Vitamin D in Pediatric Crohn's Disease
Condition: Vitamin D Deficiency
MeSH terms: Crohn Disease; Vitamin D Deficiency
Study type: Interventional
Phase: Phase 4

Summary: 
      Background: Crohn's disease (CD), a type of Inflammatory Bowel Disease (IBD), is a chronic
      relapsing inflammatory disorder of the digestive system. CD affects ~112,000 individuals in
      Canada, of whom 20-25% are diagnosed in childhood or adolescence. The specific cause of CD
      remains unknown; however, it is hypothesized that CD involves a complex interaction of
      several factors, including a genetically susceptible host, the intestinal mucosal immune
      system and microbe population. Several dietary factors have been explored for their potential
      role in the etiology of CD. However, no consensus on the role of diet has emerged. Recent
      evidence suggests a plausible link between a lack of Vitamin D and CD.

      Purpose & Hypothesis: The investigators primary hypothesis is that a greater proportion of
      pediatric CD patients will achieve optimal 25OHD concentration (> 75 nmol/L) on 2000 IU/d
      than 400 IU/d Vitamin D.

      Methods: Pediatric Crohn's Disease patients between 8-18 years of age, and have been in
      remission for at least 4 weeks as indicated by a Pediatric Crohn's Disease Activity Index
      (PCDAI) <10 will be recruited for a double-blind, randomized, controlled trial where they
      will receive one of two dosages of vitamin D (10 or 50 ug/day) and will be asked to continue
      the supplementation for 6 months. Vitamin D levels will be measured in blood at baseline, 3
      months, and 6 months. Dietary vitamin D intake will be estimated using a food frequency and
      lifestyle questionnaire. Data will be analyzed using multiple regression analysis controlling
      for baseline values.

      Expected Results and Conclusions: It is expected that a greater proportion of children
      receiving the 50 ug/day vitamin D supplement will achieve a blood vitamin level >75 nmol/L
      compared to children receiving 10 ug/day. This data will aid policy makers, parents/children
      and healthcare workers in recommending an appropriate vitamin D dosage for the pediatric
      crohn's population.
    

Detailed description: 
      Trial Objectives: Our primary hypothesis is that a greater proportion of pediatric CD
      patients will achieve optimal 25OHD concentration (> 75 nmol/L) on 2000 IU/d than 400 IU/d
      Vitamin D. Our primary objective is to determine whether the proportion of pediatric CD
      patients achieving 25OHD concentration > 75 nmol/L is greater in those receiving 2000 IU/d or
      400 IU/d Vitamin D. Our secondary objective is to determine if patients receiving 2000 IU
      Vitamin D are more likely to have remained in remission [Pediatric Crohn's Disease Activity
      Index (PCDAI) < 20] than those receiving 400 IU/d.

      Study Design: This will be a parallel study design with two levels of Vitamin D: 400 IU/d,
      and 2000 IU/d supplement of Vitamin D3.

      Study Duration: 6 Months

      Number of Sites (inside and outside of Canada):

        1. Children's and Women's Hospital of British Columbia

        2. McMaster's Children's Hospital

      List of Investigators:

        -  Tim Green, PhD. Faculty of Land and Food Systems, UBC

        -  Kevan Jacobson MD. Pediatric GI, UBC

        -  Robert Issenman MD. Pediatric GI, McMaster University

        -  Susan Barr PhD. Faculty of Land and Food Systems, UBC Sample Size: Forty-five subjects
           per group will allow us to detect as little as a 20% difference in the proportion of
           participants achieving a 25OHD >75 nmol/L between the two doses with 80% power and a one
           sided of 0.05. Assuming a 10% attrition rate we will need to recruit 50 subjects per
           group. Clinical experience indicates that approximately 50% of pediatric CD patients
           will relapse over 6 months based on an elevated PCDAI (>20). Forty-five subjects per
           group will allow us to detect a 50% difference in CD relapse between the two doses with
           80% power and a one sided of 0.05.

      Patient Population: Pediatric CD patients who are patients of the pediatric gastroenterology
      services of BC and McMaster Children's Hospitals.

      Inclusion Criteria: Patients will be eligible to participate if they have a diagnosis of CD,
      are between 8-18 years of age, and have been in remission for at least 4 weeks as indicated
      by a PCDAI <10.

      Exclusion Criteria: Patients will be ineligible if they have active disease with a PCDAI >
      10, taking corticosteroids, or taking more than 400 IU Vitamin D at enrollment.

