Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05171452 |
| Other study ID # |
APHP180450 |
| Secondary ID |
2018-A02342-53 |
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
October 3, 2019 |
| Est. completion date |
October 19, 2020 |
Study information
| Verified date |
November 2021 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The inflammatory bowel diseases (IBD) are lifelong, relapsing-remitting diseases. As the
timing of relapse is unpredictable, and current monitoring is symptoms-based, there remains a
window between the initial upregulation of the inflammatory response and the onset of
clinical symptoms at which point the inflammatory episode is well established. The use of
endoscopy as means of predicting relapse is not suitable for regular use. The potential role
of Fecal calprotectin (FC) in IBD in predicating the risk of relapse has been well
investigated with key studies. Its fecal concentration is proportional to neutrophilic influx
into the intestinal tract, which is a feature of active IBD. FC correlates well with the
severity of endoscopic lesions. After excretion, FC remains stable in the feces for 1 week at
room temperature. However, its considerable daily variation suggests interfering factors
discrete from inflammatory disease. There is increasing research into novel markers with high
correlation to the presence of mucosal healing constitute a cost-effective substitute to
repeated endoscopies. Recent studies have reported that the prostaglandin E-major urinary
metabolite (PGE-MUM) level was significantly higher in the active phase of patients with
ulcerative disease (UC) than those in the remission phase. In the active UC phase, the
stimulation of inflammatory cytokines, such as tumor necrosis factor-α, leads to the
upregulation of cyclooxygenase-2 (COX-2) leading to PGE2 secretion in mucosal tissue. PGE2
plays an important role in the progression of inflammation. A precise measure of serum PGE2
is difficult due to the short half-life of PGE2 in the blood. Conversely, the urinary
metabolite of prostaglandin E-major (PGE-MUM, 7-hydroxy-5,11-diketotetranor-prosta-1,16-dioic
acid) is stable and may reflects the histological severity of inflammation. The aim of this
concept study is to evaluate the PGE-MUM concentration in urine of patients with IBD in
parallel with the standard investigation of Calprotectin in stool and to assess if urinary
PGE-MUM should be able to serve as a simple and robust substitutive biomarker for the
non-invasive evaluation of the inflammation of the mucous membrane tissues. The measurement
of PGE-MUM in urine could give patients with IBD more comfort than the measurement of
calprotectin in stool.
Description:
Inflammatory bowel diseases (IBD) include Crohn's disease (CD) and ulcerative colitis (UC)
are chronic inflammations of the digestive tract with periods of remission of variable
duration. As the timing of relapse is unpredictable, and current monitoring is
symptoms-based, there remains a window between the initial upregulation of the inflammatory
response and the onset of clinical symptoms at which point the inflammatory episode is well
established. Endoscopy displays direct evidence of mucosal injury but as means of predicting
relapse is not suitable for regular use. Biological examinations are looking for signs of
inflammation such as the presence of inflammatory anemia or thrombocytosis, frequently found,
or increased C-reactive protein (CRP), a nonspecific marker poorly correlated with endoscopic
inflammation; or looking for signs of malabsorption such as hypoalbuminemia or vitamin
deficiencies. These serum markers are limited in fulfilling the role as a prognostic marker
of relapse.
The best non-invasive biomarker compared to endoscopic examination for the monitoring of IBD
is the fecal calprotectin (CF). Calprotectin is a 36 kiloDalton, calcium- and zinc-binding
protein that comprises up to 60% of cytosolic proteins in neutrophils, being released during
apoptosis or necrosis. Its fecal concentration is therefore proportional to neutrophilic
influx into the intestinal tract, which is a feature of active IBD. FC is therefore an
accurate surrogate marker of active endoscopic disease in IBD patients, its sensitivity is
between 70% - 100%, with a specificity of 44% - 100%, depending on the threshold value used.
FC measurement is now widely available and is being incorporated into routine clinical
practice. The advantages of fecal biomarkers are that samples (feces) are easy to obtain, can
be collected at home, can be serially obtained, and can be relatively easy to analyze with
the sample posted to the laboratory for analysis.
Point-of-care urinary markers can represent interesting candidates as tools for monitoring
inflammatory activity in IBD and for assessing the risk of imminent disease flares. According
to the latter concept, clinical remission should be paired with biological and endoscopic
evidence of mucosal inflammatory inactivity in IBD patients. Expressed in ratio to
creatinine, the more complicated collection of 24 hours urine is useless.
Recent studies have reported that prostaglandin E2 (PGE2) is produced in the mucosa of the
intestine of areas affected by IBD and the PGE2 plays important role in the progression of
inflammation. In the active UC phase, the stimulation of inflammatory cytokines, such as
tumor necrosis factor-α, leads to the upregulation of cyclooxygenase-2 (COX-2) leading to
PGE2 secretion in mucosal tissue. In blood, PGE2 is immediately metabolized by 15-hydroxy
prostaglandin dehydrogenase (15-PGDH), which is present in the lung and colon, into
15-keto-PGE2. Next, in the liver and kidney, 15-keto-PGE2 is converted into
13,14-dihydro-15-keto PGE2 by the action of Δ13-reductase, followed by β-oxidation and
ω-oxidation; this is finally converted to PGE-MUM
(7α-hydroxy-5,11-diketotetranor-prosta-1,16-dioic acid) and excreted along with urine. A
precise measure in the blood of PGE2 was considered difficult due to the short half-life of
PGE2 in the blood. Conversely, the urinary metabolite of prostaglandin E-major (PGE-MUM,
7-acid 5-hydroxy, 11-diketotetranor-prosta-1, 16-dioecious) is stable.
A correlation was reported (Arai, 2014) between PGE-MUM and inflammatory activity in IBD
using the 3 severity score indexes - clinical, colonoscopic, and histological - Simple
clinical colitis activity index (SCCAI), Mayo endoscopic scoring and Matts grading
respectively (. When the cutoff value was set to 17 mg/g creatinine to distinguish Matts 1
from Matts 2-5, the sensitivity (equals to specificity), positive predictive value, negative
predictive value, and accuracy of PGE-MUM were 0.82, 0.67, 0.93, and 0.83, respectively,
compared with 0.69, 0.49, 0.93, and 0.69 for CRP respectively. The odds ratio was of 35 for
the differentiation between cases in remission and active cases.
There is currently no study comparing urinary PGE-MUM and FC, which is the most validated and
consensus biomarker of inflammation of the intestinal mucosa in Western countries. The
proposed study aims to evaluate the correlation and bias between these two methods. The
target population will be adult patients followed for chronic inflammatory bowel disease
(IBD) diagnosed with certainty as Crohn's disease (CD) or ulcerative colitis (UC). The
subjects will be recruited by specialized doctors in gastroenterology, IBD and nutrition
assistance, on a voluntary basis after information and consent. These are patients benefiting
from the usual IBD management circuit, either in outpatient for regular follow-up or
hospitalized in case of recurrence for care aiming to limit the symptoms and duration of the
acute inflammatory, and for whom a prescription for the measurement of fecal calprotectin and
blood markers are required in routine care.
This proof-of-concept study might be used to direct future clinical validation.
