Vitamin D3 Treatment in Pediatric Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the effects of 18 weeks of high-dose vitamin D3 supplementation compared with standard-dose vitamin D3 supplementation on immune function, glucose homeostasis, and bone metabolism in children with systemic lupus erythematosus (SLE) and serum 25-hydroxyvitamin D [25(OH)D] levels ≤20 ng/mL.

Detailed Description
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This is a multi-center, phase II, 18-week, two arm, unblinded randomized clinical trial. Seventy-eight pediatric subjects with SLE and 25(OH)D levels ≤ 20 ng/mL will be randomized in a 1:1 ratio to receive either standard-dose (400 IU/day) or high-dose (6,000 IU/day) vitamin D3 for 18 weeks based upon weight at baseline. Subjects randomized to the high-dose vitamin D3 treatment arm will receive 6,000 IU per day from baseline until the subject's vitamin D levels reach ≥ 40 ng/mL at which point the vitamin D3 dose will be reduced to 4,000 IU per day. Subjects randomized to the high-dose treatment arm weighing < 40 kg will receive supplementation five days per week and all other subjects will receive supplementation seven days a week. In addition to the baseline, and weeks 6, 12, and 18 visits, subjects randomized to the high-dose treatment arm will return at Weeks 3 and 9 to assess for symptoms of vitamin D toxicity. If a subject in the high-dose arm is found to exhibit evidence of vitamin D toxicity at the week 12 visit, he/she will be asked to return to their clinical research site for an additional vitamin D toxicity assessment at week 15. Study personnel will record each subject's interval history, assess adverse events, disease activity, and collect samples for safety and mechanistic assessments.

Official Title
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Vitamin D3 Effects on Immune Function in Pediatric Systemic Lupus Erythematosus (SLE)

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Vitamin D3 6000 IU
* Drug: Vitamin D3 400 IU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent signed by the subject or parent/guardian as appropriate; child assent as appropriate; Before the age of 19, met at least 4 of the 11 modified American College of Rheumatology (ACR) 1982 Revised Criteria for the Classification of Systemic Lupus Erythematosus as updated in 1997; Date of SLE diagnosis (as described in Inclusion Criterion 2) at least 24 weeks prior to randomization; Serum 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL at Screening; SELENA SLEDAI score > 0 and < 8 at Screening and at Baseline; If taking prednisone (or equivalent corticosteroid), the dose must be ≤ 15 mg/day or ≤0.5 mg/kg/day, whichever is lower, and stable for at least four weeks prior to randomization. Note, if subjects are taking steroids every other day, divide their dose by 2 to evaluate eligibility; Stable immunosuppressive dose for at least 12 weeks prior to randomization; --Immunosuppressive medications allowed include mycophenolate (MMF), azathioprine, methotrexate, antimalarial medications (e.g., hydroxychloroquine), cyclosporine A (CsA), tacrolimus, intravenous immune globulin (IVIG), and abatacept. Body weight > 25 kg; Able to swallow pills; Males and females with reproductive potential must agree to practice effective measures of birth control. Exclusion Criteria: Any condition or treatment that, in the opinion of the investigator, places the subject at an unacceptable risk as a participant in the trial; Current pharmacologic vitamin D2 or D3 intake > 800 IU daily or use of calcitriol at any dose over the past four weeks prior to randomization; Cyclophosphamide or IV glucocorticoid exposure within 12 weeks prior to randomization; Any BILAG A or B manifestation with the exception of a BILAG B mucocutaneous manifestation at screening, and excluding the renal BILAG criteria (see rituximab or belimumab criterion, below); Significant renal insufficiency defined as: Estimated GFR < 60 mL/min/1.73m^2 or estimated GFR < 90 mL/min/1.73m^2 with a reduction of the GFR by > 15% from the last measurement; Urine dipstick value of 2+ or higher for protein, unless this is a stable value from the last measurement or, urine protein-creatinine ratio ≥ 50 mg/mmol unless the value represents an improvement of ≥ 25% from the last measurement. Rituximab or belimumab exposure use within 24 weeks prior to randomization; The following laboratory parameters at the Screening visit: Platelets < 50,000; WBC < 2,500; ANC < 1,000; Hemoglobin < 9 mg/dL; ALT, AST, bilirubin > 2x upper limit of normal (ULN); Hypercalcemia (calcium > ULN); Hypercalciuria (urinary calcium/creatinine ratio > 0.2). Primary hyperparathyroidism (known); History of nephrolithiasis (known); Diabetes mellitus requiring insulin therapy; Medications that interfere with vitamin D absorption; History of vertebral compression fractures (known); Pregnancy (girls ≥ 11 years of age must have a negative urine/serum pregnancy test); A history of non-adherence/non-compliance; Other investigational drug and/or treatment during the four weeks or seven half-lives of the other investigational drug prior to the start of study product dosing (Day 0), whichever is the greater length of time to enrollment; Current diagnosis of cancer or chronic infection such as Hepatitis B, Hepatitis C, or tuberculosis; Treatment with digoxin; Flu (influenza) vaccination within one week prior to randomization.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D3 6000 IU<br>6000 IU of vitamin D3 by mouth daily until the subject's serum 25(OH) level is ≥ 40ng/mL at which point the supplementation dose is reduced to 4,000 IU/day. Note: Subjects weighing <40 kilograms (kg) at study entry will receive their dose five days a week and all other subjects seven days a week. | Drug: Vitamin D3 6000 IU<br>* Subjects will receive 6,000 IU of vitamin D3 by mouth daily until the subject's serum 25(OH) level is ≥ 40ng/mL at which point the supplementation dose will be reduced to 4,000 IU/day. Note: Subjects weighing <40 kilograms (kg) at study entry will receive their dose five days a week and all other subjects seven days a week.<br>* Other names: high-dose 25(OH)D;|
| Active Comparator: Vitamin D3 400 IU<br>400 IU/day of vitamin D3 by mouth daily. | Drug: Vitamin D3 400 IU<br>* Subjects will receive 400 IU/day of vitamin D3 daily by mouth.<br>* Other names: standard-dose 25(OH)D;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average IFN Module Expression Level | No mechanistic analyses were performed due to recruitment feasibility issues. | Baseline to Week 18 | 
| Percentage of Subjects by Treatment Arm Experiencing Any Adverse Event (AE) ≥ Grade 3 | Adverse event grading based on National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0 | Baseline to 18 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SLE, Vitamin D3, Vitamin D deficiency, IFN alpha expression