Celiac Disease in ChildrenGLUTEN-GENNCT06179121
"Adding DNA-test for Screening of HLA-DQ2 and DQ8 to Improve Early Diagnosis of Celiac Disease"
An observational study of Celiac Disease in Children, run by Leiden University Medical Center at 1 site in Netherlands.
Trial summary
Celiac Disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten containing cereals from the normal diet, among others wheat, rye and barley. The disease is characterized by a variable combination of gluten-dependent clinical manifestations, CD specific antibodies, human leukocyte… Read more about this study
- Who is it for?
- Ages 12 months to 18 years
- Conditions the study is for
- Celiac Disease in Children
- What is being tested?
- DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac Disease
- How many people
- 508 participants
- Where
- 1 siteNetherlands
- Study dates
- 1 Sep 2022to 1 Nov 2024
- How long will I take part?
- 1 Year
- 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 12 months to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Study population: Phase 1: From 50 children attending the LUMC dept.of Pediatrics because of suspected CD in whom traditional HLA-typing is part of their standard of care or from children with diagnosed CD in whom their HLA typing is already known. The LUMC is a reference centre for CD in children. On the outpatient clinic, more than 90 children per 6 months will be seeing with (the suspicion) of CD and more than 500 children visit the clinic for the annual follow up of CD, which means that the number needed to validated the HLA-results are realistic. Phase 2 : All parents of symptomatic children, 1-4 years of age, who visit the Preventive YHCC in the region of Kennemerland, will be asked to participate in this study.
Who may be able to join
- Phase 1:
- age 1-18 years,
- consultation at the LUMC for (suspicion of) CD,
- parents have a sufficient knowledge of Dutch language,
- written informed consent from child and/or parent
- Phase 2:
Show all 12Show fewer
- age 12 months to 4 years,
- at least one of the 10 CD-related symptoms
- not diagnosed with CD,
- not on a GFD,
- parents have a sufficient knowledge of Dutch language,
- written informed consent from the parent(s)
Who cannot join
- Phase 1 and 2:
- no informed consent,
- insufficient knowledge of Dutch language and/or inability to understand the information provided,
- bleeding disorders.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Leiden University Medical Centre (LUMC)
Leiden, South Holland, 2333 ZA
About this study
Official title: "Adding DNA-test for Screening of HLA-DQ2 and DQ8 to Improve the Early Diagnosis of Celiac Disease at the Dutch Preventive Youth Healthcare Centres (GLUTEN-GEN)"
Celiac Disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten containing cereals from the normal diet, among others wheat, rye and barley. The disease is characterized by a variable combination of gluten-dependent clinical manifestations, CD specific antibodies, human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 haplotypes and chronic inflammation of the small bowel.CD is one of the most common lifelong food- related disorders; it has a frequency of 1% in the general population: this corresponds to 170.000 persons in the Netherlands, and of them at least 30.000 children. However, CD is frequently unrecognized, partially because of its variable clinical presentations and symptoms. That timely diagnosis and treatment of CD could be achieved by active case-finding, show the preliminary results of the ongoing ZonMw sponsored project GLUTENSCREEN (531002001; www.glutenscreen.nl). Currently, HLA-typing is not a part of GLUTENSCREEN because current technique presents important drawbacks in settings without the availability of a laboratory. We here propose to develop a novel test for DNA isolation for HLA typing extracted from the dried blood spots obtained from the POCT at the Preventive YHCCs for early detection of CD. Repeated testing for CD could be omitted in children tested HLA-DQ2/8 negative, this reflects to 60% of the targeted population. To embed this technique in the case finding setting at the YHCCs, the test will be offered to a significant part of the general Dutch population between 0-4 years old, since more than 95% of the general population visit the YHCC. Primary Objective: To validate the HLA-DQ typing in blood taken by a fingerprick; to make it feasible in the regular Preventive YHCCs organization. Study population: Phase 1: From 50 children attending the LUMC dept. of Pediatrics because of suspected CD in whom traditional HLA-typing is part of their standard of care or from children with diagnosed CD in whom their HLA typing is already known. Phase 2: All parents of symptomatic children, 1-4 years of age, who visit the Preventive YHCC in the region of Kennemerland, will be asked to participate in this study.
Read the detailed description
Celiac Disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten containing cereals from the normal diet, among others wheat, rye and barley. The disease is characterized by a variable combination of gluten-dependent clinical manifestations, CD specific antibodies, human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 haplotypes and chronic inflammation of the small bowel[1,2]. T-cells in the lamina propria of the small bowel recognize the gluten peptides when they are bound to the HLA class II specificities DQ2 and/or DQ8 on antigen-presenting cells.
