Autoimmune Diseases, Knee Pain Chronic, Osteoarthritis, Rheumatoid Arthritis, Systemic Inflammatory Process
Conditions
Keywords
vitamin D, omega-3 fatty acid, fish oil, prevention, trial, autoimmune disease, rheumatoid arthritis, psoriasis, systemic inflammation, Interleukin-6, C-reactive peptide, tumor necrosis factor, osteoarthritis
Brief summary
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.
Interventions
DRUGFish Oil
Subjects will receive marine omega-3 fatty acids (465 mg of eicosapentaenoic acid \[EPA\] and 375 mg of docosahexaenoic acid \[DHA\]).
DIETARY_SUPPLEMENTVitamin D
Subjects will receive vitamin D3 (cholecalciferol) 2000 IU a day.
OTHERplacebo pill
placebo
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
As for the parent trial, VITamin D and OmegA-3 TriaL (VITAL; NCT 01169259). Individuals with chronic, frequent knee pain at study baseline will be followed as a subcohort. Trial enrollment complete.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6) | Baseline and 1 year | 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. |
| Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP) | Baseline and 1 year | 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. |
| Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2) | Baseline and 1 year | 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. |
| Incident Autoimmune Diseases | 5 years | 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 |
| Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D | Baseline and 5 years | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incident Autoimmune Disease | extension of follow-up through 2 years post trial closure, up to 7 years | Development of new autoimmune disease through observational follow-up after trial termination. |
Countries
United States
Participant flow
Recruitment details
From the 25871 VITAL participants, we identified 2 main subcohorts: A systemic inflammation subcohort of 1561 participants with sufficient blood biomarker assays, balanced by sex, and matched on blood draw season, and a second knee pain subcohort including 1,398 participants who returned one knee pain questionnaire and qualified at baseline. Both subcohorts are described below in their respective aims.
Pre-assignment details
At 1 year, 95% of participants returned follow-up questionnaires, and approximately 90% were taking more than two-thirds of study pills (definition of compliance). Participants willing to provide a blood sample were sent a kit with consent form, supplies, and instructions to have blood drawn.
Participants by arm
| Arm | Count |
|---|---|
| ACTIVE Vitamin D + ACTIVE Omega-3 Fatty Acids 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 \[DHA\]). | 6,463 |
| ACTIVE Vitamin D + PLACEBO Omega-3 Fatty Acids ACTIVE Vitamin D = Vitamin D3, one 2000 IU capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day | 6,464 |
| PLACEBO Vitamin D + ACTIVE 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 \[DHA\]). | 6,470 |
| PLACEBO Vitamin D + PLACEBO Omega-3 Fatty Acids PLACEBO Vitamin D, one capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day | 6,474 |
| Total | 25,871 |
Baseline characteristics
| Characteristic | ACTIVE Vitamin D + ACTIVE Omega-3 Fatty Acids | ACTIVE Vitamin D + PLACEBO Omega-3 Fatty Acids | PLACEBO Vitamin D + ACTIVE Omega-3 Fatty Acids | PLACEBO Vitamin D + PLACEBO Omega-3 Fatty Acids | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4005 Participants | 4002 Participants | 4009 Participants | 4007 Participants | 16023 Participants |
| Age, Categorical Between 18 and 65 years | 2458 Participants | 2462 Participants | 2461 Participants | 2467 Participants | 9848 Participants |
| Age, Continuous | 67.1 Years STANDARD_DEVIATION 7.1 | 67.1 Years STANDARD_DEVIATION 7 | 67.2 Years STANDARD_DEVIATION 7.1 | 67.1 Years STANDARD_DEVIATION 7.1 | 67.1 Years STANDARD_DEVIATION 7.1 |
| Race/Ethnicity, Customized African American | 1278 Participants | 1275 Participants | 1271 Participants | 1282 Participants | 5106 Participants |
| Race/Ethnicity, Customized Asian/Pacific Islander | 102 Participants | 86 Participants | 98 Participants | 102 Participants | 388 Participants |
| Race/Ethnicity, Customized Hispanic (not African American) | 246 Participants | 270 Participants | 245 Participants | 252 Participants | 1013 Participants |
| Race/Ethnicity, Customized Native American/ Alaskan Native | 62 Participants | 56 Participants | 58 Participants | 52 Participants | 228 Participants |
| Race/Ethnicity, Customized Non-Hispanic white | 4515 Participants | 4498 Participants | 4529 Participants | 4504 Participants | 18046 Participants |
| Race/Ethnicity, Customized Other/ unknown | 126 Participants | 133 Participants | 123 Participants | 141 Participants | 523 Participants |
| Region of Enrollment United States | 6463 participants | 6464 participants | 6470 participants | 6474 participants | 25871 participants |
