Ignite Creation Date:
2024-05-06 @ 7:53 PM
Last Modification Date:
2024-10-26 @ 3:16 PM
Study NCT ID:
NCT06179121
Status:
ENROLLING_BY_INVITATION
Last Update Posted:
2023-12-21
First Post:
2023-12-12
Brief Title:
Adding DNA-test for Screening of HLA-DQ2 and DQ8 to Improve Early Diagnosis of Celiac Disease
Sponsor:
Leiden University Medical Center
Organization:
Leiden University Medical Center
Study Overview
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
Status:
ENROLLING_BY_INVITATION
Status Verified Date:
2023-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GLUTEN-GEN
Brief 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 antigen HLA-DQ2 or HLA-DQ8 haplotypes and chronic inflammation of the small bowelCD is one of the most common lifelong food- related disorders it has a frequency of 1 in the general population this corresponds to 170000 persons in the Netherlands and of them at least 30000 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 wwwglutenscreennl 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-DQ28 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 bowel12 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 andor 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 170000 persons in the Netherlands and of them at least 30000 children3-7 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 osteoporosisreduced bone mineral density gastrointestinal symptoms or elevated liver enzymes 578 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 patients 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 wwwglutenscreennl 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 care12 The preliminary results of GLUTENSCREEN are beyond expectations From the 14917 children attending the YHCCs 5512 370 of them had one or more CD-related symptoms
The parents of 3203 581 children gave informed consent for a POC-test In 61 19 children the POC-test was positive After additional investigations at our hospital CD was confirmed in 55 children 17 of the tested children serum IgA TGA 10xULN and IgA against endomysium EMA positive and ruled out in 5 children with dubiouspositive POC test in two children HLA-DQ28 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 wwwglutenscreennl 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 andor 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-DQ2DQ8 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-DQ2DQ8 typing in this setting11
Adding HLA-DQ28 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-DQ28 negative this reflects to 60 of the targeted population This study will result in
1 More efficient and decrease of the burden of the HLA-DQ28 negative children less children have to be tested
2 Clarity of the acceptability of HLA typing for CD in parents from young children
3 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
CD is one of the most common lifelong food- related disorders it has a frequency of 1 in the general population this corresponds to 170000 persons in the Netherlands and of them at least 30000 children3-7 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 osteoporosisreduced bone mineral density gastrointestinal symptoms or elevated liver enzymes 578 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 patients 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 wwwglutenscreennl 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 care12 The preliminary results of GLUTENSCREEN are beyond expectations From the 14917 children attending the YHCCs 5512 370 of them had one or more CD-related symptoms
The parents of 3203 581 children gave informed consent for a POC-test In 61 19 children the POC-test was positive After additional investigations at our hospital CD was confirmed in 55 children 17 of the tested children serum IgA TGA 10xULN and IgA against endomysium EMA positive and ruled out in 5 children with dubiouspositive POC test in two children HLA-DQ28 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 wwwglutenscreennl 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 andor 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-DQ2DQ8 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-DQ2DQ8 typing in this setting11
Adding HLA-DQ28 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-DQ28 negative this reflects to 60 of the targeted population This study will result in
1 More efficient and decrease of the burden of the HLA-DQ28 negative children less children have to be tested
2 Clarity of the acceptability of HLA typing for CD in parents from young children
3 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 05550402110016 | OTHER_GRANT | ZonMw Preventie Vroege opsporing program | None |