Vitamin D3 in Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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The purpose of this study is to explore the impact of vitamin D3 on the expression of alpha interferon (IFN alpha) expression in systemic lupus erythematosus (SLE) patients with vitamin D deficiency.

Detailed Description
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Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies with subsequent immune complex deposition and tissue inflammation. The role of interferon (IFN) alpha in the development of SLE has been repeatedly documented. Vitamin D deficiency is common among lupus patients. Vitamin D is recognized as a regulator of immune response. This study will explore the impact of vitamin D3 supplementation on IFN alpha expression in SLE patients. The study will last approximately 12 weeks and consist of three treatment groups: 1.) Participants will receive vitamin D3 2000 IU daily 2.) Participants will receive vitamin D3 4000 IU daily 3.) Participants will receive a vitamin D3 placebo daily. There will be four study visits for each participant. Visits will occur at screening, study entry, and Weeks 6 and 12. Physical examination, vital signs, and blood and urine tests will occur at all visits. For females of childbearing potential, a pregnancy test will be performed at screening and Week 6.

Official Title
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Effect of Vitamin D3 on the IFN Alpha Signature in Patients With Systemic Lupus Erythematosus (ALE02)

Conditions
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Systemic Lupus Erythematosus, SLE, Lupus

Intervention / Treatment
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* Drug: Vitamin D3
* Drug: Vitamin D3 placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of SLE by American College of Rheumatology (ACR) criteria Serum 25-OH vitamin D level of 20 ng/mL or less Stable disease at screening, defined as a modified Safety of Estrogens in Lupus Erythematosus National Assessment SLE Disease Activity Index (SELENA-SLEDAI) of 4 or less Interferon (IFN) signature present. More information about this criterion can be found in the protocol Positive anti-double-stranded (anti-ds) DNA antibody blood test at screening If on corticosteroids, the dose must be less than 20 mg per day and stable for 4 weeks prior to screening and at study entry If on immunosuppressive or immunomodulatory medication such as azathioprine, methotrexate, leflunomide, mycophenolate, or hydroxychloroquine, the dose must be stable for 3 months prior to screening and at study entry If receiving a multivitamin or a vitamin D supplement, the dose of vitamin D must be 800 IU daily or less and stable for the 3 months prior to screening and at study entry Agree to use effective contraceptive methods for the duration of the study Exclusion Criteria: Unwilling to stop using drugs or substances that may interfere with fat absorption Hypercalcemia Hypercalciuria History of hyperparathyroidism History of kidney stones History of cancer, except cervical carcinoma in situ and resected basal and squamous cell carcinomas of the skin Known history of chronic viral infections, including human immunodeficiency virus (HIV), Hepatitis B, and Hepatitis C Known active tuberculosis Any British Isles Lupus Assessment Group (BILAG) A or B manifestation with the exception of a BILAG B mucocutaneous manifestation Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) liver function tests greater than or equal to two times the upper limit of normal Dialysis or serum creatinine greater than 1.5 mg/dL Expectation by the investigator to increase corticosteroid or immunosuppressive or immunomodulatory medication dose at screening, study entry, or over the course of the study Treatment with cyclophosphamide within 3 months of screening Treatment with rituximab within 12 months of screening Other investigational drug and or treatment during the 4 weeks or seven half lives of the other investigational drug prior to study entry Drug or alcohol abuse within 6 months prior to study entry Treatment with digoxin Treatment with teriparatide Any condition that, in the opinion of the investigator, would jeopardize the subject's safety following exposure to the study drug Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: vitamin D3 2000 IU<br>Participants in this arm take a vitamin D3 dose of 2000 international units (IU) daily by mouth for a duration of 12 weeks. | Drug: Vitamin D3<br>* 8% vitamin D3 powder, 84% microcrystalline cellulose, 8% fumed silica by weight<br>* Other names: Cholecalciferol;|