CD is one of the most common lifelong food- related disorders; it has a frequency of 1% in the general population: this corresponds to 170.000 persons in the Netherlands, and of them at least 30.000 children[3-7]. However, CD is frequently unrecognized, partially because of its variable clinical presentations and symptoms, ranging from malabsorption with chronic diarrhoea, poor growth in children and weight loss, to nonspecific signs and symptoms like chronic fatigue, osteoporosis/reduced bone mineral density, gastrointestinal symptoms or elevated liver enzymes [5,7,8]. Unrecognized and thereby undiagnosed and untreated disease is associated with short- and long-term complications such as delayed puberty, neuropsychiatric disturbances, associated autoimmune disease, miscarriages, small-for-date-births, osteoporosis, and, rarely, malignancy. CD has a considerable health burden for society and yields extensive negative economic consequences, thereby presenting a resource challenge for current and future health systems [9]. Once diagnosed, the patient's health status improves after treatment with a gluten free diet (GFD).
That timely diagnosis and treatment of CD could be achieved by active case-finding, show the preliminary results of the ongoing ZonMw sponsored project GLUTENSCREEN (531002001; www.glutenscreen.nl). In this active case finding project, started at February 2019, all children aged 1-4 years who attend the Preventive Youth Health Care Centres (YHCCs) in the region of Kennemerland are yearly assessed for 10 CD-related symptoms during their regular consultation. If a child has one or more symptoms, the parents of the child are invited to participate. After informed consent, a point of care test (POCT) assessing CD-specific antibodies against tissue-transglutaminase (TGA) from a droplet of blood, is performed onsite at the YHCCs. If the POCT is positive (TGA present), CD is highly suspected and the child is referred to the Leiden University Medical Centre (LUMC) for diagnosis according to the standard of care[1,2]. The preliminary results of GLUTENSCREEN are beyond expectations: From the 14.917 children attending the YHCCs, 5.512 (37.0%) of them had one or more CD-related symptoms.
The parents of 3.203 (58.1%) children gave informed consent for a POC-test. In 61 (1.9%) children the POC-test was positive. After additional investigations at our hospital, CD was confirmed in 55 children (1.7% of the tested children) (serum IgA TGA >10xULN and IgA against endomysium (EMA) positive) and ruled out in 5 children with dubious/positive POC test: in two children HLA-DQ2/8 was negative with negative TGA in serum (ELISA-test), in 3 children with TGA <10 x ULN (ELISA-test) in whom small bowel biopsies showed Marsh 1 lesions. One child still needs to be seen in the hospital (parents refused till now) (www.glutenscreen.nl). From the parents who were invited for GLUTENSCREEN, almost 80% is willing to participate if the POCT could be performed during the regular visit at the YHCC. All health care professionals reported that early CD detection by case-finding adds value to the preventive care they offer at the YHCCs.
These preliminary results of our active CD case-finding project at the Preventive YHCCs in the Netherlands illustrate that early detection of CD at the Preventive YHC is feasible and well-accepted by parents and health care professionals.
In GLUTENSCREEN all symptomatic children will be annually tested for CD at the Preventive YHCCs till the age of 4 years. In the region Kennemerland, GLUTENSCREEN has already been implemented in the regular care and POCT will be performed during consultation. However, the development of CD requires genetic susceptibility, present in 40% of the general population. Since the disease almost exclusively occurs in individuals with the human leukocyte antigen (HLA)-DQ2 and/or HLA- DQ8 haplotypes, codified by chromosome 6. The absence of HLA-DQ2/-DQ8 can exclude the possibility or future development of CD with a certainty close to 100%. Because of the high negative predictive value of HLA-typing for development of CD, repeated CD testing will be unnecessary in HLA-DQ2/DQ8 negative individuals (60% of the general population) [10].
Currently, HLA-typing is not a part of GLUTENSCREEN because current technique presents important drawbacks in settings without the availability of a laboratory, like the Preventive Care setting as the YHCCs, since it requires DNA extraction. Material for DNA extraction is usually obtained from whole blood (minimum quantity 4-5 ml) or from other cells, such as buccal mucosa. However, venipunctures are not feasible at the YHCCs and buccal mucosa DNA extraction in children is time-consuming.
We here propose to validate and implement the test for DNA isolation for HLA typing extracted from the dried blood spots to early detection for CD on the Preventive YHCCs.
