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| ID | Type | Description | Link |
|---|---|---|---|
| R01AR059086 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) | NIH |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fish Oil | Experimental | Subjects will receive marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]). |
|
| Vitamin D | Experimental | Subjects will receive vitamin D3 (cholecalciferol) 2000 IU a day. |
|
| placebo | Placebo Comparator | Subjects will receive placebo pill. |
|
| Vitamin D and Fish Oil | Experimental | Subjects will receive marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fish Oil | Drug | Subjects will receive marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]). |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline and 1 year |
| 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. | Baseline and 1 year |
| 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. | Baseline and 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| Incident Autoimmune Disease | Development of new autoimmune disease through observational follow-up after trial termination. | extension of follow-up through 2 years post trial closure, up to 7 years |
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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.
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| Name | Affiliation | Role |
|---|---|---|
| Karen H Costenbader, MD, MPH | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38518540 | Result | Oakes EG, Vlasakov I, Kotler G, Bubes V, Mora S, Tatituri R, Cook NR, Manson JE, Costenbader KH. Joint effects of one year of marine omega-3 fatty acid supplementation and participant dietary fish intake upon circulating lipid mediators of inflammation resolution in a randomized controlled trial. Nutrition. 2024 Jul;123:112413. doi: 10.1016/j.nut.2024.112413. Epub 2024 Feb 28. | |
| 38272846 | Result | Costenbader KH, Cook NR, Lee IM, Hahn J, Walter J, Bubes V, Kotler G, Yang N, Friedman S, Alexander EK, Manson JE. Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes Two Years After Completion of a Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2024 Jun;76(6):973-983. doi: 10.1002/art.42811. Epub 2024 Feb 20. |
| Label | URL |
|---|---|
| Welcome to the VITAL Study Website | View source |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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]). |
| FG001 | 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 |
| FG002 | 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]). |
| FG003 | PLACEBO Vitamin D + PLACEBO Omega-3 Fatty Acids | PLACEBO Vitamin D, one capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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]). |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Subsample of the VITAL trial participants at baseline and one year. | Posted | Geometric Mean | 95% Confidence Interval | pg/ml | Baseline and 1 year |
|
5 years
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
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active Vitamin D/ Active Omega-3 Fatty Acids | 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). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal bleeding | Blood and lymphatic system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Easy bruising | Blood and lymphatic system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Karen Costenbader | Brigham and Women's Hospital/ Harvard Medical School | 16177326088 | kcostenbader@bwh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 9, 2009 | Dec 10, 2020 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D001327 | Autoimmune Diseases |
| D010003 | Osteoarthritis |
| D001172 | Arthritis, Rheumatoid |
| D011565 | Psoriasis |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
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| ID | Term |
|---|---|
| D005395 | Fish Oils |
| D015118 | Eicosapentaenoic Acid |
| D004281 | Docosahexaenoic Acids |
| D015525 | Fatty Acids, Omega-3 |
| D014807 | Vitamin D |
| D002762 | Cholecalciferol |
| ID | Term |
|---|---|
| D009821 | Oils |
| D008055 | Lipids |
| D004042 | Dietary Fats, Unsaturated |
| D004041 | Dietary Fats |
Not provided
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Not provided
Not provided
Not provided
Not provided
|
| Vitamin D | Dietary Supplement | Subjects will receive vitamin D3 (cholecalciferol) 2000 IU a day. |
|
|
| placebo pill | Other | placebo |
|
| 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 | 5 years |
| 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 | Baseline and 5 years |