| Experimental: vitamin D3 4000 IU<br>Participants in this arm take a vitamin D3 dose of 4000 international units (IU) daily by mouth for a duration of 12 weeks. | Drug: Vitamin D3<br>* 8% vitamin D3 powder, 84% microcrystalline cellulose, 8% fumed silica by weight<br>* Other names: Cholecalciferol;|
| Placebo Comparator: vitamin D3 placebo<br>Participants in this arm take a vitamin D3 placebo daily by mouth for a duration of 12 weeks. | Drug: Vitamin D3 placebo<br>* 86% microcrystalline cellulose, 14% fumed silica by weight<br>* Other names: Cholecalciferol placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With an IFN Alpha Signature Response at Week 12 | Presence of an Interferon (IFN) Alpha signature response is defined as: a reduction in expression from baseline (Screening) of at least 50% for 1 of 3 IFN Alpha responsive genes (Ifit1, Ifi44, Mx1) with concurrent expression in the remaining 2 genes at a level not more than 25% above baseline, or a reduction in expression from baseline of at least 25% for 2 of the 3 IFN Alpha responsive genes with concurrent expression in the third gene at a level of no more than 25% above baseline. Gene expression was measured on peripheral blood samples using qRT-PCR. Missing data were considered as response failures during calculation. | 0, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With an IFN Alpha Signature Response at Week 6 | Presence of an Interferon (IFN) Alpha signature response is defined as: a reduction in expression from baseline (Screening) of at least 50% for 1 of 3 IFN Alpha responsive genes (Ifit1, Ifi44, Mx1) with concurrent expression in the remaining 2 genes at a level not more than 25% above baseline, or a reduction in expression from baseline of at least 25% for 2 of the 3 IFN Alpha responsive genes with concurrent expression in the third gene at a level of no more than 25% above baseline. Gene expression was measured on peripheral blood samples using qRT-PCR. Missing data were considered as response failures during calculation. | 0, Week 6 | 
| Percent of Participants With IFN Alpha Signature at Week 12 | An Interferon (IFN) Alpha signature is defined as: expression of Mx1, Ifit1, or Ifi44 at a level greater than or equal to 4 standard deviations above the mean of a set of normal controls, or expression of 2 of the 3 genes at a level greater than or equal to 2 standard deviations above the mean of a set of normal controls. Gene expression was measured on peripheral blood samples using qRT-PCR. Missing data were assumed as signatures during calculation. | 0, Week 12 | 
| Percent of Participants With IFN Alpha Signature at Week 6 | An Interferon (IFN) Alpha signature is defined as: expression of Mx1, Ifit1, or Ifi44 at a level greater than or equal to 4 standard deviations above the mean of a set of normal controls, or expression of 2 of the 3 genes at a level greater than or equal to 2 standard deviations above the mean of a set of normal controls. Gene expression was measured on peripheral blood samples using qRT-PCR. Missing data were assumed as signatures during calculation. | Week 6 | 
| qRT-PCR Fold Change in Ifit1 Gene Expression From Baseline to Week 12 | The Ifit1 gene is one of three genes included in the definition of the alpha-interferon signature used for this study. This gene encodes an interferon-induced protein with tetratricopeptide repeats. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure gene expression in peripheral blood mononuclear cells obtained by blood draw. Gene expression is quantified as fold change relative to normal controls and is computed using a comparative CT (threshold cycle) method. A study hypothesis was that expression of alpha-interferon signature genes would decrease with increasing vitamin D levels. A decrease in gene expression from baseline to Week 12 is represented as a negative value (and vice versa). | 0, Week 12 | 
| qRT-PCR Fold Change in Ifit1 Gene Expression From Baseline to Week 6 | The Ifit1 gene is one of three genes included in the definition of the alpha-interferon signature used for this study. It encodes an interferon-induced protein with tetratricopeptide repeats. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure gene expression in peripheral blood mononuclear cells obtained by blood draw. Gene expression is quantified as fold change relative to normal controls and is computed using a comparative CT (threshold cycle) method. A study hypothesis was that expression of alpha-interferon signature genes would decrease with increasing vitamin D levels. A decrease in gene expression from baseline to Week 6 is represented as a negative value (and vice versa). | 0, Week 6 | 
