<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03037190</url>
  </required_header>
  <id_info>
    <org_study_id>LUDU</org_study_id>
    <nct_id>NCT03037190</nct_id>
  </id_info>
  <brief_title>Preservation of Residual Beta Cell Mass and Prevention of Celiac Disease in Children With Recent Onset Type 1 Diabetes</brief_title>
  <acronym>Diabglut</acronym>
  <official_title>Investigation Whether a Gluten Free Diet After the Onset of Type 1 Diabetes (T1D) Can Better Preserve the Remaining Beta Cell Mass and at the Same Time Prevent the Development of Celiac Disease (CD) in These Patients.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lund University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lund University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The overall aim of this project is to investigate whether a gluten free diet after the onset&#xD;
      of type 1 diabetes (T1D) can better preserve the remaining beta cell mass and at the same&#xD;
      time prevent the development of Celiac Disease (CD) in these patients.&#xD;
&#xD;
      Specific aims&#xD;
&#xD;
      • To study whether gluten free diet during one year after the onset of diabetes influence the&#xD;
      appearance and duration of clinical remission in children with Type 1 diabetes.&#xD;
&#xD;
      New data show that a gluten free diet is beneficial concerning the insulin production after&#xD;
      the onset of diabetes. The investigators want to investigate if gluten is a triggering&#xD;
      protein for the destruction of the beta cell function after the onset of diabetes by&#xD;
      comparing children who have a normal diet compared to children with a gluten free diet during&#xD;
      one year after the onset of the disease.&#xD;
&#xD;
        -  To study whether a gluten free diet during one year after the onset of diabetes prevent&#xD;
           the development of Celiac Disease in these children and the impact of having two&#xD;
           diseases It is known that it is almost 10 times more common that children with Type 1&#xD;
           Diabetes (IDDM) develop Celiac Disease (CD) than the general population and that most of&#xD;
           these children (6-7 %) develop CD after the onset of Diabetes and within 5 years. Based&#xD;
           on our new data that CD is preventable to some extent the investigators plan to perform&#xD;
           randomized controlled studies if it is possible to prevent or postpone CD by means after&#xD;
           the onset of IDDM.&#xD;
&#xD;
        -  To investigate the impact of gluten free diet on the regulation of autoimmune responses&#xD;
           The investigators will test the hypothesis that gluten free diet in children with recent&#xD;
           onset T1D will implement immune regulation and inhibit the activation of potentially&#xD;
           autoreactive T cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      General project outline Our aim is to perform a intervention study whether one year gluten&#xD;
      free diet in children with newly diagnosed TID would make it possible to influence the speed&#xD;
      of the beta-cells destruction and if this diet decrease the risk to develop CD after the&#xD;
      disease A power calculation shows that we would need 600 participants to detect clinically&#xD;
      relevant effects (see power calculation). As the power calculation is based on estimated&#xD;
      effects we plan to first perform a pilot study including 100 patients. Based on the results&#xD;
      of the pilot study we then plan to continue to design a larger study to get more robust&#xD;
      information.&#xD;
&#xD;
      All children will also at the start study and, after 1 and 2 years receive a KID-screen form&#xD;
      to study the quality of life of time in children with diabetes and to compare children with&#xD;
      diabetes without CD and to them who will develop or have undiagnosed CD. Furthermore all&#xD;
      children will also be monitored by a dietician during the study period, at onset, after 1 and&#xD;
      2 years according to the content (protein, fat, carbohydrate, gluten and vitamins) during the&#xD;
      study.&#xD;
&#xD;
      Population Consecutive patients with recent onset of diabetes at Swedish paediatric clinics&#xD;
      are given information about the study and they and their parents are asked to participate in&#xD;
      the trial.&#xD;
&#xD;
      Informed consent given by patients and guardians/parents and inclusion criteria are; 1. Type&#xD;
      1 diabetes according to the ADA classification with &lt; 1 months diabetes duration at time of&#xD;
      screening 2. Age 3.00 -17.99 years at time of screening 3. Fasting C-peptide at time of&#xD;
      screening ≥ 0.12 nmol/L Exclusion Criteria&#xD;
&#xD;
        1. Inability or unwillingness to comply with the provisions of this protocol&#xD;
&#xD;
        2. Deemed by the investigator not being able to follow instructions and/or follow the study&#xD;
           protocol Recruitment and Screening Eligible subjects and their parent(s) / guardian(s)&#xD;
           will have the study explained to them, and will receive a written patient information.&#xD;
           If, after this, the subjects agree to participate, they will personally sign and date&#xD;
