Symptoms and General Pathology

All Conditions

Musculoskeletal Diseases

Skin and Connective Tissue Diseases

Immune System Diseases

Rare Diseases

Inflammation

Osteoarthritis

Arthritis

Necrosis

Psoriasis

Autoimmune Diseases

Arthritis, Rheumatoid

Pain

Joint Diseases

Rheumatic Diseases

Collagen Diseases

Connective Tissue Diseases

Chronic Graft Versus Host Disease

Micronutrients

All Drugs and Chemicals

Bone Density Conservation Agents

Other Dietary Supplements

Vitamins

Vitamin D

Cholecalciferol

Ergocalciferols

Trace Elements

Hormones

Calcium

Calcium, Dietary

Omega 3 Fatty Acid

Vitamin D3

Calciferol

Ergocalciferol

Vitamin D2

Subjects will receive marine omega-3 fatty acids (465 mg of eicosapentaenoic acid \[EPA\] and 375 mg of docosahexaenoic acid \[DHA\]).

Subjects will receive vitamin D3 (cholecalciferol) 2000 IU a day.

Fish Oil

placebo pill

Karen H Costenbader, MD, MPH

The VITamin D and OmegA-3 TriaL (VITAL; NCT 01169259) is a randomized clinical trial in 25,871 U.S. men and women investigating whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids (Omacor® fish oil, 1 gram) reduces the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. This ancillary study is being conducted among VITAL participants and will examine whether vitamin D or fish oil have effects upon A) autoimmune disease incidence, B) biomarkers of systemic inflammation, and C) chronic knee pain. Blood samples at baseline and in follow-up will be collected in a randomly selected subcohort of 1500 individuals and analyzed for changes in biomarkers of systemic inflammation: C-reactive protein, interleukin-6, and tumor necrosis factor-receptor 2. Approximately 1300 individuals with chronic, frequent knee pain will be followed with annual questionnaires to evaluate the effects of the supplements on chronic knee pain.

Vitamin D and Fish Oil for Autoimmune Disease, Inflammation and Knee Pain

In a subsample of the randomized trial population across the four arms, blood samples at baseline and in follow-up were collected and analyzed for changes in biomarkers of systemic inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-receptor 2 (TNFR2). We tested whether either or both supplements were associated with a decrease in the biomarkers of systemic inflammation (blood biomarker levels among those receiving supplements vs. placebo). We also tested whether there were interactions between the two supplements in their effects on changes in the IL-6 serum biomarker of systemic inflammation.

In a subsample of the randomized trial population across the four arms, blood samples at baseline and in follow-up were collected and analyzed for changes in biomarkers of systemic inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-receptor 2 (TNFR2). We tested whether either or both supplements were associated with a decrease in the biomarkers of systemic inflammation (blood biomarker levels among those receiving supplements vs. placebo). We also tested whether there were interactions between the two supplements in their effects on changes in the CRP serum biomarker of systemic inflammation.

In a subsample of the randomized trial population across the four arms, blood samples at baseline and in follow-up were collected and analyzed for changes in biomarkers of systemic inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-receptor 2 (TNFR2). We tested whether either or both supplements were associated with a decrease in the biomarkers of systemic inflammation (blood biomarker levels among those receiving supplements vs. placebo). We also tested whether there were interactions between the two supplements in their effects on changes in the TNFR2 serum biomarker of systemic inflammation.

All participants were followed for the development of new autoimmune diseases, including, but not limited to, rheumatoid arthritis, psoriasis, autoimmune thyroid disease, inflammatory bowel disease and polymyalgia rheumatica. The primary endpoint was all incident autoimmune disease confirmed by extensive medical record review. Participants self-reported all incident autoimmune diseases from baseline through follow-up. We used Cox proportional hazards models to test the effects of vitamin D and n-3 fatty acids upon autoimmune disease incidence.