Other projects have shown that the usage of real-time polymerase chain reaction (RT-PCR) on DNA acquired from dried blood samples is successful and can easily be applied to HLA-DQ2/DQ8 typing in this setting[11].
Adding HLA-DQ2/8 typing to the case finding strategy for CD at the Preventive YHCC is innovative since HLA-typing for CD has not previously been done in dried blood spots in the proposed setting. Furthermore, embedding this technique represents a novel approach to active case-finding of CD and consequently will improve secondary prevention of CD by early diagnosis at the Preventive YHCCs.
The outcome of the proposed study will have impact on the active case finding procedure of CD at the YHCCs. Repeated testing for CD could be omitted in children tested HLA-DQ2/8 negative, this reflects to 60% of the targeted population. This study will result in:
- More efficient and decrease of the burden of the HLA-DQ2/8 negative children: less children have to be tested.
- Clarity of the acceptability of HLA typing for CD in parents from young children.
- Costs saving by reducing unnecessary follow up of children. To embed this technique in the case finding setting at the YHCCs, the test will be offered to a significant part of the general Dutch population between 0-4 years old, since more than 95% of the general population visit the YHCC.
- Consult references at the end of this document
- Conditions
- Celiac Disease in Children
- Being tested
- DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac Disease
- Keywords
- Coeliac disease, Preventive Youth Health Care Center
- Medical subject headings
- Celiac Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac DiseaseOther
Phase 1 and 2: After blood collection (in combination with regular care) and informed consent, a blood droplet obtained by an additional fingerprick (Phase 1 and just an extra droplet from an existing finger prick for Phase 2) will be deposited on filter paper S\&S 903™ (Schleicher and Schuell). DNA will be isolated using the QIAamp method designated for this purpose from dried blood spots (Qiagen). The results of the HLA-DQ2 and DQ8-typing using the dried blood spots will be compared with the results of the traditional HLA-typing. Factors that may influence the quality of the material will be taken into account in the validation process.
| Study group | Role | What they receive |
|---|---|---|
| Phase 1 Cohort (Validation of HLA- DQ2/8 typing) | Children (1-18 years old) coming for consultation at the LUMC for (suspicion of) CD Receives: Other: DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac Disease | |
| Phase 2 Cohort (Implementation of HLA-DQ2/8 typing on the Preventive YHCCs) | Children (12 months to 4 years old), at least with one of the 10 CD-related symptoms, not diagnosed with CD, and not on a GFD, Receives: Other: DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac Disease |
What is being measured
The primary outcome is the main question the study is designed to answer.
Sensitivity and specificity of the HLA-test in dried blood spots will be calculated (Phase 1)
The results of the HLA-DQ2 and DQ8-typing using the dried blood spots will be compared with the results of the traditional HLA-typing. DNA extraction for HLA-DQ typing from dry blood spots will be performed using the QIAamp method [12-15]. A protocol to isolate DNA has been developed and the isolation is executable by all the well skilled laboratory analysts. DNA extraction per sample takes about 15 minutes and it is possible to determine several samples at the same time. The equipment and optical technology are already present at the LUMC.
Measured: Month 6 to month 9 (total duration of the study: 18 months)
Prevalence of HLA-DQ2/8 in the general population (Phase 2) population (parents) and the health care professionals.(Phase 2)
Children with positive HLA-DQ2/8 typing (n/%), Children with negative HLA-DQ2/8 typing (n/%), Children in whom the test failed (including reason), Evaluation of the acceptance and impact of the HLA-typing for CD by the Dutchpopulation (parents) and the health care professionals For the HLA-DQ typing approximately 15 μL is necessary which corresponds with 1-2 droplets of blood. After informed consent, an extra droplet of blood will be collected for the novel HLA-DQ2/8 typing by the finger prick when performing the POCT for TGA determination as done in GLUTENSCREEN. The filter-papers will be stored, at room temperature, safely at the YHCCs. Once a week, all the collected filter papers with dried blood spots will be sent to the department of the Immunology in specially marked envelops. After the DNA isolation, HLA-DQ typing and interpretation.
Measured: Month 9 to month 12 (after the validation phase 1)
Secondary outcomes (1)
Cost-effectiveness of the investigational strategy (Time investment by medical and nursing staff at the YHCCs (sec), costs of the investigational strategy (time, materials) (€))
To evaluate the cost-effectiveness of case finding with and without HLA-DQ2/8 typing. This part of the study will be done by the health economist. Factors that will be included are cost for: the novel genetic test, health care professionals at the YHCC and laboratorial, storage and transport of the material for the genetic test. These costs will compared to the costs in the situation without HLA-DQ2/8 testing as done in GLUTENSCREEN
Measured: Month 9 to month 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Dec 2023
- Study start1 Sep 2022
- Primary completion1 May 2024 (estimated)
- Study completion1 Nov 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (21)Papers the sponsor has linked to this study.