      NHP Formulation: Vitamin D at doses of 10 and 50 ug (400, and 2000 IU) 400 IU DIN #02231624
      2000 IU Dosage Regimen: Patients will be randomly assigned to one of two supplemental doses
      of vitamin D3 (10, and 50 ug/d) Prestudy Screening and Baseline Evaluation: Patients and
      their parent/guardian who meet the inclusion criteria and who consent will be enrolled and
      assigned without bias to a dose group. A one-hour fasting blood sample and a spot urine
      collection will be collected, a PCDAI will be administered, and patients will complete a food
      frequency questionnaire (FFQ) that will include information on Vitamin D and calcium
      supplement use (including dose and duration) as well as a lifestyle and demographic
      questionnaire.

      Treatment Visit: One-hour fasting blood and spot urine will be collected and the PCDAI will
      be administered at baseline, 3 months (+/- 1 week), and 6 months (+/- 1 week) after baseline.
      25OHD concentrations are thought to stabilize after 8 weeks of supplementation at a constant
      dose.

      Premature Withdrawal/Discontinuation Criteria: Discontinuation criteria for individual
      subjects include violation of any of the exclusion criteria, severe non-compliance with the
      protocol, or occurrence of adverse events that are judged to be severe enough for
      discontinuation. Subjects are also free to voluntarily discontinue the study at any time.

      Rescue Medication: Regular dosage of 400 IU vitamin D Washout Period: None Dietary
      Assessment: Calcium and Vitamin D intake from food over the previous month will be estimated
      using a food frequency questionnaire validated for use in a variety of ethnic groups (From S
      Whiting; U Sask).

      Pediatric Crohn's Disease Activity Index: The PCDAI will be used to assess the severity of
      disease. It consists of a patient recall, laboratory values, and a clinical examination.
      Scores below 10 indicate remission and scores above 20 indicate active disease (attached).

      Laboratory Assessment: Erythrocyte Sedimentation Rate, serum calcium, serum albumin, serum
      creatinine, urinary calcium and urinary creatinine will be measured by the hospital pathology
      labs using standard procedures. Serum 25OHD, PTH will be measured using automated
      chemiluminescent assay system (Liaison, Diasorin) by BC Biolabs.

      Efficacy Analysis: The proportion of patients achieving a 25OHD of 75 nmol/L on each of the
      dosages at 6 months will be compared using a Chi-squared test. Likewise the proportion of
      participants remaining in remission (PCDAI <20) will also be compared using a Chi-squared
      test. Data will initially be analyzed as intent-to-treat for all outcomes. In the case of
      dropouts or missing data the last observation will be carried-forward. A second analysis will
      be carried out for each outcome only using subjects with complete data and who were over 80%
      compliant in supplement use (as-treated analysis). Differences in the characteristics of the
      participants in the groups at baseline will be determined using Student's t-test for
      continuous and the chi-square test or Fisher's Exact Test for categorical variables.

      Safety Analysis: Adverse events will be recorded according to Good Clinical Practice
      Guidelines and the guidelines of our university's human research ethics board. Adverse event
      occurrences will be compared descriptively between the treatment and placebo groups. Safety
      will also be assessed as part of the blood collection (Serum Ca and Serum PTH and Serum P).

      Statistical Analysis: Data will initially be analyzed as intent-to-treat for all outcomes. In
      the case of dropouts or missing data the last observation will be carried-forward. A second
      analysis will be carried out for each outcome only using subjects with complete data and who
      were over 80% complaint in supplement use (as-treated analysis). Differences in the
      characteristics of the participants in the groups at baseline will be determined using
      Student's t-test for continuous and the chi-square test of Fisher's Exact Test for
      categorical variables. The primary endpoints will be the dosages at 3 months will be
      evaluated using a Chi-squared test. Dose response (as ug Vitamin D3 per nmol/L increase in
      25OHD) in children will be determined using multiple regression analysis with 25OHD as the
      dependent variable, vitamin D dose entered as a continuous variable, and baseline vitamin D
      as a covariate.
    

Intervention name(s): Vitamin D; Vitamin D
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 10 ug/day Vitamin D, taken for 6 months.; 50 ug/day Vitamin D, taken for 6 months.
Intervention MeSH terms: Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Prevention
Keywords: Vitamin D; Crohn's Disease; Dose Response