We compared the separate main effects of vitamin D or n-3 fatty acid supplement assignment on AD incidence using Cox regression models. To account for randomization stratification and study design, we additionally adjusted for age, sex, self-reported race, and randomization to the other supplement. Person-time was counted until diagnosis of a new confirmed AD, death, or the end of the trial. We also test interactions between the two supplements

Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Pain was the primary outcome on a scale of 0-100 with 100= worst pain.

Subsample of VITAL participants with chronic, frequent knee pain at trial baseline were followed with annual WOMAC questionnaires to test for change in severity of chronic knee pain in those taking Omega-3 fish oil (n-3 FA) supplements compared to those taking placebo and for those taking Vitamin D supplements compared to those taking placebo. We tested whether n-3 FA supplements and Vitamin D are associated with reduced levels of WOMAC knee pain at the end of the trial (comparing knee pain outcomes in those receiving supplements to placebo). We will also test whether there were multiplicative interactions between the two supplements for the outcome of knee pain severity by WOMAC-Pain index

Development of new autoimmune disease through observational follow-up after trial termination.

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Brigham and Women's Hospital

Associate Physician

Vit D Monitored safety cond'ns: hypercalcemia, kidney stones, parathyroid disease, kidney failure or dialysis; Other symptoms, side effects: GI bleeding, easy bruising; stomach upset or pain; nausea; constipation, diarrhea, skin rash

Omega-3 FA Monitored safety cond'ns: GI bleeding; blood in urine; easy bruising; freq nosebleeds; kidney failure or dialysis; Other symptoms, side effects: stomach upset or pain; nausea; constipation; diarrhea; skin rash; bad taste in mouth; increased burping

Vitamin D3, one 2000 IU capsule/day

Omacor, one 1-g capsule/day. Each capsule of Omacor contains 840 mg of marine omega-3 fatty acids (465 mg of EPA + 375 mg of DHA).

Active Vitamin D/ Active Omega-3 Fatty Acids

Vitamin D3, one 2000 IU capsule/day

Omega-3 fatty acids placebo, one capsule/day

Active Vitamin D/ Active Omega-3 Placebo

Omacor, one 1-g capsule/day. Each capsule of Omacor contains 840 mg of marine omega-3 fatty acids (465 mg of EPA + 375 mg of DHA).

Vitamin D placebo, one capsule/day

Active Omega-3 Fatty Acids, Placebo Vitamin D

Omega-3 fatty acids placebo, one capsule/day

Vitamin D placebo, one capsule/day

Omega-3 Fatty Acids Placebo/ Placebo Vitamin D

ACTIVE Vitamin D = Vitamin D3, one 2000 IU capsule/day; ACTIVE Omega-3 Fatty Acids = Omacor, one 1-gram capsule/day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid \[EPA\] and 375 mg of docosahexaenoic acid \[DHA\]).

ACTIVE Vitamin D + ACTIVE Omega-3 Fatty Acids

ACTIVE Vitamin D = Vitamin D3, one 2000 IU capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day

ACTIVE Vitamin D + PLACEBO Omega-3 Fatty Acids

PLACEBO Vitamin D, one capsule/day; ACTIVE Omega-3 Fatty Acids = Omacor, one 1-gram capsule/day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid \[EPA\] and 375 mg of docosahexaenoic acid \[DHA\]).

PLACEBO Vitamin D + ACTIVE Omega-3 Fatty Acids

PLACEBO Vitamin D, one capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day

PLACEBO Vitamin D + PLACEBO Omega-3 Fatty Acids

Total

Age, Categorical

Age, Continuous

Female

Male

Sex/Gender, Customized

Non-Hispanic white

African American

Hispanic (not African American)

Asian/Pacific Islander

Native American/ Alaskan Native

Other/ unknown

Race/Ethnicity measured using different categories in systemic inflammation versus knee pain subcohorts.

Race/Ethnicity, Customized

United States

Region of Enrollment

In this 2x2 factorial design trial, the primary analyses were: all active vitamin D vs. all placebo vitamin D and all active omega-3 fatty acids vs. all placebo omega-3 fatty acids.

