Systemic Lupus Erythematosus
Conditions
Keywords
SLE, Vitamin D3, Vitamin D deficiency, IFN alpha expression
Brief summary
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
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.
Interventions
DRUGVitamin D3 6000 IU
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.
DRUGVitamin D3 400 IU
Subjects will receive 400 IU/day of vitamin D3 daily by mouth.
Sponsors
Autoimmunity Centers of Excellence
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 20 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Average IFN Module Expression Level | Baseline to Week 18 | No mechanistic analyses were performed due to recruitment feasibility issues. |
| Percentage of Subjects by Treatment Arm Experiencing Any Adverse Event (AE) ≥ Grade 3 | Baseline to 18 Weeks | Adverse event grading based on National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vitamin D3 6000 IU Participants received an 18-week course of oral Vitamin D3 (cholecalciferol, 6,000 international units \[IU\] daily). | 3 |
| Vitamin D3 400 IU Participants received an 18-week course of oral Vitamin D3 (cholecalciferol, 400 international units \[IU\] daily). | 4 |
| Total | 7 |
Baseline characteristics
| Characteristic | Total | Vitamin D3 400 IU | Vitamin D3 6000 IU |
|---|---|---|---|
| 25(OH)D at Screening | 13.2 ng/mL STANDARD_DEVIATION 4.6 | 16.1 ng/mL STANDARD_DEVIATION 2.5 | 9.3 ng/mL STANDARD_DEVIATION 3.9 |
| Age, Continuous | 14.7 years STANDARD_DEVIATION 2.7 | 13.5 years STANDARD_DEVIATION 0.6 | 16.3 years STANDARD_DEVIATION 3.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 4 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 7 participants | 4 participants | 3 participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 3 | 1 / 4 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 |
Outcome results
Primary
Change in Average IFN Module Expression Level
No mechanistic analyses were performed due to recruitment feasibility issues.
Time frame: Baseline to Week 18
Population: Data were not collected and therefore no analyses could be performed.
Primary
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
Time frame: Baseline to 18 Weeks
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin D3 6000 IU | Percentage of Subjects by Treatment Arm Experiencing Any Adverse Event (AE) ≥ Grade 3 | 0 Percentage of Participants |
| Vitamin D3 400 IU | Percentage of Subjects by Treatment Arm Experiencing Any Adverse Event (AE) ≥ Grade 3 | 25 Percentage of Participants |