Head-to-head Comparison of Two Fecal Biomarkers to Screen Children for IBD

NCT ID: NCT02197780

Last Updated: 2017-05-04

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 355 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2014-09-30
• Study Completion Date: 2017-04-30

Brief Summary

RATIONALE:

A substantial proportion of children and teenagers with suspected inflammatory bowel disease (IBD) referred for endoscopy do not have the disease. The investigators designed a clinical decision rule that included a calprotectin stool test to discern which patients require further investigations. The accuracy of this diagnostic strategy is 88.5% with a low risk of missing IBD cases. Although the number of negative endoscopies was reduced after introduction of this strategy, still 22% of the referred children and teenagers underwent an unnecessary invasive test. S100A12 (calgranulin C) is a cytoplasmic protein secreted exclusively by activated neutrophils and this stool marker may be more IBD-specific than calprotectin.

OBJECTIVE:

To determine whether the specificity of S100A12 is superior to the specificity of calprotectin without sacrificing sensitivity

HYPOTHESIS:

Inclusion of the calgranulin C stool test will improve the specificity of the screening-strategy.

Detailed Description

DESIGN:

A prospective diagnostic accuracy study in several outpatient clinics for general paediatrics and several tertiary care hospitals in the Netherlands and Belgium.

STUDY POPULATION:

Eligible for inclusion are consecutive children and teenagers between 6 and 18 years who consult their pediatrician and have gastro-intestinal symptoms suggestive of IBD.

INTERVENTION:

Patients will be managed according to a calprotectin-based-referral strategy. Those with an elevated calprotectin level without colon pathogens are considered to have a high probability of IBD and may require referral for endoscopy (the preferred reference standard). Patients with confirmed gastrointestinal infection are advised to have their stools retested. Patients with normal calprotectin levels are considered to have a low probability of IBD and will therefore have a low change to be subjected to endoscopy. In these patients with low probablity of IBD an alternative reference standard may be performed, being clinical follow-up for 6 months. The decision for endoscopy or clinical follow up is up to the clinician's discretion, based on the combination of all symptoms, physical examination, blood results, fecal markers and colon pathogens.

Next to calprotectin, also S100A12 will be measured in all stool samples. We will perform a post hoc scenario analysis to compare the test characteristics of both fecal markers.

OUTCOME MEASURES:

The primary outcome measure is the difference in specificity between FC and S100A12 among the total number of non-IBD patients.

We adjusted our previously formulated outcome measure, being the proportion of patients with non-inflammatory conditions among the total number of patient subjected to endoscopy, for two reasons.

1. During an interim analysis in August 2016 the proportion of patients subjected to endoscopy was lower as expected (34% instead 46%). To reach the required amount of patients with the reference standard (endoscopy) we needed to extend the study for several months.

2. Triggered by a recently published paper by Naaktgeboren et al in the BMJ, we realized that our initial design would lead to biased results.

Secondary endpoints are the difference in sensitivity among the total number of patients with IBD and the diagnostic accuracy characteristics (sensitivity, specificity, positive predictive value, negative predictive value, area under the curve, best cut-off point) for both markers individually. All diagnostic accuracy characteristics will be calculated with 1) a pre-specified cut-off value based on literature, 2) the best cut-off point calculated with the data from this trial.

POWER/DATA ANALYSIS:

At the start of our trial we defined a sample size calculation, based on the previously described outcome measure including only patients with endoscopy. Based on a previous cohort study we expected that 46% of the recruited patients would undergo endoscopy. Using a sample size calculation based on independent samples calculated with a Fisher's exact test, we calculated that with 154 patients subjected to endoscopy the study would have 80% power to detect a 50% relative reduction of the primary outcome from 22% false positives with FC to 11% false positives with S100A12, at a one-sided alpha level of 0.05. The total number of patients to be recruited for this diagnostic accuracy study was therefore calculated at 335.

In the slipstream of the adjustment of the primary outcome measure, we adjusted our sample size. We now use McNemar's test for paired samples to compare the proportion of concordant and discordant results between FC and S100A12 in all patients with the disease or without the disease.

To calculate the new sample size we used a specificity of FC of 0.70, based on recent individual patient data meta-analysis of Degraeuwe and we expected S100A12 would lead to 50% relative improvement. A sample size of 130 subjects achieves 80% power to detect a difference of 0,15 between the two diagnostic tests whose specificities are 0,70 and 0,85. This procedure uses a two-sided McNemar test with a significance level of 0,05. The prevalence of non-IBD in the population is 0,64. The proportion of discordant pairs is 0,23.

