutoff values,
usually ranging between 3.0-4.0 mm. There is an ongoing discussion within the scientific
community about cutoff values. In general, sensitivity decreases and specificity increases
with a higher value. Vascularization is another important measure and can be estimated with
DS and the Limberg score to define the presence of a high blood flow; a high blood flow
correlates well with inflammation. Further, the bowel wall layers are easily identified due
to echo-stratification on ultrasound. These layers are still present in the mild and moderate
UC cases, whereas the stratification can be lost in severe UC. Severe inflammation can also
cause colonic de-haustration, although this parameter might also correlate to the chronicity
of the condition. Inflammatory mesenteric fat wrapped around the affected intestine is rarely
seen in UC patients but frequently in Crohn's disease.
No study examining the ability of GIUS to predict treatment response in ASUC patients has yet
been conducted on a shorter timeframe than 6 weeks. The investigators have unpublished
preliminary data suggesting a rapid detectable change in GIUS parameters in patients
responding to high-dose corticosteroids. If GIUS can be used as an objective point-of-care
tool for treatment response, it may be useful to identify corticosteroid non-responders at an
early stage, thus providing an opportunity for optimized individual treatment, i.e. rescue
infliximab treatment, and hopefully a decreased morbidity and mortality rate.
Methods and analysis
Study aims The primary aim is to determine if early changes in GIUS parameters (BWT,
vascularization, echostratification, inflammatory mesenteric fat and haustration) from
baseline to 48 ± 24 hours after intravenous corticosteroids initiation in hospitalized
patients with ASUC, can predict clinical corticosteroid non-response and need for biological
treatment and/or colectomy.
The secondary aims are to:
1. Determine if changes in GIUS parameters from baseline to day 6 ± 1 and 3 months after
intravenous corticosteroids initiation can predict treatment non-response and need for
colectomy.
2. Identify the potential interrater variability between investigators and central reading
for GIUS parameters.
3. Correlate GIUS parameters with changes in fecal calprotectin and endoscopic disease
activity (Mayo endoscopic sub-score and Ulcerative Colitis Endoscopic Index of Severity
(UCEIS)) at baseline and 3 months after hospitalization.
4. Correlate GIUS parameters with changes in clinical scores (Mayo score and Simple
Clinical Colitis Activity Index (SCCAI)), blood samples (hemoglobin, CRP, albumin and
alpha-1-antitrypsin), pulse, blood pressure, temperature and time since last meal at 48
± 24 hours, 6 ± 1 days and 3 months after hospitalization.
5. Examine GIUS´s ability to assess disease extent compared to endoscopy and CT (if a
CT-scan is performed after an ordination by a treating physician).
6. Determine the ideal cutoff values for GIUS parameters for optimal sensitivity,
specificity and accuracy.
Study design The study design is a prospective clinician blinded multi-center observational
study. Fifty patients will be included and followed for 12 months. The study is approved by
the Danish National committee on health research ethics H-18031264 and the Danish data
protection agency VD-2018-319.
Procedures and scheduled follow-up visits
Included patients will prior to intravenous corticosteroid treatment have the following
information registered as baseline characteristics:
- Date of birth, age at disease diagnoses, previous and present IBD medication, previous
intestinal surgery, previous extent of disease, other known chronic diseases, smoking
status, extra-intestinal manifestations, weight and height, symptoms (blood and
frequency of stools, urgency of defecation, general well-being, physician's general
assessment), family history of IBD and previously known gastrointestinal infections
(Clostridium difficile, Salmonella, Campylobacter jejuni, CMV, Yersinia enterocolitica
or other).
- Mayo endoscopic sub-score, UCEIS and current endoscopic extent of inflammation.
- Blood samples (hemoglobin, CRP, albumin, alpha - 1 - antitrypsin), fecal calprotectin
results, pulse, blood pressure and temperature.
- GIUS assessment of the BWT, vascularization, echostratification, inflammatory mesenteric
fat and haustration.