           the written informed consent form. In accordance with the Declaration of Helsinki, the&#xD;
           investigator must explain to the patient that they have the right to withdraw from the&#xD;
           study at any time, and that this will in no way prejudice their future treatment&#xD;
&#xD;
      Sample size, power calculation:&#xD;
&#xD;
      We are planning the study as a continuous response from independent control and experimental&#xD;
      subjects with 1 control per experimental subject. In a similar study the response within each&#xD;
      subject group was normally distributed with standard deviation 0,19. If the true difference&#xD;
      in the experimental and control means is 0,05 we will need to study 250 subjects and 250&#xD;
      controls to be able to reject the null hypothesis that the population means of the&#xD;
      experimental and control group are equal with a probability (power) 0,8. The Type 1 error&#xD;
      probability associated with this test of this null hypothesis is 0,05. Recalculation of&#xD;
      sample size is needed on a pilot study, which we have chosen to 100 subjects, 50 in each&#xD;
      group. This field also benefit from that smaller and shorter trials are conducted to obtain&#xD;
      initial sense of efficacy prior to undertake a fully powered study.&#xD;
&#xD;
      The risk to develop CD in the children with gluten free diet will be compared to the 8000&#xD;
      children in the BDD who had been followed yearly with transglutaminse autoantibodies for CD.&#xD;
&#xD;
      Study Design The trial is designed as a 2-arm not randomized, open, multicentre study&#xD;
      comparing 1 year of gluten free diet with normal diet. In the pilot study 100 patients will&#xD;
      be recruited at 7 sites in Sweden (and if the pilot study shows expected results we will&#xD;
      include all 43 Swedish pediatric clinics and altogether an estimated 600 patients). The&#xD;
      patients will not be randomized into two parallel groups as it could influence the compliance&#xD;
      to a normal diet. Instead we will recruit group A (50 patients) during the first year and&#xD;
      group B with 50 age and sex-matched patients during the second year. Group A will eat gluten&#xD;
      free diet for a year after the onset of diabetes and B normal diet. Both groups will follow&#xD;
      the same procedures according to the study visits and clinical routines in our diabetes care&#xD;
      and follow up.&#xD;
&#xD;
      Eligibility: Patients who qualify for the study have to have a C-peptide over above 0.12&#xD;
      nmol/L and will be assigned with a number and this screening number together with the&#xD;
      clinics, site number, will be used as patient identification. The patients will be assessed&#xD;
      for eligibility at the screening visit (Visit 1) prior to the start of treatment with&#xD;
      glutenfree diet and screened with a MMTT (mixed meal tolerance test) and fasting C-peptide&#xD;
      levels.&#xD;
&#xD;
      The patients will be followed for a total study period of 60 months which includes not more&#xD;
      than 6 extra visits for the study (however these visits may be combined with regular diabetes&#xD;
      care visits though all children with diabetes use to attend outpatient clinic at least every&#xD;
      3 month and more often at the onset of the disease) Visit 1; 2 month within the onset, MMT&#xD;
      and fasting C-peptide Visit 2; If eligible, randomized to group A (the first 50), contact&#xD;
      with a dietitian, information of GFD, within 3 month from onset Visit 3; at 6 months; fasting&#xD;
      C-peptide, immunological analyses and contact with a dietician; questionnaire and a registry&#xD;
      (before the visit one week registry of the diet intake) Visit 4; at 12 months; MMTT fasting&#xD;
      C-peptide, HbA1c, immunological analyses. HbA1c, immunological analyses for research, contact&#xD;
      with a dietician; questionnaire and a registry (before the visit one week registry of the&#xD;
      diet intake) Visit 5; at 18 months, MMTT fasting C-peptide, HbA1c, immunological analyses.&#xD;
      HbA1c, immunological analyses, including Ttg (transglutaminse) Visit 6; at 24 months, MMTT&#xD;
      fasting C-peptide, HbA1c, immunological analyses. HbA1c, immunological analyses, including&#xD;
      Ttg (transglutaminse) yearly until 60 months. Questionnaire about quality of life and gluten&#xD;
      content.&#xD;
&#xD;
      Both group A and B will have same information and visits according to the diabetes care where&#xD;
      contacts with a dietician is mandatory, but arm A will need special information about a&#xD;
      gluten free diet and will also have x-support according to gluten free products.&#xD;
&#xD;
      Both group A and B will be followed according to CD risk during 5 years with Ttg annually as&#xD;
      a clinical routine.&#xD;
&#xD;
      Experimental strategy&#xD;
&#xD;
      AIM 1&#xD;
&#xD;
        -  To investigate changes in beta-cell function the patients will undergo an MMTT&#xD;
           (measuring C-peptide, 90 minute value and AUCmean 0-120 min) at basile baseline (Visit&#xD;
           1) to 12 and 18 months). Our research nurse will perform this test on all patients&#xD;