- Other trials for Celiac Disease in ChildrenStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe 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
- 508 participants (estimated)
- Target duration
- 1 Year
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Principal investigator, crmeijerboekel, Leiden University Medical Center
- Investigators
- Caroline R Meijer-Boekel, PhD, Principal investigator, Leiden University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06179121
- Sponsor's protocol ID
- P23.025 (METC LDD)
- Other IDs
- 05550402110016
- Acronym
- GLUTEN-GEN
- Status last verified
- Dec 2023
- First submitted
- 12 Dec 2023
- Last updated
- 21 Dec 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Maki M, Ribes-Koninckx C, Ventura A, Zimmer KP; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):136-60. doi: 10.1097/MPG.0b013e31821a23d0.
PubMed 22197856Jansson-Knodell CL, Hujoel IA, West CP, Taneja V, Prokop LJ, Rubio-Tapia A, Murray JA. Sex Difference in Celiac Disease in Undiagnosed Populations: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2019 Sep;17(10):1954-1968.e13. doi: 10.1016/j.cgh.2018.11.013. Epub 2018 Nov 16.
PubMed 30448593Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, Kelly CP, Ahuja V, Makharia GK. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018 Jun;16(6):823-836.e2. doi: 10.1016/j.cgh.2017.06.037. Epub 2018 Mar 16.
PubMed 29551598Lindfors K, Ciacci C, Kurppa K, Lundin KEA, Makharia GK, Mearin ML, Murray JA, Verdu EF, Kaukinen K. Coeliac disease. Nat Rev Dis Primers. 2019 Jan 10;5(1):3. doi: 10.1038/s41572-018-0054-z.
PubMed 30631077Jansen M, van Zelm M, Groeneweg M, Jaddoe V, Dik W, Schreurs M, Hooijkaas H, Moll H, Escher J. The identification of celiac disease in asymptomatic children: the Generation R Study. J Gastroenterol. 2018 Mar;53(3):377-386. doi: 10.1007/s00535-017-1354-x. Epub 2017 Jun 6.
PubMed 28589338Csizmadia CG, Mearin ML, von Blomberg BM, Brand R, Verloove-Vanhorick SP. An iceberg of childhood coeliac disease in the Netherlands. Lancet. 1999 Mar 6;353(9155):813-4. doi: 10.1016/S0140-6736(99)00243-3. No abstract available.
PubMed 10459972Steens RF, Csizmadia CG, George EK, Ninaber MK, Hira Sing RA, Mearin ML. A national prospective study on childhood celiac disease in the Netherlands 1993-2000: an increasing recognition and a changing clinical picture. J Pediatr. 2005 Aug;147(2):239-43. doi: 10.1016/j.jpeds.2005.04.013.
PubMed 16126057Meijer CR, Schweizer JJ, Peeters A, Putter H, Mearin ML. Efficient implementation of the 'non-biopsy approach' for the diagnosis of childhood celiac disease in the Netherlands: a national prospective evaluation 2010-2013. Eur J Pediatr. 2021 Aug;180(8):2485-2492. doi: 10.1007/s00431-021-04068-1. Epub 2021 Apr 15.
PubMed 33856540Shamir R, Hernell O, Leshno M. Cost-effectiveness analysis of screening for celiac disease in the adult population. Med Decis Making. 2006 May-Jun;26(3):282-93. doi: 10.1177/0272989X06289012.
PubMed 16751327Wolters VM, Wijmenga C. Genetic background of celiac disease and its clinical implications. Am J Gastroenterol. 2008 Jan;103(1):190-5. doi: 10.1111/j.1572-0241.2007.01471.x.
PubMed 18184122Tran TM, Aghili A, Li S, Ongoiba A, Kayentao K, Doumbo S, Traore B, Crompton PD. A nested real-time PCR assay for the quantification of Plasmodium falciparum DNA extracted from dried blood spots. Malar J. 2014 Oct 4;13:393. doi: 10.1186/1475-2875-13-393.
PubMed 25282516McCabe ER. Utility of PCR for DNA analysis from dried blood spots on filter paper blotters. PCR Methods Appl. 1991 Nov;1(2):99-106. doi: 10.1101/gr.1.2.99. No abstract available.