- Time since last meal prior to GIUS examination. The intestinal ultrasound together with
blood samples and recordings of pulse, blood pressure, temperature, time since last
meal, time since first intravenous corticosteroid administration as well as clinical
scores will be repeated 48 ± 24 hours, 6 ± 1 days and 3 months after the first dose of
intravenous corticosteroids. Endoscopic examination and fecal calprotectin will be
repeated after 3 months. Treatment outcome (response to corticosteroid, infliximab or
colectomy) will be registered at 48 ± 24 hours, 6 ± 1 days, 3 months and 12 months after
the first dose of intravenous corticosteroids. Results of eventual CT-scans or extra
endoscopies will be stored.
Clinical assessment Patient disease status is monitored during hospitalization using the Mayo
clinical score and SCCAI. Mayo clinical score is based on blood and stool frequency, baseline
endoscopy results and the physician's global assessment. SCCAI is based on bowel frequency
divided by night and day, urgency of defecation, blood in stool, patient general well-being
and extra-intestinal features. Endoscopic severity is graded using the Mayo endoscopic
subscore and the UCEIS, which is based on the severity of the vascular pattern, presence of
blood, erosions and ulcers. The clinical assessment and endoscopies will be performed by a
physician blinded to the GIUS measurements. Endoscopic assessment is based on the worst
segment and documented with still images on a secure drive.
GIUS assessment and measurements Each examination will be performed by a GIUS trained
gastroenterologist using the same high-end ultrasound scanner and 9L probe for the same
patient. Probe frequency will be between 5-8 MHz. Scans are performed by localizing the
sigmoid colon at the site of the iliac vessels and then followed in both anal and oral
direction. The most severe part of the bowel segment will be assessed and documented by still
images and cineloop files and stored in DICOM format on a secure drive. Sigmoid colon is
always assessed as the primary point of interest. However, if topical treatment has been
applied or a more oral located bowel segment has a higher BWT this segment will also be
documented as above and stored. GIUS examination recordings will be subjected to central
reading by an independent GIUS specialist, blinded to the original scans. Fasting will not be
required, but the time passed since patients last meal will be registered. The GIUS examiner
will have no knowledge about the patient disease status (blood and stool sample results,
clinical scores or endoscopic activity).
• BWT is measured in the most severe segment (largest BWT) using the average value of four
measurements with one decimal (two longitudinal scans, more than 1 cm apart and two
cross-sectional scans, which can be in the same image, but in different quadrants). A BWT
value < 3.0 mm is regarded as no inflammation and ≥ 3.0 mm is regarded as active disease.
In segments with a BWT ≥ 3.0 mm, vascularization will be classified using a color Doppler and
a modified Limberg score, as well as echostratification and the eventual presence of
inflammatory mesenteric fat and absence of haustration.
- Vascularization is measured in both the cross-sectional and longitudinal plane.
Pathological vascularization is defined as a modified Limberg score > 1 and normal
vascularization is defined as ≤ 1. No signal, 0 points; minimal pixels, 1 point;
increased doppler signal limited to the wall, 2 points; and if the signal is significant
in the wall as well as the mesentery, 3 points.
- Normal echostratification is measured in a longitudinal plane and defined as 3-5 echo
layers in each bowel wall (mucosa, submucosa, lamina muscularis) and will be
characterized as 1. normal/preserved, 2. uncertain, 3. focal disruption < 3 cm or 4.
extensive disruption ≥ 3 cm.
- Inflammatory mesenteric fat will be defined as a bright looking mass surrounding or
wrapping the bowel, usually brighter and more homogenous than normal intraabdominal fat
in obese; characterized as either 1. absent, 2. uncertain or 3. present.
- Haustration will be defined as either 1. present (normal), 2. uncertain or 3. absent.
Centre selection The study is devised by leading researchers in IBD and trained bowel
ultrasound experts at the Department of Gastroenterology, Herlev Hospital, Denmark. The IBD
clinic at Herlev Hospital is one of the largest clinical and academic IBD centers in Denmark
and an international training center for GIUS. Recruitment and examination of the patients
will be conducted at the gastroenterological departments of the university hospitals in
Herlev, Aarhus, Vejle and Hvidovre. All GIUS gastroenterologists engaged in the study meet
and train together to make the procedures identical and standardized before patient
inclusion.