           included at the different sites and the samples are analyzed at the Clinical Chemistry&#xD;
           at SUS, Malmö.&#xD;
&#xD;
        -  We will also investigate and compare the proportion of patients with a stimulated&#xD;
           maximum C-peptide level above 0.2 nmol/L after 12 and 18 months respectively as well as&#xD;
           fasting C-peptide, change between baseline and month 6, 12 and 18 months between the&#xD;
           groups.&#xD;
&#xD;
        -  Differences between metabolic control, Hemoglobin A1c (HbA1c), change between baseline&#xD;
           and subsequent visits&#xD;
&#xD;
        -  Hemoglobin A1c (HbA1c, marker of metabolic control)) as marker for long term&#xD;
           hyperglycemia will be analyzed at baseline and subsequent visits in both groups. We will&#xD;
           also study if there are differences in exogenous insulin dose per kg body weight and 24&#xD;
           hours, change between baseline and subsequent visits as indirect marker of beta cell&#xD;
           insulin secretion.&#xD;
&#xD;
      AIM 2 To follow the development of gluten-induced humoral autoimmunity, IgA&#xD;
      anti-tissue-transglutaminase autoantibodies (Ttg) will be determined in blood samples&#xD;
      collected at the onset, before insulin therapy,, and yearly up to five year after the onset&#xD;
      of TID. Ttg autoantibodies will be analyzed by enzyme-linked immunosorbent assay Aim 3&#xD;
&#xD;
      • To investigate the immunoregulatory effect of gluten-free diet we will perform a detailed&#xD;
      analysis of the magnitude and the phenotype of both gliadin- and tTG-specific T cells.&#xD;
      Quantitative analysis of antigen-specific T cells will be performed using multicolor flow&#xD;
      cytometry and cytokine secretion Gender and ethnicity All our data will respect to gender and&#xD;
      ethnicity is evaluated if there are any predictive factors associated: Diabetes is the&#xD;
      autoimmune disease, which is more common in boys than girl, and the reason for this is&#xD;
      unknown and Celiac Disease is more common in girls.&#xD;
&#xD;
      Ethical considerations In spite of a very heavy, intensive, expensive treatment many patients&#xD;
      with TID get life-threatening serious both acute and late complications. At diagnosis many&#xD;
      patients have some slight residual insulin secretion. As long as this is the case it is much&#xD;
      easier to keep blood glucose stable, the incidence of hypoglycaemia decreases as well as the&#xD;
      risk of keto-acidosis. A trial with a gluten free diet is not very complicated and it is safe&#xD;
      but may be a burden for the children and families involved. Gluten free special products are&#xD;
      often more expensive, few products and are often considered not so tasty but when summarizing&#xD;
      the pros and cons, there is a clear possibility of therapeutic benefit of great importance&#xD;
      with no risk.&#xD;
&#xD;
      Clinical implications Toward an individualized treatment: To find predictive a factors&#xD;
      determining the remission period is important for people who develop diabetes. Every month in&#xD;
      remission increase the quality of life, increase metabol control and thereby postpone late&#xD;
      complications. To find triggering factors for to rate of beta-cells destruction unable us to&#xD;
      design a more individualized treatment in respective individual. Increased remission period&#xD;
      and decreased risk of developing Celiac Disease. Gluten free diet is a safe administer, well&#xD;
      tolerable for the patients and the main long-term goal is to find a treatment at onset of&#xD;
      Type 1 diabetes in young patients which is easy and safe and preserve residual insulin&#xD;
      secretion and give the patients a better quality of life, with less acute complications and&#xD;
      in the long run less risk of late complications. The identification of exogenous factors&#xD;
      triggering and driving beta-cell destruction offers a potential means for intervention aimed&#xD;
      at the prevention of T1D. Environmental modification is likely to offer the most powerful&#xD;
      strategy for effective prevention of T1D, because such an approach can target the whole&#xD;
      population or at least that proportion of the population carrying increased genetic disease&#xD;
      susceptibility.&#xD;
&#xD;
      Diet is a cornerstone in the diabetes treatment and individuals with diabetes must always be&#xD;
      much aware of the carbohydrate content in the food which limits the arena of different&#xD;
      beverages and make life more complicated and if the individual has both IDDM and CD this is&#xD;
      even more complicated and limit the social and quality of life. If this study could prevent&#xD;
      some individuals to develop CD it would increase their life quality extensively.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">December 2015</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">December 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>•The trial is designed as a 2-arm not randomized, open, multicentre study comparing 1 year of gluten free diet with normal diet</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Preservation of beta cells function</measure>
