Vitamin D3 Treatment in Pediatric Systemic Lupus Erythematosus

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.

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.