Sample size calculation The sample size was calculated to be able to detect a 0.7-fold
decrease in thickness of the intestinal wall with a common standard deviation (sigma) of 30 %
and a desired power of 80 % to determine a statistically significant difference (α = 0.05,
two-sided test). The estimated sample size is 17 subjects in each group
(responders/non-responders). The investigators aim to include 20 UC patients in each group,
and since 40 % are expected to be non-responders to steroids, the overall aim is to include
50 patients. Our department currently admits 3-5 patients/month with ASUC. Together with the
other departments, the estimated inclusion period is 15 months.
Statistical analysis Clinical data will be entered into a validated data capture system
provided by the Danish Capital Region. The data system will include password protection and
internal quality checks, such as automatic range checks, to identify data that appear
inconsistent, incomplete or inaccurate. Descriptive data will be provided for all outcomes
(table 2) according to data type; number of patients, mean, SD (for interval data), median 25
% and 75 % quartiles (for ordinal data). Frequency (absolute and relative) distributions will
be provided for categorical data. Two-sided p values will be presented throughout. Data
management and analysis will be performed using REDCap and SPSS.
Primary endpoint analysis Patients will be divided into steroid responders and steroid
non-responders and compared to GIUS parameters (BWT, modified Limberg score,
echostratification, inflammatory mesenteric fat and haustration at baseline to 48 ± 24 hours)
using non-parametric statistics (Mann-Whitney and Wilcoxon test) and time to endpoints by
survival statistics (Kaplan Meier).
Secondary endpoints analysis The same statistical tests as used for primary endpoint analysis
will be applied to predict responders versus non-responders throughout the observational
period. GIUS measurements at baseline compared to 6 ± 1 days and 3 months, with a follow up
at 12 months. GIUS interrater-variability between GIUS examiners and proof reader will be
calculated as kappa values, interclass correlation co-efficiency and Limits of Agreement for
continues variables. Correlation between the GIUS measurements and endoscopic variables will
be assessed using Spearman's rank correlation coefficient, multiple logistic regression and
receiver operating characteristics (ROC) analyses. An additional ROC analyses will be
performed to determine the best cutoff values for GIUS parameters for optimal sensitivity,
specificity and accuracy.
Variables associated with non-responders and responders GIUS measurements (CRP, Hemoglobin,
Albumin, alpha-1-antitrypsin, Mayo clinical score, SCCAI, pulse, blood pressure, temperature,
time since last meal and fecal calprotectin) will be assessed with univariate analyses. Those
who achieve a p-value of < 0.2 will be included into a multivariable logistic regression
analysis.
Discussion There is an unfulfilled need for a reliable, easy, non-invasive and safe modality
to repeatedly assess treatment response in patients admitted with ASUC. GIUS presents itself
as such a modality and the investigators hypothesize that within 48 hours after
corticosteroid treatment GIUS has the potential to identify steroid non-responders. This has
not previously been investigated. An early identification allows for an accelerated treatment
decision in steroid resistant ASUC patients and thus a potential decrease in the need of
acute colectomies. To achieve this goal, the investigators first need to validate GIUS as a
point-of-care tool to predict treatment outcome in patients with ASUC.
Ethics and dissemination In accordance with the Helsinki V declaration and the Ethics
committee of the Capital Region of Denmark enrollment in the study is based on voluntary
informed written consent. All patients can at any time withdraw their participation without
any change in standard care or treatment. Written information about the project will ensure
patient knowledge of their rights. Ultrasound is a safe and patient friendly examination
without any side effects, damage or radiation for the patient. The trial will contribute to a
new partially unexplored field with promises of improving disease activity monitoring and
consequently more rational and timely treatment intervention and decreased morbidity and
mortality. Results will be published in international journals and disseminated at
international conferences.