    <time_frame>within 2years after the onset of type 1 diabetes</time_frame>
    <description>Differences in c-peptide production between the Groups A and B, 12 and 18 months after the onset of diabetes.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Prevention of Celiac DIsease</measure>
    <time_frame>Five years after the onset of Diabetes</time_frame>
    <description>Differencies in incidence of Celiac Disease between the two groups, after onset of diabetes</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">160</enrollment>
  <condition>Diabetes Mellitus, Type 1</condition>
  <condition>Remission</condition>
  <condition>Celiac Disease in Children</condition>
  <arm_group>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group A:withdrawal of gluten from the diet, Group A will have a gluten free diet for a year after the onset of diabetes</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B normal diet</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Group B will have normal not glutenfree diet, no planned intervention</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>withdrawal of gluten from the diet</intervention_name>
    <description>Gluten free diet the same recommendations as for patients with diabetes and known celiac disease</description>
    <arm_group_label>Group A</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Type 1 diabetes according to the ADA classification with &lt; 1 months diabetes duration&#xD;
             at time of screening&#xD;
&#xD;
          -  Age 3.00 -17.99 years at time of screening&#xD;
&#xD;
          -  Fasting C-peptide at time of screening ≥ 0.12 nmol/L&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability or unwillingness to comply with the provisions of this protocol&#xD;
&#xD;
          -  Deemed by the investigator not being able to follow instructions and/or follow the&#xD;
             study protocol&#xD;
&#xD;
        NB: new ethical approval will be applied for children between 1-3 years of age&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Annelie Carlsson, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Lund University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Annelie Carlsson, MD PhD</last_name>
    <phone>+46768267170</phone>
    <email>annelie.carlsson@med.lu.se</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Iren Tiberg, MD PhD</last_name>
    <email>iren.tiberg@med.lu.se</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Skanes University Hospital</name>
      <address>
        <city>Lund</city>
        <state>Region Skane</state>
        <zip>22185</zip>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Annelie Carlsson, MD PhD</last_name>
      <phone>+46768267170</phone>
      <email>annelie.carlsson@med.lu.se</email>
    </contact>
    <contact_backup>
      <last_name>Iren Tiberg, PhD, nurse</last_name>
      <email>iren.tiberg@med.lu.se</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <reference>
    <citation>Pastore MR, Bazzigaluppi E, Belloni C, Arcovio C, Bonifacio E, Bosi E. Six months of gluten-free diet do not influence autoantibody titers, but improve insulin secretion in subjects at high risk for type 1 diabetes. J Clin Endocrinol Metab. 2003 Jan;88(1):162-5. doi: 10.1210/jc.2002-021177.</citation>
    <PMID>12519846</PMID>
  </reference>
  <reference>
    <citation>Hummel S, Pfluger M, Hummel M, Bonifacio E, Ziegler AG. Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care. 2011 Jun;34(6):1301-5. doi: 10.2337/dc10-2456. Epub 2011 Apr 22.</citation>
    <PMID>21515839</PMID>
  </reference>
  <reference>
    <citation>Sildorf SM, Fredheim S, Svensson J, Buschard K. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012 Jun 21;2012:bcr0220125878. doi: 10.1136/bcr.02.2012.5878.</citation>
    <PMID>22729336</PMID>
  </reference>
  <reference>
    <citation>Ivarsson A, Myleus A, Norstrom F, van der Pals M, Rosen A, Hogberg L, Danielsson L, Halvarsson B, Hammarroth S, Hernell O, Karlsson E, Stenhammar L, Webb C, Sandstrom O, Carlsson A. Prevalence of childhood celiac disease and changes in infant feeding. Pediatrics. 2013 Mar;131(3):e687-94. doi: 10.1542/peds.2012-1015. Epub 2013 Feb 18.</citation>
    <PMID>23420914</PMID>
  </reference>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>January 26, 2017</study_first_submitted>
  <study_first_submitted_qc>January 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 31, 2017</study_first_posted>
  <last_update_submitted>August 22, 2018</last_update_submitted>
  <last_update_submitted_qc>August 22, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Lund University</investigator_affiliation>
    <investigator_full_name>Annelie Carlsson</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Celiac Disease</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03037190
org study id: LUDU
nct id: NCT03037190
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The overall aim of this project is to investigate whether a gluten free diet after the onset
      of type 1 diabetes (T1D) can better preserve the remaining beta cell mass and at the same
      time prevent the development of Celiac Disease (CD) in these patients.