| qRT-PCR Fold Change in Ifi44 Gene Expression From Baseline to Week 12 | The Ifi44 gene is one of three genes included in the definition of the alpha-interferon signature used for this study. It encodes interferon-induced protein 44. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure gene expression in peripheral blood mononuclear cells obtained by blood draw. Gene expression is quantified as fold change relative to normal controls and is computed using a comparative CT (threshold cycle) method. A study hypothesis was that expression of alpha-interferon signature genes would decrease with increasing vitamin D levels. A decrease in gene expression from baseline to Week 12 is represented as a negative value (and vice versa). | 0, Week 12 | 
| qRT-PCR Fold Change in Ifi44 Gene Expression From Baseline to Week 6 | The Ifi44 gene is one of three genes included in the definition of the alpha-interferon signature used for this study. It encodes interferon-induced protein 44. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure gene expression in peripheral blood mononuclear cells obtained by blood draw. Gene expression is quantified as fold change relative to normal controls and is computed using a comparative CT (threshold cycle) method. A study hypothesis was that expression of alpha-interferon signature genes would decrease with increasing vitamin D levels. A decrease in gene expression from baseline to Week 6 is represented as a negative value (and vice versa). | 0, Week 6 | 
| qRT-PCR Fold Change in Mx1 Gene Expression From Baseline to Week 12 | The Mx1 gene is one of three genes included in the definition of the alpha-interferon signature used for this study. It encodes for the homolog of mouse myxovirus (influenza virus) resistance 1 protein. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure gene expression in peripheral blood mononuclear cells obtained by blood draw. Gene expression is quantified as fold change relative to normal controls and is computed using a comparative CT (threshold cycle) method. A study hypothesis was that expression of alpha-interferon signature genes would decrease with increasing vitamin D levels. A decrease in gene expression from baseline to Week 12 is represented as a negative value (and vice versa). | 0, Week 12 | 
| qRT-PCR Fold Change in Mx1 Gene Expression From Baseline to Week 6 | The Mx1 gene is one of three genes included in the definition of the alpha-interferon signature used for this study. It encodes for the homolog of mouse myxovirus (influenza virus) resistance 1 protein. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure gene expression in peripheral blood mononuclear cells obtained by blood draw. Gene expression is quantified as fold change relative to normal controls and is computed using a comparative CT (threshold cycle) method. A study hypothesis was that expression of alpha-interferon signature genes would decrease with increasing vitamin D levels. A decrease in gene expression from baseline to Week 6 is represented as a negative value (and vice versa). | 0, Week 6 | 
| Change in Serum C3 Level From Baseline to Week 12 | C3 is a blood test that measures the activity of the complement component 3 (C3) protein. The normal C3 range is 75 to 135 mg/dL. Patients with active systemic lupus erythematosus may have a lower-than-normal level of C3. A decrease in C3 level over time may indicate disease activity. An increase in C3 from baseline to Week 12 is represented as a positive value (and vice versa). | 0, Week 12 | 
| Change in Serum C3 Level From Baseline to Week 6 | C3 is a blood test that measures the activity of the complement component 3 (C3) protein. The normal C3 range is 75 to 135 mg/dL. Patients with active systemic lupus erythematosus may have a lower-than-normal level of C3. A decrease in C3 level over time may indicate disease activity. An increase in C3 from baseline to Week 6 is represented as a positive value (and vice versa). | 0, Week 6 | 
