Vitamin D3 Treatment in Pediatric Systemic Lupus Erythematosus

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.

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.

Eligibility Criteria:
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.