Karen Costenbader

Geometric means of biomarker concentrations with 95% CIs were calculated for baseline and 1 year biomarkers (IL-6, TNFR2 and CRP) by treatment group (active vs. placebo vitamin D). Linear repeated measures models calculated the % change in means for each biomarker from baseline to year one and the overall effects of randomized treatments with 95% CIs.

Test for interaction between effect of vitamin D and effect of omega-3 fatty acids on IL-6 change from baseline to 1 year

Baseline ln (IL-6) pg/ml, geometric mean (95% Cl)

Year 1 ln (IL-6) pg/mL, geometric mean (95% CI)

Active Vitamin D

Placebo Vitamin D

Omacor, one 1-g capsule/day. Each capsule of Omacor contains 840 mg of marine omega-3 fatty acids (465 mg of EPA + 375 mg of DHA).

Active n-3 FA

Omega-3 fatty acids placebo, one capsule/day

Placebo n-3 FA

Subsample of the VITAL trial participants at baseline and one year.

Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6)

Test for multiplicative interaction between effect of vitamin D and effect of omega-3. based on linear models of ln biomarker from baseline to year 1.

Baseline ln (hsCRP) mg/L, geometric mean (95% Cl)

Year 1 ln (hsCRP) mg/L, geometric mean (95% CI)

Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP)

Baseline ln (TNFR2) pg/ml, geometric mean (95% Cl)

Year 1 ln (TNFR2) pg/mL, geometric mean (95% CI)

Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2)

Test for multiplicative interaction between the effects of randomized treatment groups, vitamin D and n-3 fa on incidence of autoimmune disease.

All participants in VITAL followed for the development of new autoimmune diseases, including, but not limited to, rheumatoid arthritis, psoriasis, autoimmune thyroid disease, inflammatory bowel disease and polymyalgia rheumatica. Categorized by vitamin D (active/placebo) and n-3 (active/placebo)

Incident Autoimmune Diseases

Intention to treat analysis using a repeated measures model with unstructured variance to assess the effect of treatment arm on WOMAC Pain adjusting for age, sex, and the other treatment arm. The linear time by treatment interaction term assessed change in WOMAC Pain over time between participants randomized to treatment versus placebo.

We assessed for effect modification between vitamin D and N-3 FA and tested for other pre-specified interactions. We again used a repeated measures model with censoring for TKR. We adjusted for age, sex and N-3 FA treatment arm (in analyses in which N-3 FA treatment arm was not investigated as a potential modifier).

Active n3fa vs placebo n3fa among those on placebo vitamin D.

Vitamin D vs. vitamin D placebo among those on placebo omega-3 fatty acids- stratified analyses.

Omega-3 fatty acids vs. omega-3 fatty acids placebo among those on active vitamin D.

Omega-3 fatty acids vs. omega-3 fatty acids placebo among those on placebo vitamin D.

Baseline mean WOMAC Pain

Follow Up mean WOMAC pain

Omacor, one 1-g capsule/day. Each capsule of Omacor contains 840 mg of marine omega-3 fatty acids (465 mg of EPA + 375 mg of DHA) + Vitamin D3, one 2000 IU capsule/day or Vitamin D placebo, one capsule/day

Omega-3 fatty acids placebo, one capsule/day + Vitamin D3, one 2000 IU capsule/day or Vitamin D placebo, one capsule/day

Vitamin D3, one 2000 IU capsule/day + Omega 3 Omacor fatty acid, 1-g capsule/day or Omega-3 fatty acid placebo

Placebo vitamin D3, one 2000 IU capsule/day + Omega 3 Omacor fatty acid, 1-g capsule/day or Omega-3 fatty acid placebo

Subsample of the VITAL trial who reported chronic frequent knee pain prior to randomization.

Spots Global Cancer Trial Database for systemic inflammatory process