      Specific aims

      • To study whether gluten free diet during one year after the onset of diabetes influence the
      appearance and duration of clinical remission in children with Type 1 diabetes.

      New data show that a gluten free diet is beneficial concerning the insulin production after
      the onset of diabetes. The investigators want to investigate if gluten is a triggering
      protein for the destruction of the beta cell function after the onset of diabetes by
      comparing children who have a normal diet compared to children with a gluten free diet during
      one year after the onset of the disease.

        -  To study whether a gluten free diet during one year after the onset of diabetes prevent
           the development of Celiac Disease in these children and the impact of having two
           diseases It is known that it is almost 10 times more common that children with Type 1
           Diabetes (IDDM) develop Celiac Disease (CD) than the general population and that most of
           these children (6-7 %) develop CD after the onset of Diabetes and within 5 years. Based
           on our new data that CD is preventable to some extent the investigators plan to perform
           randomized controlled studies if it is possible to prevent or postpone CD by means after
           the onset of IDDM.

        -  To investigate the impact of gluten free diet on the regulation of autoimmune responses
           The investigators will test the hypothesis that gluten free diet in children with recent
           onset T1D will implement immune regulation and inhibit the activation of potentially
           autoreactive T cells.
General project outline Our aim is to perform a intervention study whether one year gluten
      free diet in children with newly diagnosed TID would make it possible to influence the speed
      of the beta-cells destruction and if this diet decrease the risk to develop CD after the
      disease A power calculation shows that we would need 600 participants to detect clinically
      relevant effects (see power calculation). As the power calculation is based on estimated
      effects we plan to first perform a pilot study including 100 patients. Based on the results
      of the pilot study we then plan to continue to design a larger study to get more robust
      information.

