Vitamin D3 Treatment in Pediatric Systemic Lupus Erythematosus

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

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.

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.