ETHICAL CONSIDERATIONS:

The Medical Ethical Committee of the University Medical Center in Groningen has granted exemption from WMO-approval, as it involves the collection of data generated by routine medical care. After measurement of calprotectin levels and testing for microbial gut pathogens the residual material will be used for the measurement of calgranulin C levels. When patients and their parents give permission, residual feces will be stored for a maximum period of 15 years for future diagnostic research.

TIME SCHEDULE:

Total running time is 30 months, including 6 months to complete the follow up and 2 months for analysis and reporting.

Conditions

Abdominal Pain; Rectal Bloodloss; Diarrhea; Inflammatory Bowel Disease; Crohn's Disease; Ulcerative Colitis; Irritable Bowel Syndrome

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Eligibility Criteria

Inclusion Criteria

• Persistent diarrhea (at least 4 wks)
• Recurrent abdominal pain with diarrhea (at least 2 episodes in 6 months)
• Rectal bloodloss
• Peri-anal disease

OR at least two of the following criteria:

• Involuntary weight loss
• First degree family member with IBD
• Anemia (HB < -2 SD for age and gender)
• Increased marker of inflammation (ESR >20 mm/hour or CRP >10 mg/L)
• Extra-intestinal symptoms (erythema nodosum, arthritis, uveitis, thromboembolism, aphtous ulcera)

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cisbio Bioassays

INDUSTRY

Sponsor Role: collaborator

University Medical Center Groningen

OTHER

Sponsor Role: lead

Responsible Party

P.F. van Rheenen

Pediatric Gastroenterologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Patrick F van Rheenen, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University Medical Center Groningen

Locations

Sint Vincentiusziekenhuis

Antwerp, , Belgium

University Hospital Antwerpen

Antwerp, , Belgium

University Hospital Gent

Ghent, , Belgium

ZGT Almelo

Almelo, , Netherlands

Wilhelmina Ziekenhuis

Assen, , Netherlands

Deventer Ziekenhuis

Deventer, , Netherlands

Ziekenhuis Nij Smellinghe

Drachten, , Netherlands

Scheper Ziekenhuis

Emmen, , Netherlands

Medisch Spectrum Twente

Enschede, , Netherlands

Admiraal de Ruyter ziekenhuis

Goes, , Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Martini Ziekenhuis

Groningen, , Netherlands

Tjongerschans

Heerenveen, , Netherlands

Bethesda Hospital

Hoogeveen, , Netherlands

Medisch Centrum Leeuwarden (MCL)

Leeuwarden, , Netherlands

Bravis ziekenhuis

Roosendaal, , Netherlands

Refaja Ziekenhuis

Stadskanaal, , Netherlands

Ommelander Ziekenhuis Groep

Winschoten, , Netherlands

Isala Kliniek

Zwolle, , Netherlands

Countries

Belgium; Netherlands

References

Van de Vijver E, Heida A, Ioannou S, Van Biervliet S, Hummel T, Yuksel Z, Gonera-de Jong G, Schulenberg R, Muller Kobold A, Verkade HJ, van Rheenen PF; CACATU CONSORTIUM. Test Strategies to Predict Inflammatory Bowel Disease Among Children With Nonbloody Diarrhea. Pediatrics. 2020 Aug;146(2):e20192235. doi: 10.1542/peds.2019-2235. Epub 2020 Jul 21.

Reference Type: DERIVED

PMID: 32694147 (View on PubMed)

Heida A, Van de Vijver E, van Ravenzwaaij D, Van Biervliet S, Hummel TZ, Yuksel Z, Gonera-de Jong G, Schulenberg R, Muller Kobold A, van Rheenen PF; CACATU consortium. Predicting inflammatory bowel disease in children with abdominal pain and diarrhoea: calgranulin-C versus calprotectin stool tests. Arch Dis Child. 2018 Jun;103(6):565-571. doi: 10.1136/archdischild-2017-314081. Epub 2018 Mar 7.

Reference Type: DERIVED

PMID: 29514815 (View on PubMed)

Heida A, Van de Vijver E, Muller Kobold A, van Rheenen P. Selecting children with suspected inflammatory bowel disease for endoscopy with the calgranulin C or calprotectin stool test: protocol of the CACATU study. BMJ Open. 2017 May 29;7(5):e015636. doi: 10.1136/bmjopen-2016-015636.

Reference Type: DERIVED

PMID: 28554936 (View on PubMed)

Heida A, Dijkstra A, Dantuma SK, van Rheenen PF. A Cross-Sectional Study on the Perceptions and Practices of Teenagers With Inflammatory Bowel Disease About Repeated Stool Sampling. J Adolesc Health. 2016 Oct;59(4):479-81. doi: 10.1016/j.jadohealth.2016.06.009. Epub 2016 Aug 6.

Reference Type: DERIVED

PMID: 27506279 (View on PubMed)

Other Identifiers

UMCG-2013N636

Identifier Type: -

Identifier Source: org_study_id