| Sex/Gender, Customized Female | 3276 Participants | 3271 Participants | 3271 Participants | 3267 Participants | 13085 Participants |
| Sex/Gender, Customized Male | 3187 Participants | 3193 Participants | 3199 Participants | 3207 Participants | 12786 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 241 / 6,463 | 244 / 6,464 | 252 / 6,470 | 241 / 6,474 |
| other Total, other adverse events | 5,101 / 6,463 | 5,027 / 6,464 | 5,037 / 6,470 | 5,101 / 6,474 |
| serious Total, serious adverse events | 791 / 6,463 | 782 / 6,464 | 822 / 6,470 | 837 / 6,474 |
Outcome results
Primary
Incident Autoimmune Diseases
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
Time frame: 5 years
Population: 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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Vitamin D | Incident Autoimmune Diseases | 123 Participants |
| Placebo Vitamin D | Incident Autoimmune Diseases | 155 Participants |
| Active n-3 FA | Incident Autoimmune Diseases | 130 Participants |
| Placebo n-3 FA | Incident Autoimmune Diseases | 148 Participants |
p-value: 0.0595% CI: [0.61, 0.99]Regression, Cox
p-value: 0.1995% CI: [0.67, 1.08]Regression, Cox
Comparison: Test for multiplicative interaction between the effects of randomized treatment groups, vitamin D and n-3 fa on incidence of autoimmune disease.p-value: 0.2P for interaction
Primary
Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP)
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.
Time frame: Baseline and 1 year
Population: Subsample of the VITAL trial participants at baseline and one year.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Active Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP) | Baseline ln (hsCRP) mg/L, geometric mean (95% Cl) | 1.48 mg/L |
| Active Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP) | Year 1 ln (hsCRP) mg/L, geometric mean (95% CI) | 1.62 mg/L |
| Placebo Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP) | Year 1 ln (hsCRP) mg/L, geometric mean (95% CI) | 1.54 mg/L |
| Placebo Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP) | Baseline ln (hsCRP) mg/L, geometric mean (95% Cl) | 1.51 mg/L |
| Active n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP) | Baseline ln (hsCRP) mg/L, geometric mean (95% Cl) | 1.57 mg/L |
| Active n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP) | Year 1 ln (hsCRP) mg/L, geometric mean (95% CI) | 1.63 mg/L |
| Placebo n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP) | Baseline ln (hsCRP) mg/L, geometric mean (95% Cl) | 1.43 mg/L |
| Placebo n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP) | Year 1 ln (hsCRP) mg/L, geometric mean (95% CI) | 1.53 mg/L |
Comparison: 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.p-value: 0.1695% CI: [-1.81, 16.87]as above
Comparison: 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.p-value: 0.4495% CI: [-11.92, 4.86]as above
Comparison: 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.p-value: 0.38P for interaction
Primary
Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6)
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.
Time frame: Baseline and 1 year
Population: Subsample of the VITAL trial participants at baseline and one year.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Active Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6) | Baseline ln (IL-6) pg/ml, geometric mean (95% Cl) | 1.71 pg/ml |
| Active Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6) | Year 1 ln (IL-6) pg/mL, geometric mean (95% CI) | 1.80 pg/ml |
| Placebo Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6) | Year 1 ln (IL-6) pg/mL, geometric mean (95% CI) | 1.63 pg/ml |
| Placebo Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6) | Baseline ln (IL-6) pg/ml, geometric mean (95% Cl) | 1.68 pg/ml |
| Active n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6) | Baseline ln (IL-6) pg/ml, geometric mean (95% Cl) | 1.69 pg/ml |
| Active n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6) | Year 1 ln (IL-6) pg/mL, geometric mean (95% CI) | 1.70 pg/ml |
| Placebo n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6) | Baseline ln (IL-6) pg/ml, geometric mean (95% Cl) | 1.70 pg/ml |
| Placebo n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6) | Year 1 ln (IL-6) pg/mL, geometric mean (95% CI) | 1.72 pg/ml |
Comparison: 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.p-value: 0.0295% CI: [1.52, 15.31]as above
Comparison: 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.p-value: 0.9795% CI: [-6.87, 5.81]as above
Comparison: Test for interaction between effect of vitamin D and effect of omega-3 fatty acids on IL-6 change from baseline to 1 yearp-value: 0.12p for interaction
Primary
Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2)
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.
