Vitamin D3 in Systemic Lupus Erythematosus

Phase 2

Completed

• Conditions: SLE; Lupus; Systemic Lupus Erythematosus
• Interventions: Drug: Vitamin D3 placebo; Drug: Vitamin D3

• Registration Number: NCT00710021
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2008-07-01
• Study First Submitted QC: 2008-07-01
• Study First Posted: 2008-07-03
• Study Start: 2008-11
• Primary Completion: 2011-07
• Study Completion: 2011-07
• Results First Submitted: 2014-01-09
• Results First Submitted QC: 2014-03-25
• Results First Posted: 2014-04-25
• Status Verified: 2017-03
• Last Update Submitted: 2017-03-24
• Last Update Posted: 2017-04-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 57

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
vitamin D3 placebo	Vitamin D3 placebo	Participants in this arm take a vitamin D3 placebo daily by mouth for a duration of 12 weeks.
vitamin D3 2000 IU	Vitamin D3	Participants in this arm take a vitamin D3 dose of 2000 international units (IU) daily by mouth for a duration of 12 weeks.
vitamin D3 4000 IU	Vitamin D3	Participants in this arm take a vitamin D3 dose of 4000 international units (IU) daily by mouth for a duration of 12 weeks.

Primary Outcome Measures

Name	Time	Method
Percent of Participants With an IFN Alpha Signature Response at Week 12	0, 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.

Secondary Outcome Measures

Name	Time	Method
Percent of Participants With IFN Alpha Signature at Week 12	0, 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.
Percent of Participants With an IFN Alpha Signature Response at Week 6	0, 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.
Change in Serum C3 Level From Baseline to Week 6	0, 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).
Change in Status for Anti-double-stranded DNA Autoantibody From Baseline to Week 12	0, 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.
Percent of Participants With IFN Alpha Signature at Week 6	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.
qRT-PCR Fold Change in Mx1 Gene Expression From Baseline to Week 6	0, 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).
qRT-PCR Fold Change in Ifit1 Gene Expression From Baseline to Week 12	0, 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).
qRT-PCR Fold Change in Mx1 Gene Expression From Baseline to Week 12	0, 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).
Change in Status for Anti-double-stranded DNA Autoantibody From Baseline to Week 6	0, 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.
Ophthalmic BILAG Status at Week 12	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.
qRT-PCR Fold Change in Ifit1 Gene Expression From Baseline to Week 6	0, 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).
qRT-PCR Fold Change in Ifi44 Gene Expression From Baseline to Week 12	0, 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).
qRT-PCR Fold Change in Ifi44 Gene Expression From Baseline to Week 6	0, 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).
Change in SELENA-SLEDAI Total Score From Baseline to Week 12	0, 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.
Constitutional BILAG Status at Week 12	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.
Gastrointestinal BILAG Status at Week 12	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.
Mucocutaneous BILAG Status at Week 12	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.
Renal BILAG Status at Week 12	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.
Change in Serum C3 Level From Baseline to Week 12	0, 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).
Change in Serum C4 Level From Baseline to Week 12	0, 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).
Change in Serum C4 Level From Baseline to Week 6	0, 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).
Neuropsychiatric BILAG Status at Week 12	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.
Cardiorespiratory BILAG Status at Week 12	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.
Hematological BILAG Status at Week 12	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.
Musculoskeletal BILAG Status at Week 12	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.
Percent of Participants With Adverse Events of Grade 3 or Above	From start of study treatment through Week 12	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.

Trial Locations

Locations (8)

University of Rochester; 🇺🇸 Rochester, New York, United States

University of Alabama; 🇺🇸 Birmingham, Alabama, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

Feinstein Institute for Medical Research; 🇺🇸 Manhassett, New York, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States