      All children will also at the start study and, after 1 and 2 years receive a KID-screen form
      to study the quality of life of time in children with diabetes and to compare children with
      diabetes without CD and to them who will develop or have undiagnosed CD. Furthermore all
      children will also be monitored by a dietician during the study period, at onset, after 1 and
      2 years according to the content (protein, fat, carbohydrate, gluten and vitamins) during the
      study.

      Population Consecutive patients with recent onset of diabetes at Swedish paediatric clinics
      are given information about the study and they and their parents are asked to participate in
      the trial.

      Informed consent given by patients and guardians/parents and inclusion criteria are; 1. Type
      1 diabetes according to the ADA classification with < 1 months diabetes duration at time of
      screening 2. Age 3.00 -17.99 years at time of screening 3. Fasting C-peptide at time of
      screening ≥ 0.12 nmol/L Exclusion Criteria

        1. Inability or unwillingness to comply with the provisions of this protocol

        2. Deemed by the investigator not being able to follow instructions and/or follow the study
           protocol Recruitment and Screening Eligible subjects and their parent(s) / guardian(s)
           will have the study explained to them, and will receive a written patient information.
           If, after this, the subjects agree to participate, they will personally sign and date
           the written informed consent form. In accordance with the Declaration of Helsinki, the
           investigator must explain to the patient that they have the right to withdraw from the
           study at any time, and that this will in no way prejudice their future treatment

      Sample size, power calculation:

      We are planning the study as a continuous response from independent control and experimental
      subjects with 1 control per experimental subject. In a similar study the response within each
      subject group was normally distributed with standard deviation 0,19. If the true difference
      in the experimental and control means is 0,05 we will need to study 250 subjects and 250
      controls to be able to reject the null hypothesis that the population means of the
      experimental and control group are equal with a probability (power) 0,8. The Type 1 error
      probability associated with this test of this null hypothesis is 0,05. Recalculation of
      sample size is needed on a pilot study, which we have chosen to 100 subjects, 50 in each
      group. This field also benefit from that smaller and shorter trials are conducted to obtain
      initial sense of efficacy prior to undertake a fully powered study.

      The risk to develop CD in the children with gluten free diet will be compared to the 8000
      children in the BDD who had been followed yearly with transglutaminse autoantibodies for CD.

      Study Design The trial is designed as a 2-arm not randomized, open, multicentre study
      comparing 1 year of gluten free diet with normal diet. In the pilot study 100 patients will
      be recruited at 7 sites in Sweden (and if the pilot study shows expected results we will
      include all 43 Swedish pediatric clinics and altogether an estimated 600 patients). The
      patients will not be randomized into two parallel groups as it could influence the compliance
      to a normal diet. Instead we will recruit group A (50 patients) during the first year and
      group B with 50 age and sex-matched patients during the second year. Group A will eat gluten
      free diet for a year after the onset of diabetes and B normal diet. Both groups will follow
      the same procedures according to the study visits and clinical routines in our diabetes care
      and follow up.

      Eligibility: Patients who qualify for the study have to have a C-peptide over above 0.12
      nmol/L and will be assigned with a number and this screening number together with the
      clinics, site number, will be used as patient identification. The patients will be assessed
      for eligibility at the screening visit (Visit 1) prior to the start of treatment with
      glutenfree diet and screened with a MMTT (mixed meal tolerance test) and fasting C-peptide
      levels.