PubMed 1842936Shaik M, Shivanna DK, Kamate M, Ab V, Tp KV. Single Lysis-Salting Out Method of Genomic DNA Extraction From Dried Blood Spots. J Clin Lab Anal. 2016 Nov;30(6):1009-1012. doi: 10.1002/jcla.21972. Epub 2016 Apr 13.
PubMed 27074880Karhus LL, Thuesen BH, Skaaby T, Rumessen JJ, Linneberg A. The distribution of HLA DQ2 and DQ8 haplotypes and their association with health indicators in a general Danish population. United European Gastroenterol J. 2018 Jul;6(6):866-878. doi: 10.1177/2050640618765506. Epub 2018 Mar 8.
PubMed 30023064Ruiz-Ortiz E, Montraveta M, Cabre E, Herrero-Mata MJ, Pujol-Borrell R, Palou E, Faner R. HLA-DQ2/DQ8 and HLA-DQB1*02 homozygosity typing by real-time polymerase chain reaction for the assessment of celiac disease genetic risk: evaluation of a Spanish celiac population. Tissue Antigens. 2014 Dec;84(6):545-53. doi: 10.1111/tan.12472.
PubMed 25413104
Study at a glance
From the registry record, last updated by the sponsor on 21 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- "Adding DNA-test for Screening of HLA-DQ2 and DQ8 to Improve the Early Diagnosis of Celiac Disease at the Dutch Preventive Youth Healthcare Centres (GLUTEN-GEN)"
- ClinicalTrials.gov ID
- NCT06179121
- Acronym / sponsor ID
- GLUTEN-GEN / P23.025 (METC LDD)
- Conditions
- Celiac Disease in Children
- Keywords
- Coeliac disease, Preventive Youth Health Care Center
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 508 participants (estimated)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- 1 Sep 2022 (actual)
- Primary completion
- 1 May 2024 (estimated)
- Study completion
- 1 Nov 2024 (estimated)
- First posted
- 21 Dec 2023 (actual)
- 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.
Celiac Disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten containing cereals from the normal diet, among others wheat, rye and barley. The disease is characterized by a variable combination of gluten-dependent clinical manifestations, CD specific antibodies, human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 haplotypes and chronic inflammation of the small bowel.CD is one of the most common lifelong food- related disorders; it has a frequency of 1% in the general population: this corresponds to 170.000 persons in the Netherlands, and of them at least 30.000 children. However, CD is frequently unrecognized, partially because of its variable clinical presentations and symptoms. That timely diagnosis and treatment of CD could be achieved by active case-finding, show the preliminary results of the ongoing ZonMw sponsored project GLUTENSCREEN (531002001; www.glutenscreen.nl). Currently, HLA-typing is not a part of GLUTENSCREEN because current technique presents important drawbacks in settings without the availability of a laboratory. We here propose to develop a novel test for DNA isolation for HLA typing extracted from the dried blood spots obtained from the POCT at the Preventive YHCCs for early detection of CD. Repeated testing for CD could be omitted in children tested HLA-DQ2/8 negative, this reflects to 60% of the targeted population. To embed this technique in the case finding setting at the YHCCs, the test will be offered to a significant part of the general Dutch population between 0-4 years old, since more than 95% of the general population visit the YHCC. Primary Objective: To validate the HLA-DQ typing in blood taken by a fingerprick; to make it feasible in the regular Preventive YHCCs organization. Study population: Phase 1: From 50 children attending the LUMC dept. of Pediatrics because of suspected CD in whom traditional HLA-typing is part of their standard of care or from children with diagnosed CD in whom their HLA typing is already known. Phase 2: All parents of symptomatic children, 1-4 years of age, who visit the Preventive YHCC in the region of Kennemerland, will be asked to participate in this study.
Detailed description
Celiac Disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten containing cereals from the normal diet, among others wheat, rye and barley. The disease is characterized by a variable combination of gluten-dependent clinical manifestations, CD specific antibodies, human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 haplotypes and chronic inflammation of the small bowel[1,2]. T-cells in the lamina propria of the small bowel recognize the gluten peptides when they are bound to the HLA class II specificities DQ2 and/or DQ8 on antigen-presenting cells.
CD is one of the most common lifelong food- related disorders; it has a frequency of 1% in the general population: this corresponds to 170.000 persons in the Netherlands, and of them at least 30.000 children[3-7]. However, CD is frequently unrecognized, partially because of its variable clinical presentations and symptoms, ranging from malabsorption with chronic diarrhoea, poor growth in children and weight loss, to nonspecific signs and symptoms like chronic fatigue, osteoporosis/reduced bone mineral density, gastrointestinal symptoms or elevated liver enzymes [5,7,8]. Unrecognized and thereby undiagnosed and untreated disease is associated with short- and long-term complications such as delayed puberty, neuropsychiatric disturbances, associated autoimmune disease, miscarriages, small-for-date-births, osteoporosis, and, rarely, malignancy. CD has a considerable health burden for society and yields extensive negative economic consequences, thereby presenting a resource challenge for current and future health systems [9]. Once diagnosed, the patient's health status improves after treatment with a gluten free diet (GFD).