| 31699704 | Result | Costenbader KH, MacFarlane LA, Lee IM, Buring JE, Mora S, Bubes V, Kotler G, Camargo CA Jr, Manson JE, Cook NR. Effects of One Year of Vitamin D and Marine Omega-3 Fatty Acid Supplementation on Biomarkers of Systemic Inflammation in Older US Adults. Clin Chem. 2019 Dec;65(12):1508-1521. doi: 10.1373/clinchem.2019.306902. Epub 2019 Nov 7. |
| 32583982 | Result | MacFarlane LA, Cook NR, Kim E, Lee IM, Iversen MD, Gordon D, Buring JE, Katz JN, Manson JE, Costenbader KH. The Effects of Vitamin D and Marine Omega-3 Fatty Acid Supplementation on Chronic Knee Pain in Older US Adults: Results From a Randomized Trial. Arthritis Rheumatol. 2020 Nov;72(11):1836-1844. doi: 10.1002/art.41416. Epub 2020 Oct 3. |
| 35082139 | Result | Hahn J, Cook NR, Alexander EK, Friedman S, Walter J, Bubes V, Kotler G, Lee IM, Manson JE, Costenbader KH. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022 Jan 26;376:e066452. doi: 10.1136/bmj-2021-066452. |
| 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 |
| BG002 | 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]). |
| BG003 | PLACEBO Vitamin D + PLACEBO Omega-3 Fatty Acids | PLACEBO Vitamin D, one capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | Years |
|
| Sex/Gender, Customized | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Race/Ethnicity measured using different categories in systemic inflammation versus knee pain subcohorts. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Vitamin D3, one 2000 IU capsule/day
| OG001 | Placebo Vitamin D | Vitamin D placebo, one capsule/day |
| OG002 | Active n-3 FA | 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). |
| OG003 | Placebo n-3 FA | Omega-3 fatty acids placebo, one capsule/day |
|
|
|
| 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. | Subsample of the VITAL trial participants at baseline and one year. | Posted | Geometric Mean | 95% Confidence Interval | mg/L | Baseline and 1 year |
|
|
|
|
| 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. | Subsample of the VITAL trial participants at baseline and one year. | Posted | Geometric Mean | 95% Confidence Interval | pg/ml | Baseline and 1 year |
|
|
|
|
| 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 | 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) | Posted | Count of Participants | Participants | 5 years |
|
|
|
|
| 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 | Subsample of the VITAL trial who reported chronic frequent knee pain prior to randomization. | Posted | Mean | Standard Deviation | WOMAC units on a scale | Baseline and 5 years |
|
|
|
|
| Secondary | Incident Autoimmune Disease | Development of new autoimmune disease through observational follow-up after trial termination. | Baseline enrolled populations | Posted | Count of Participants | Participants | extension of follow-up through 2 years post trial closure, up to 7 years |
|
|
|
|
| 241 |
| 6,463 |
| 791 |
| 6,463 |
| 5,101 |
| 6,463 |
| EG001 | Active Vitamin D/ Active Omega-3 Placebo | Vitamin D3, one 2000 IU capsule/day Omega-3 fatty acids placebo, one capsule/day | 244 | 6,464 | 782 | 6,464 | 5,027 | 6,464 |
| EG002 | Active Omega-3 Fatty Acids, 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). Vitamin D placebo, one capsule/day | 252 | 6,470 | 822 | 6,470 | 5,037 | 6,470 |
| EG003 | Omega-3 Fatty Acids Placebo/ Placebo Vitamin D | Omega-3 fatty acids placebo, one capsule/day Vitamin D placebo, one capsule/day | 241 | 6,474 | 837 | 6,474 | 5,101 | 6,474 |
| Hypercalcemia | Endocrine disorders | Systematic Assessment |
|
| Invasive cancer of any type | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment | Total cancer = invasive cancer of any type |
|
| Death from cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Breast cancer (in women) | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Prostate cancer (in men) | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Colorectal cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Major cardiovascular event | Vascular disorders | Systematic Assessment | Major cardiovascular event = a composite endpoint of myocardial infarction, stroke, and death from cardiovascular causes |
|
| Myocardial infarction | Vascular disorders | Systematic Assessment |
|
| Stroke | Vascular disorders | Systematic Assessment |
|
| Death from cardiovascular causes | Vascular disorders | Systematic Assessment |
|
| Frequent nosebleeds | Blood and lymphatic system disorders | Systematic Assessment |
|
| Blood in urine | Blood and lymphatic system disorders | Systematic Assessment |
|
| Parathyroid condition | Endocrine disorders | Systematic Assessment | Parathyroid condition = hyperparathyroidism or hypoparathyroidism |
