Abdominal PainCACATUNCT02197780
Head-to-head Comparison of Two Fecal Biomarkers to Screen Children for IBD
An observational study of Abdominal Pain and Rectal Bloodloss, run by University Medical Center Groningen at 19 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 to 18 years
- Conditions the study is for
- Abdominal Pain, Rectal Bloodloss, Diarrhea
- How many people
- 355 participants
- Where
- 19 sitesin 2 countries
- Study dates
- Sep 2014to Apr 2017
- How long will I take part?
- 6 Months
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Study population: Eligible for inclusion are consecutive children and teenagers who consult their pediatrician and have gastro-intestinal symptoms suggestive of IBD. Participating centers are located in the Northern and Southern region of the Netherlands and the Flemish-speaking region of Belgium.
Eligible patients are those aged between 6 and 18 years with at least one of the following 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)
We did not define any exclusion criteria.
Trial locations and contacts
19 sites in 2 countries.
19 sites in 2 countries
Netherlands16 sites
ZGT Almelo
Almelo, 7609 PP
Wilhelmina Ziekenhuis
Assen, 9401 RK
Deventer Ziekenhuis
Deventer, 7416 SE
Ziekenhuis Nij Smellinghe
Drachten, 9292 NN
Scheper Ziekenhuis
Emmen, 7824 AA
Medisch Spectrum Twente
Enschede, 7513 ER
Admiraal de Ruyter ziekenhuis
Goes
University Medical Center Groningen
Groningen, 9700 RB
Martini Ziekenhuis
Groningen, 9728 NT
Tjongerschans
Heerenveen, 8441 PW
Bethesda Hospital
Hoogeveen, 7909 AA
Medisch Centrum Leeuwarden (MCL)
Leeuwarden, 8934 AD
Bravis ziekenhuis
Roosendaal
Refaja Ziekenhuis
Stadskanaal, 9501 HE
Ommelander Ziekenhuis Groep
Winschoten, 9671 CX
Isala Kliniek
Zwolle, 8025 AB
Belgium3 sites
Sint Vincentiusziekenhuis
Antwerp
University Hospital Antwerpen
Antwerp
University Hospital Gent
Ghent
About this study
Official title: Calprotectin or Calgranulin C-test Before Undergoing Endoscopy: a Prospective Diagnostic Accuracy Study Comparing Two Fecal Biomarkers for Pediatric IBD
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.
Read more
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.
Read the 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.
- 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.
- 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
- Keywords
- Diagnostic accuracy, Fecal biomarker, Clinical Decision Rule, Cohort Study
- Medical subject headings
- Abdominal Pain, Diarrhea, Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative, Irritable Bowel Syndrome
What is being measured
The primary outcome is the main question the study is designed to answer.
The difference in specificity between FC and S100A12 among the total number of non-IBD patients.
Measured: 6 months
Secondary outcomes (2)
The difference in sensitivity between FC and S100A12 among the total number of IBD patients.
Measured: 6 months
Diagnostic test accuracy characteristics for both FC and S100A12
Calculate sensitivity, specificity, positive predictive value, negative predictive value, area under ROC-curve, best cut-off point. The sensitivity, specificity, positive predictive value and negative predictive value will be presented with 1) a pre-specified cutoff value based on literature and 2) with the best cut-off points from this trial
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jul 2014 (estimated)
- Study startSep 2014
- Primary completionMar 2017
- Study completionApr 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Abdominal PainStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 355 participants (actual)
- Target duration
- 6 Months
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- Cisbio Bioassays
- Responsible party
- Principal investigator, P.F. van Rheenen, University Medical Center Groningen
- Investigators
- Patrick F van Rheenen, MD PhD, Principal investigator, University Medical Center Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02197780
- Sponsor's protocol ID
- UMCG-2013N636
- Acronym
- CACATU
- Status last verified
- May 2017
- First submitted
- 21 Jul 2014
- Last updated
- 4 May 2017
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 32694147Heida 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.
PubMed 29514815Heida 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.
PubMed 28554936Heida 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.
PubMed 27506279
Study at a glance
From the registry record, last updated by the sponsor on 4 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Calprotectin or Calgranulin C-test Before Undergoing Endoscopy: a Prospective Diagnostic Accuracy Study Comparing Two Fecal Biomarkers for Pediatric IBD
- ClinicalTrials.gov ID
- NCT02197780
- Acronym / sponsor ID
- CACATU / UMCG-2013N636
- Conditions
- Abdominal Pain, Rectal Bloodloss, Diarrhea, Inflammatory Bowel Disease, Crohn's Disease, Ulcerative Colitis
- Keywords
- Diagnostic accuracy, Fecal biomarker, Clinical Decision Rule, Cohort Study
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 355 participants (actual)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Collaborators
- Cisbio Bioassays
- Study start
- Sep 2014
- Primary completion
- Mar 2017 (actual)
- Study completion
- Apr 2017 (actual)
- First posted
- 23 Jul 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
- 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.
- 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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 6 Months
Who may qualify
- Ages
- 6 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
- Study population
- Eligible for inclusion are consecutive children and teenagers who consult their pediatrician and have gastro-intestinal symptoms suggestive of IBD. Participating centers are located in the Northern and Southern region of the Netherlands and the Flemish-speaking region of Belgium.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
The difference in specificity between FC and S100A12 among the total number of non-IBD patients.
Time frame: 6 months
2 secondary outcomes
The difference in sensitivity between FC and S100A12 among the total number of IBD patients.
Time frame: 6 months
Diagnostic test accuracy characteristics for both FC and S100A12
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 May 2017.
- Derived from this study: PubMed 32694147Van 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.
- Derived from this study: PubMed 29514815Heida 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.
- Derived from this study: PubMed 28554936Heida 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.
- Derived from this study: PubMed 27506279Heida 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Patrick F van Rheenen, MD PhD principal investigator
University Medical Center Groningen
19 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Abdominal Pain and Rectal Bloodloss, run by University Medical Center Groningen at 19 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 May 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The difference in specificity between FC and S100A12 among the total number of non-IBD patients. (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02197780, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 May 2017.