That timely diagnosis and treatment of CD could be achieved by active case-finding, show the preliminary results of the ongoing ZonMw sponsored project GLUTENSCREEN (531002001; www.glutenscreen.nl). In this active case finding project, started at February 2019, all children aged 1-4 years who attend the Preventive Youth Health Care Centres (YHCCs) in the region of Kennemerland are yearly assessed for 10 CD-related symptoms during their regular consultation. If a child has one or more symptoms, the parents of the child are invited to participate. After informed consent, a point of care test (POCT) assessing CD-specific antibodies against tissue-transglutaminase (TGA) from a droplet of blood, is performed onsite at the YHCCs. If the POCT is positive (TGA present), CD is highly suspected and the child is referred to the Leiden University Medical Centre (LUMC) for diagnosis according to the standard of care[1,2]. The preliminary results of GLUTENSCREEN are beyond expectations: From the 14.917 children attending the YHCCs, 5.512 (37.0%) of them had one or more CD-related symptoms.
The parents of 3.203 (58.1%) children gave informed consent for a POC-test. In 61 (1.9%) children the POC-test was positive. After additional investigations at our hospital, CD was confirmed in 55 children (1.7% of the tested children) (serum IgA TGA >10xULN and IgA against endomysium (EMA) positive) and ruled out in 5 children with dubious/positive POC test: in two children HLA-DQ2/8 was negative with negative TGA in serum (ELISA-test), in 3 children with TGA <10 x ULN (ELISA-test) in whom small bowel biopsies showed Marsh 1 lesions. One child still needs to be seen in the hospital (parents refused till now) (www.glutenscreen.nl). From the parents who were invited for GLUTENSCREEN, almost 80% is willing to participate if the POCT could be performed during the regular visit at the YHCC. All health care professionals reported that early CD detection by case-finding adds value to the preventive care they offer at the YHCCs.
These preliminary results of our active CD case-finding project at the Preventive YHCCs in the Netherlands illustrate that early detection of CD at the Preventive YHC is feasible and well-accepted by parents and health care professionals.
In GLUTENSCREEN all symptomatic children will be annually tested for CD at the Preventive YHCCs till the age of 4 years. In the region Kennemerland, GLUTENSCREEN has already been implemented in the regular care and POCT will be performed during consultation. However, the development of CD requires genetic susceptibility, present in 40% of the general population. Since the disease almost exclusively occurs in individuals with the human leukocyte antigen (HLA)-DQ2 and/or HLA- DQ8 haplotypes, codified by chromosome 6. The absence of HLA-DQ2/-DQ8 can exclude the possibility or future development of CD with a certainty close to 100%. Because of the high negative predictive value of HLA-typing for development of CD, repeated CD testing will be unnecessary in HLA-DQ2/DQ8 negative individuals (60% of the general population) [10].
Currently, HLA-typing is not a part of GLUTENSCREEN because current technique presents important drawbacks in settings without the availability of a laboratory, like the Preventive Care setting as the YHCCs, since it requires DNA extraction. Material for DNA extraction is usually obtained from whole blood (minimum quantity 4-5 ml) or from other cells, such as buccal mucosa. However, venipunctures are not feasible at the YHCCs and buccal mucosa DNA extraction in children is time-consuming.
We here propose to validate and implement the test for DNA isolation for HLA typing extracted from the dried blood spots to early detection for CD on the Preventive YHCCs.
Other projects have shown that the usage of real-time polymerase chain reaction (RT-PCR) on DNA acquired from dried blood samples is successful and can easily be applied to HLA-DQ2/DQ8 typing in this setting[11].
Adding HLA-DQ2/8 typing to the case finding strategy for CD at the Preventive YHCC is innovative since HLA-typing for CD has not previously been done in dried blood spots in the proposed setting. Furthermore, embedding this technique represents a novel approach to active case-finding of CD and consequently will improve secondary prevention of CD by early diagnosis at the Preventive YHCCs.