Time frame: Baseline and 1 year
Population: Subsample of the VITAL trial participants at baseline and one year.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Active Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2) | Baseline ln (TNFR2) pg/ml, geometric mean (95% Cl) | 2546.5 pg/ml |
| Active Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2) | Year 1 ln (TNFR2) pg/mL, geometric mean (95% CI) | 2604.7 pg/ml |
| Placebo Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2) | Year 1 ln (TNFR2) pg/mL, geometric mean (95% CI) | 2567.9 pg/ml |
| Placebo Vitamin D | Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2) | Baseline ln (TNFR2) pg/ml, geometric mean (95% Cl) | 2525.4 pg/ml |
| Active n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2) | Baseline ln (TNFR2) pg/ml, geometric mean (95% Cl) | 2571.3 pg/ml |
| Active n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2) | Year 1 ln (TNFR2) pg/mL, geometric mean (95% CI) | 2605.3 pg/ml |
| Placebo n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2) | Baseline ln (TNFR2) pg/ml, geometric mean (95% Cl) | 2500.9 pg/ml |
| Placebo n-3 FA | Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2) | Year 1 ln (TNFR2) pg/mL, geometric mean (95% CI) | 2567.3 pg/ml |
Comparison: 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.p-value: 0.5795% CI: [-1.03, 2.31]as above
Comparison: 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.p-value: 0.1395% CI: [-2.89, 0.39]as above
Comparison: 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.p-value: 0.74P for interaction
Primary
Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D
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
Time frame: Baseline and 5 years
Population: Subsample of the VITAL trial who reported chronic frequent knee pain prior to randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Vitamin D | Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D | Baseline mean WOMAC Pain | 36.5 WOMAC units on a scale | Standard Deviation 0.7 |
| Active Vitamin D | Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D | Follow Up mean WOMAC pain | 33.6 WOMAC units on a scale | Standard Deviation 0.9 |
| Placebo Vitamin D | Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D | Follow Up mean WOMAC pain | 33.7 WOMAC units on a scale | Standard Deviation 0.9 |
| Placebo Vitamin D | Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D | Baseline mean WOMAC Pain | 35.4 WOMAC units on a scale | Standard Deviation 0.7 |
| Active n-3 FA | Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D | Baseline mean WOMAC Pain | 35.4 WOMAC units on a scale | Standard Deviation 0.7 |
| Active n-3 FA | Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D | Follow Up mean WOMAC pain | 32.7 WOMAC units on a scale | Standard Deviation 0.9 |
| Placebo n-3 FA | Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D | Baseline mean WOMAC Pain | 36.5 WOMAC units on a scale | Standard Deviation 0.7 |
| Placebo n-3 FA | Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA & Vitamin D | Follow Up mean WOMAC pain | 34.6 WOMAC units on a scale | Standard Deviation 0.9 |
Comparison: 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.p-value: 0.77Mixed Models Analysis
Comparison: 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.p-value: 0.41Mixed Models Analysis
Comparison: Active n3fa vs placebo n3fa among those on placebo vitamin D.p-value: 0.42Regression, Linear
Comparison: Vitamin D vs. vitamin D placebo among those on placebo omega-3 fatty acids- stratified analyses.p-value: 0.18Regression, Linear
Comparison: Omega-3 fatty acids vs. omega-3 fatty acids placebo among those on active vitamin D.p-value: 0.84Regression, Linear
Comparison: Omega-3 fatty acids vs. omega-3 fatty acids placebo among those on placebo vitamin D.p-value: 0.76Regression, Linear
Secondary
Incident Autoimmune Disease
Development of new autoimmune disease through observational follow-up after trial termination.
Time frame: extension of follow-up through 2 years post trial closure, up to 7 years
Population: Baseline enrolled populations
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Vitamin D | Incident Autoimmune Disease | 255 Participants |
| Placebo Vitamin D | Incident Autoimmune Disease | 259 Participants |
| Active n-3 FA | Incident Autoimmune Disease | 234 Participants |
| Placebo n-3 FA | Incident Autoimmune Disease | 280 Participants |
Comparison: HR for incident autoimmune disease in intervention groups vs. placebo (ref=1.0) using Cox models with 95% confidence intervalsp-value: <0.05Regression, Cox