      The patients will be followed for a total study period of 60 months which includes not more
      than 6 extra visits for the study (however these visits may be combined with regular diabetes
      care visits though all children with diabetes use to attend outpatient clinic at least every
      3 month and more often at the onset of the disease) Visit 1; 2 month within the onset, MMT
      and fasting C-peptide Visit 2; If eligible, randomized to group A (the first 50), contact
      with a dietitian, information of GFD, within 3 month from onset Visit 3; at 6 months; fasting
      C-peptide, immunological analyses and contact with a dietician; questionnaire and a registry
      (before the visit one week registry of the diet intake) Visit 4; at 12 months; MMTT fasting
      C-peptide, HbA1c, immunological analyses. HbA1c, immunological analyses for research, contact
      with a dietician; questionnaire and a registry (before the visit one week registry of the
      diet intake) Visit 5; at 18 months, MMTT fasting C-peptide, HbA1c, immunological analyses.
      HbA1c, immunological analyses, including Ttg (transglutaminse) Visit 6; at 24 months, MMTT
      fasting C-peptide, HbA1c, immunological analyses. HbA1c, immunological analyses, including
      Ttg (transglutaminse) yearly until 60 months. Questionnaire about quality of life and gluten
      content.

      Both group A and B will have same information and visits according to the diabetes care where
      contacts with a dietician is mandatory, but arm A will need special information about a
      gluten free diet and will also have x-support according to gluten free products.

      Both group A and B will be followed according to CD risk during 5 years with Ttg annually as
      a clinical routine.

      Experimental strategy

      AIM 1

        -  To investigate changes in beta-cell function the patients will undergo an MMTT
           (measuring C-peptide, 90 minute value and AUCmean 0-120 min) at basile baseline (Visit
           1) to 12 and 18 months). Our research nurse will perform this test on all patients
           included at the different sites and the samples are analyzed at the Clinical Chemistry
           at SUS, Malmö.

        -  We will also investigate and compare the proportion of patients with a stimulated
           maximum C-peptide level above 0.2 nmol/L after 12 and 18 months respectively as well as
           fasting C-peptide, change between baseline and month 6, 12 and 18 months between the
           groups.

        -  Differences between metabolic control, Hemoglobin A1c (HbA1c), change between baseline
           and subsequent visits

        -  Hemoglobin A1c (HbA1c, marker of metabolic control)) as marker for long term
           hyperglycemia will be analyzed at baseline and subsequent visits in both groups. We will
           also study if there are differences in exogenous insulin dose per kg body weight and 24
           hours, change between baseline and subsequent visits as indirect marker of beta cell
           insulin secretion.

      AIM 2 To follow the development of gluten-induced humoral autoimmunity, IgA
      anti-tissue-transglutaminase autoantibodies (Ttg) will be determined in blood samples
      collected at the onset, before insulin therapy,, and yearly up to five year after the onset
      of TID. Ttg autoantibodies will be analyzed by enzyme-linked immunosorbent assay Aim 3

      • To investigate the immunoregulatory effect of gluten-free diet we will perform a detailed
      analysis of the magnitude and the phenotype of both gliadin- and tTG-specific T cells.
      Quantitative analysis of antigen-specific T cells will be performed using multicolor flow
      cytometry and cytokine secretion Gender and ethnicity All our data will respect to gender and
      ethnicity is evaluated if there are any predictive factors associated: Diabetes is the
      autoimmune disease, which is more common in boys than girl, and the reason for this is
      unknown and Celiac Disease is more common in girls.

      Ethical considerations In spite of a very heavy, intensive, expensive treatment many patients
      with TID get life-threatening serious both acute and late complications. At diagnosis many
      patients have some slight residual insulin secretion. As long as this is the case it is much
      easier to keep blood glucose stable, the incidence of hypoglycaemia decreases as well as the
      risk of keto-acidosis. A trial with a gluten free diet is not very complicated and it is safe
      but may be a burden for the children and families involved. Gluten free special products are
      often more expensive, few products and are often considered not so tasty but when summarizing
      the pros and cons, there is a clear possibility of therapeutic benefit of great importance
      with no risk.