The outcome of the proposed study will have impact on the active case finding procedure of CD at the YHCCs. Repeated testing for CD could be omitted in children tested HLA-DQ2/8 negative, this reflects to 60% of the targeted population. This study will result in:
- More efficient and decrease of the burden of the HLA-DQ2/8 negative children: less children have to be tested.
- Clarity of the acceptability of HLA typing for CD in parents from young children.
- Costs saving by reducing unnecessary follow up of children. To embed this technique in the case finding setting at the YHCCs, the test will be offered to a significant part of the general Dutch population between 0-4 years old, since more than 95% of the general population visit the YHCC.
- Consult references at the end of this document
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 1 Year
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Phase 1 Cohort (Validation of HLA- DQ2/8 typing) | – | Other: DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac DiseaseChildren (1-18 years old) coming for consultation at the LUMC for (suspicion of) CD |
| Phase 2 Cohort (Implementation of HLA-DQ2/8 typing on the Preventive YHCCs) | – | Other: DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac DiseaseChildren (12 months to 4 years old), at least with one of the 10 CD-related symptoms, not diagnosed with CD, and not on a GFD, |
Who may qualify
- Ages
- 12 months to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
- Study population
- Phase 1: From 50 children attending the LUMC dept.of Pediatrics because of suspected CD in whom traditional HLA-typing is part of their standard of care or from children with diagnosed CD in whom their HLA typing is already known. The LUMC is a reference centre for CD in children. On the outpatient clinic, more than 90 children per 6 months will be seeing with (the suspicion) of CD and more than 500 children visit the clinic for the annual follow up of CD, which means that the number needed to validated the HLA-results are realistic. Phase 2 : All parents of symptomatic children, 1-4 years of age, who visit the Preventive YHCC in the region of Kennemerland, will be asked to participate in this study.
Key inclusion criteria (12 listed)
- age 1-18 years,
- consultation at the LUMC for (suspicion of) CD,
- parents have a sufficient knowledge of Dutch language,
- written informed consent from child and/or parent
- age 12 months to 4 years,
Key exclusion criteria (4 listed)
- no informed consent,
- insufficient knowledge of Dutch language and/or inability to understand the information provided,
- bleeding disorders.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DNA test for screening HLA-DQ2 and DQ8 from dried blood spots to early detect Celiac DiseasePhase 1 and 2: After blood collection (in combination with regular care) and informed consent, a blood droplet obtained by an additional fingerprick (Phase 1 and just an extra droplet from an existing finger prick for Phase 2) will be deposited on filter paper S\&S 903™ (Schleicher and Schuell). DNA will be isolated using the QIAamp method designated for this purpose from dried blood spots (Qiagen). The results of the HLA-DQ2 and DQ8-typing using the dried blood spots will be compared with the results of the traditional HLA-typing. Factors that may influence the quality of the material will be taken into account in the validation process. | Other | Phase 1 Cohort (Validation of HLA- DQ2/8 typing), Phase 2 Cohort (Implementation of HLA-DQ2/8 typing on the Preventive YHCCs) |
Primary outcome
Sensitivity and specificity of the HLA-test in dried blood spots will be calculated (Phase 1)
Time frame: Month 6 to month 9 (total duration of the study: 18 months)
The results of the HLA-DQ2 and DQ8-typing using the dried blood spots will be compared with the results of the traditional HLA-typing. DNA extraction for HLA-DQ typing from dry blood spots will be performed using the QIAamp method [12-15]. A protocol to isolate DNA has been developed and the isolation is executable by all the well skilled laboratory analysts. DNA extraction per sample takes about 15 minutes and it is possible to determine several samples at the same time. The equipment and optical technology are already present at the LUMC.
Prevalence of HLA-DQ2/8 in the general population (Phase 2) population (parents) and the health care professionals.(Phase 2)
Time frame: Month 9 to month 12 (after the validation phase 1)
Children with positive HLA-DQ2/8 typing (n/%), Children with negative HLA-DQ2/8 typing (n/%), Children in whom the test failed (including reason), Evaluation of the acceptance and impact of the HLA-typing for CD by the Dutchpopulation (parents) and the health care professionals For the HLA-DQ typing approximately 15 μL is necessary which corresponds with 1-2 droplets of blood. After informed consent, an extra droplet of blood will be collected for the novel HLA-DQ2/8 typing by the finger prick when performing the POCT for TGA determination as done in GLUTENSCREEN. The filter-papers will be stored, at room temperature, safely at the YHCCs. Once a week, all the collected filter papers with dried blood spots will be sent to the department of the Immunology in specially marked envelops. After the DNA isolation, HLA-DQ typing and interpretation.