| Change in Serum C4 Level From Baseline to Week 12 | C4 is a blood test that measures the activity of the complement component 4 (C4) protein. The normal range for males is 12 to 72 mg/dL and the normal range for females is 13 to 75 mg/dL. Patients with active systemic lupus erythematosus may have a lower-than-normal level of C4. A decrease in C4 level over time may indicate disease activity. An increase in C4 from baseline to Week 12 is represented as a positive value (and vice versa). | 0, Week 12 | 
| Change in Serum C4 Level From Baseline to Week 6 | Outcome measure description: C4 is a blood test that measures the activity of the complement component 4 (C4) protein. The normal range for males is 12 to 72 mg/dL and the normal range for females is 13 to 75 mg/dL. Patients with active systemic lupus erythematosus may have a lower-than-normal level of C4. A decrease in C4 level over time may indicate disease activity. An increase in C4 from baseline to Week 6 is represented as a positive value (and vice versa). | 0, Week 6 | 
| Change in Status for Anti-double-stranded DNA Autoantibody From Baseline to Week 12 | Patients with systemic lupus erythematosus (SLE) may have autoantibodies (e.g., self against self) to double-stranded DNA. Double-stranded DNA is one of multiple diagnostic tests for SLE and levels may be associated with disease activity. A positive test for autoantibodies to double-stranded DNA is based on the normal range from the local laboratory. Change in status (+ or -) from baseline is evaluated. | 0, Week 12 | 
| Change in Status for Anti-double-stranded DNA Autoantibody From Baseline to Week 6 | Patients with systemic lupus erythematosus (SLE) may have autoantibodies (e.g., self against self) to double-stranded DNA. Double-stranded DNA is one of multiple diagnostic tests for SLE and levels may be associated with disease activity. A positive test for autoantibodies to double-stranded DNA is based on the normal range from the local laboratory. Change in status (+ or -) from baseline is evaluated. | 0, Week 6 | 
| Change in SELENA-SLEDAI Total Score From Baseline to Week 12 | The modified Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus (SLE) Disease Activity Index (SELENA-SLEDAI) score is a weighted scale score ranging from 0 to 105 based on the presence or absence of 24 manifestations of SLE. The SELENA-SLEDAI assesses disease activity for 10 days prior to and including the day of assessment. For this study, the SELENA-SLEDAI score was modified to include proteinuria defined by dipstick rather than 24 hour urine. Positive change in the SELENA-SLEDAI score indicate increased disease activity. | 0, Week 12 | 
| Cardiorespiratory BILAG Status at Week 12 | The British Isles Lupus Assessment Group (BILAG) assessment gives a grade for each of 9 body systems (e.g., domains). Grades reflect systemic lupus erythematosus disease activity as follows: A (severe), B (moderate), C (mild), D (inactive at present but previously affected), E (inactive and system never involved). To be randomized, subjects had to have mild or inactive disease (C,D,E) in all but the mucocutaneous system in which B(moderate) disease was also allowed. The percent of subjects experiencing A or B level activity at Week 12 is assessed for the Cardiorespiratory-specific body system. | Week 12 | 
| Constitutional BILAG Status at Week 12 | The British Isles Lupus Assessment Group (BILAG) assessment gives a grade for each of 9 body systems (e.g., domains). Grades reflect systemic lupus erythematosus disease activity as follows: A (severe), B (moderate), C (mild), D (inactive at present but previously affected), E (inactive and system never involved). To be randomized, subjects had to have mild or inactive disease (C,D,E) in all but the mucocutaneous system in which B(moderate) disease was also allowed. The percent of subjects experiencing A or B level activity at Week 12 is assessed for the Constitutional-specific body system. | Week 12 | 
| Gastrointestinal BILAG Status at Week 12 | The British Isles Lupus Assessment Group (BILAG) assessment gives a grade for each of 9 body systems (e.g., domains). Grades reflect systemic lupus erythematosus disease activity as follows: A (severe), B (moderate), C (mild), D (inactive at present but previously affected), E (inactive and system never involved). To be randomized, subjects had to have mild or inactive disease (C,D,E) in all but the mucocutaneous system in which B(moderate) disease was also allowed. The percent of subjects experiencing A or B level activity at Week 12 is assessed for the Gastrointestinal-specific body system. | Week 12 | 