      Clinical implications Toward an individualized treatment: To find predictive a factors
      determining the remission period is important for people who develop diabetes. Every month in
      remission increase the quality of life, increase metabol control and thereby postpone late
      complications. To find triggering factors for to rate of beta-cells destruction unable us to
      design a more individualized treatment in respective individual. Increased remission period
      and decreased risk of developing Celiac Disease. Gluten free diet is a safe administer, well
      tolerable for the patients and the main long-term goal is to find a treatment at onset of
      Type 1 diabetes in young patients which is easy and safe and preserve residual insulin
      secretion and give the patients a better quality of life, with less acute complications and
      in the long run less risk of late complications. The identification of exogenous factors
      triggering and driving beta-cell destruction offers a potential means for intervention aimed
      at the prevention of T1D. Environmental modification is likely to offer the most powerful
      strategy for effective prevention of T1D, because such an approach can target the whole
      population or at least that proportion of the population carrying increased genetic disease
      susceptibility.

      Diet is a cornerstone in the diabetes treatment and individuals with diabetes must always be
      much aware of the carbohydrate content in the food which limits the arena of different
      beverages and make life more complicated and if the individual has both IDDM and CD this is
      even more complicated and limit the social and quality of life. If this study could prevent
      some individuals to develop CD it would increase their life quality extensively.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: •The trial is designed as a 2-arm not randomized, open, multicentre study comparing 1 year of gluten free diet with normal diet
primary purpose: Prevention
masking: None (Open Label)
measure: Preservation of beta cells function
time frame: within 2years after the onset of type 1 diabetes
description: Differences in c-peptide production between the Groups A and B, 12 and 18 months after the onset of diabetes.
measure: Prevention of Celiac DIsease
time frame: Five years after the onset of Diabetes
description: Differencies in incidence of Celiac Disease between the two groups, after onset of diabetes
arm group label: Group A
arm group type: Experimental
description: Group A:withdrawal of gluten from the diet, Group A will have a gluten free diet for a year after the onset of diabetes
arm group label: B normal diet
arm group type: No Intervention
description: Group B will have normal not glutenfree diet, no planned intervention
intervention type: Other
intervention name: withdrawal of gluten from the diet
description: Gluten free diet the same recommendations as for patients with diabetes and known celiac disease
arm group label: Group A
criteria: 
gender: All
minimum age: 3 Years
maximum age: 18 Years
healthy volunteers: No
last name: Annelie Carlsson, MD PhD
role: Principal Investigator
affiliation: Lund University
last name: Annelie Carlsson, MD PhD
phone: +46768267170
email: annelie.carlsson@med.lu.se
last name: Iren Tiberg, MD PhD
email: iren.tiberg@med.lu.se
facility: 
status: Recruiting
contact: 
contact backup: 
country: Sweden
citation: Pastore MR, Bazzigaluppi E, Belloni C, Arcovio C, Bonifacio E, Bosi E. Six months of gluten-free diet do not influence autoantibody titers, but improve insulin secretion in subjects at high risk for type 1 diabetes. J Clin Endocrinol Metab. 2003 Jan;88(1):162-5. doi: 10.1210/jc.2002-021177.
PMID: 12519846
citation: Hummel S, Pfluger M, Hummel M, Bonifacio E, Ziegler AG. Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care. 2011 Jun;34(6):1301-5. doi: 10.2337/dc10-2456. Epub 2011 Apr 22.
PMID: 21515839
citation: Sildorf SM, Fredheim S, Svensson J, Buschard K. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012 Jun 21;2012:bcr0220125878. doi: 10.1136/bcr.02.2012.5878.
PMID: 22729336
citation: Ivarsson A, Myleus A, Norstrom F, van der Pals M, Rosen A, Hogberg L, Danielsson L, Halvarsson B, Hammarroth S, Hernell O, Karlsson E, Stenhammar L, Webb C, Sandstrom O, Carlsson A. Prevalence of childhood celiac disease and changes in infant feeding. Pediatrics. 2013 Mar;131(3):e687-94. doi: 10.1542/peds.2012-1015. Epub 2013 Feb 18.
PMID: 23420914
responsible party type: Principal Investigator
investigator affiliation: Lund University
investigator full name: Annelie Carlsson
investigator title: Associate Professor
mesh term: Celiac Disease
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
sharing ipd: Undecided