1 secondary outcome
Cost-effectiveness of the investigational strategy (Time investment by medical and nursing staff at the YHCCs (sec), costs of the investigational strategy (time, materials) (€))
Time frame: Month 9 to month 12
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Dec 2023.
- Results publication: PubMed 22197856Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Maki M, Ribes-Koninckx C, Ventura A, Zimmer KP; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):136-60. doi: 10.1097/MPG.0b013e31821a23d0.
- Results publication: PubMed 30448593Jansson-Knodell CL, Hujoel IA, West CP, Taneja V, Prokop LJ, Rubio-Tapia A, Murray JA. Sex Difference in Celiac Disease in Undiagnosed Populations: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2019 Sep;17(10):1954-1968.e13. doi: 10.1016/j.cgh.2018.11.013. Epub 2018 Nov 16.
- Results publication: PubMed 29551598Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, Kelly CP, Ahuja V, Makharia GK. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018 Jun;16(6):823-836.e2. doi: 10.1016/j.cgh.2017.06.037. Epub 2018 Mar 16.
- Results publication: PubMed 30631077Lindfors K, Ciacci C, Kurppa K, Lundin KEA, Makharia GK, Mearin ML, Murray JA, Verdu EF, Kaukinen K. Coeliac disease. Nat Rev Dis Primers. 2019 Jan 10;5(1):3. doi: 10.1038/s41572-018-0054-z.
- Results publication: PubMed 28589338Jansen M, van Zelm M, Groeneweg M, Jaddoe V, Dik W, Schreurs M, Hooijkaas H, Moll H, Escher J. The identification of celiac disease in asymptomatic children: the Generation R Study. J Gastroenterol. 2018 Mar;53(3):377-386. doi: 10.1007/s00535-017-1354-x. Epub 2017 Jun 6.
- Results publication: PubMed 10459972Csizmadia CG, Mearin ML, von Blomberg BM, Brand R, Verloove-Vanhorick SP. An iceberg of childhood coeliac disease in the Netherlands. Lancet. 1999 Mar 6;353(9155):813-4. doi: 10.1016/S0140-6736(99)00243-3. No abstract available.
- Results publication: PubMed 16126057Steens RF, Csizmadia CG, George EK, Ninaber MK, Hira Sing RA, Mearin ML. A national prospective study on childhood celiac disease in the Netherlands 1993-2000: an increasing recognition and a changing clinical picture. J Pediatr. 2005 Aug;147(2):239-43. doi: 10.1016/j.jpeds.2005.04.013.
- Results publication: PubMed 33856540Meijer CR, Schweizer JJ, Peeters A, Putter H, Mearin ML. Efficient implementation of the 'non-biopsy approach' for the diagnosis of childhood celiac disease in the Netherlands: a national prospective evaluation 2010-2013. Eur J Pediatr. 2021 Aug;180(8):2485-2492. doi: 10.1007/s00431-021-04068-1. Epub 2021 Apr 15.
- Results publication: PubMed 16751327Shamir R, Hernell O, Leshno M. Cost-effectiveness analysis of screening for celiac disease in the adult population. Med Decis Making. 2006 May-Jun;26(3):282-93. doi: 10.1177/0272989X06289012.
- Results publication: PubMed 18184122Wolters VM, Wijmenga C. Genetic background of celiac disease and its clinical implications. Am J Gastroenterol. 2008 Jan;103(1):190-5. doi: 10.1111/j.1572-0241.2007.01471.x.
- Results publication: PubMed 25282516Tran TM, Aghili A, Li S, Ongoiba A, Kayentao K, Doumbo S, Traore B, Crompton PD. A nested real-time PCR assay for the quantification of Plasmodium falciparum DNA extracted from dried blood spots. Malar J. 2014 Oct 4;13:393. doi: 10.1186/1475-2875-13-393.
- Results publication: PubMed 1842936McCabe ER. Utility of PCR for DNA analysis from dried blood spots on filter paper blotters. PCR Methods Appl. 1991 Nov;1(2):99-106. doi: 10.1101/gr.1.2.99. No abstract available.
- 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.
Caroline R Meijer-Boekel, PhD principal investigator
Leiden University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Celiac Disease in Children, run by Leiden University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 4 exclusion criteria. 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: status not confirmed, as of the sponsor's last update on 21 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. 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?
Results are not available in the source record.
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?
Sensitivity and specificity of the HLA-test in dried blood spots will be calculated (Phase 1) (time frame: Month 6 to month 9 (total duration of the study: 18 months)). The study lists 2 primary outcomes in all. 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 NCT06179121, which also lists 21 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 21 Dec 2023.