| Hematological BILAG Status at Week 12 | The British Isles Lupus Assessment Group (BILAG) assessment gives a grade for each of 9 body systems (e.g., domains). Grades reflect systemic lupus erythematosus disease activity as follows: A (severe), B (moderate), C (mild), D (inactive at present but previously affected), E (inactive and system never involved). To be randomized, subjects had to have mild or inactive disease (C,D,E) in all but the mucocutaneous system in which B(moderate) disease was also allowed. The percent of subjects experiencing A or B level activity at Week 12 is assessed for the Hematological-specific body system. | Week 12 | 
| Mucocutaneous BILAG Status at Week 12 | The British Isles Lupus Assessment Group (BILAG) assessment gives a grade for each of 9 body systems (e.g., domains). Grades reflect systemic lupus erythematosus disease activity as follows: A (severe), B (moderate), C (mild), D (inactive at present but previously affected), E (inactive and system never involved). To be randomized, subjects had to have mild or inactive disease (C,D,E) in all but the mucocutaneous system in which B(moderate) disease was also allowed. The percent of subjects experiencing A or B level activity at Week 12 is assessed for the Mucocutaneous-specific body system. | Week 12 | 
| Musculoskeletal BILAG Status at Week 12 | Outcome measure description: The British Isles Lupus Assessment Group (BILAG) assessment gives a grade for each of 9 body systems (e.g., domains). Grades reflect systemic lupus erythematosus disease activity as follows: A (severe), B (moderate), C (mild), D (inactive at present but previously affected), E (inactive and system never involved). To be randomized, subjects had to have mild or inactive disease (C,D,E) in all but the mucocutaneous system in which B(moderate) disease was also allowed. The percent of subjects experiencing A or B level activity at Week 12 is assessed for the Musculoskeletal-specific body system. | Week 12 | 
| Neuropsychiatric BILAG Status at Week 12 | The British Isles Lupus Assessment Group (BILAG) assessment gives a grade for each of 9 body systems (e.g., domains). Grades reflect systemic lupus erythematosus disease activity as follows: A (severe), B (moderate), C (mild), D (inactive at present but previously affected), E (inactive and system never involved). To be randomized, subjects had to have mild or inactive disease (C,D,E) in all but the mucocutaneous system in which B(moderate) disease was also allowed. The percent of subjects experiencing A or B level activity at Week 12 is assessed for the Neuropsychiatric-specific body system. | Week 12 | 
| Ophthalmic BILAG Status at Week 12 | The British Isles Lupus Assessment Group (BILAG) assessment gives a grade for each of 9 body systems (e.g., domains). Grades reflect systemic lupus erythematosus disease activity as follows: A (severe), B (moderate), C (mild), D (inactive at present but previously affected), E (inactive and system never involved). To be randomized, subjects had to have mild or inactive disease (C,D,E) in all but the mucocutaneous system in which B(moderate) disease was also allowed. The percent of subjects experiencing A or B level activity at Week 12 is assessed for the Ophthalmic-specific body system. | Week 12 | 
| Renal BILAG Status at Week 12 | The British Isles Lupus Assessment Group (BILAG) assessment gives a grade for each of 9 body systems (e.g., domains). Grades reflect systemic lupus erythematosus disease activity as follows: A (severe), B (moderate), C (mild), D (inactive at present but previously affected), E (inactive and system never involved). To be randomized, subjects had to have mild or inactive disease (C,D,E) in all but the mucocutaneous system in which B(moderate) disease was also allowed. The percent of subjects experiencing A or B level activity at Week 12 is assessed for the Renal-specific body system. | Week 12 | 
| Percent of Participants With Adverse Events of Grade 3 or Above | Grades are based on National Cancer Institute--Common Terminology Criteria (NCI-CTCAE) Version 3.0 over the duration of the study. Participants who experienced at least one grade 3 or higher adverse event (AE) are counted only once. The adverse events are treatment-emergent, which means that the AE occurred after taking the first dose of study drug. | From start of study treatment through Week 12 | 

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