|
| Stomach upset or pain | Gastrointestinal disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Increased burping | Gastrointestinal disorders | Systematic Assessment |
|
| Bad taste in mouth | General disorders | Systematic Assessment |
|
| Kidney stones | Renal and urinary disorders | Systematic Assessment |
|
| Kidney failure or dialysis | Renal and urinary disorders | Systematic Assessment |
|
| Skin rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
Not provided
Not provided
| D012216 |
| Rheumatic Diseases |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D017444 | Skin Diseases, Papulosquamous |
| D012871 | Skin Diseases |
| D005223 |
| Fats |
| D015777 | Eicosanoids |
| D005231 | Fatty Acids, Unsaturated |
| D005227 | Fatty Acids |
| D012632 | Secosteroids |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D002782 | Cholestenes |
| D002776 | Cholestanes |
| D013261 | Sterols |
| D008563 | Membrane Lipids |
| Year 1 ln (hsCRP) mg/L, geometric mean (95% CI) |
|
| Other |
Test of change from baseline as above. |
| 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. | as above | p above adjusted for age, sex, race and vitamin D randomized treatment group. | 0.44 | 6. HsCRP from baseline to one year: overall % change= -3.89% (95%CI -11.92-4.86). | Percent change in geometric means | -3.89 | 2-Sided | 95 | -11.92 | 4.86 | Other | Test of change from baseline as above. |
| 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 for interaction | 0.38 | Superiority |
| Year 1 ln (TNFR2) pg/mL, geometric mean (95% CI) |
|
| Other |
Test of change from baseline as above. |
| 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. | as above | p above adjusted for age, sex, race and vitamin D randomized treatment group. | 0.13 | 5. TNFR2 from baseline to one year: overall % change= -1.27% (95%CI -2.89 to 0.39). | Percent change in geometric means | -1.27 | 2-Sided | 95 | -2.89 | 0.39 | Other | Test of change from baseline as above. |
| 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 for interaction | 0.74 | Superiority | Multiplicative interaction between strata based on linear models of ln biomarker from baseline to year 1 with p for interaction between strata. |
| Cox Proportional Hazard |
| 0.85 |
| 2-Sided |
| 95 |
| 0.67 |
| 1.08 |
| Superiority |
| Test for multiplicative interaction between the effects of randomized treatment groups, vitamin D and n-3 fa on incidence of autoimmune disease. | P for interaction | p multiplicative interaction between effects of vitamin D and n-3 fa supplements | 0.20 | Superiority |
| Follow Up mean WOMAC pain |
|
| Other |
We assessed the main effects of the treatment arms comparing all those randomized to omega-3 fatty acids or omega-3 fatty acid placebo, regardless of vitamin D randomization status. |
| 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. | Mixed Models Analysis | Linear time by treatment interaction (comparing change in WOMAC pain over time in two randomized groups) | 0.41 | Repeated measures model with unstructured variance to assess effect of treatment on WOMAC Pain adjusting for age, sex, and other treatment. Linear time by treatment interaction term assessed change in WOMAC Pain over time in treatment vs placebo. | Other | We assessed the main effects of the treatment arms comparing all those randomized to vitamin D or vitamin D placebo, regardless of omega-3 fatty acid randomization status. | 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. | Regression, Linear | 0.42 | Mean Difference (Net) | -1.5 | Standard Error of the Mean | 1.9 | 2-Sided | Other | Linear regression - WOMAC pain over time mean (Standard error - SE). Differences in WOMAC pain scores in stratified groups. |
| Vitamin D vs. vitamin D placebo among those on placebo omega-3 fatty acids- stratified analyses. | Regression, Linear | 0.18 | Mean Difference (Net) | -2.5 | Standard Error of the Mean | 1.8 | 2-Sided | Other | Linear regression - WOMAC pain over time mean (Standard error - SE). Differences in WOMAC pain scores in stratified groups. |
| Omega-3 fatty acids vs. omega-3 fatty acids placebo among those on active vitamin D. | Regression, Linear | 0.84 | Mean Difference (Net) | 0.39 | Standard Error of the Mean | 1.89 | 2-Sided | Other | Linear regression - WOMAC pain over time mean (Standard error - SE). Report only in final year. Differences in WOMAC pain scores in cross-classified groups. |
| Omega-3 fatty acids vs. omega-3 fatty acids placebo among those on placebo vitamin D. | Regression, Linear | 0.76 | Mean Difference (Net) | -0.55 | Standard Error of the Mean | 1.80 | 2-Sided | Other | Linear regression - WOMAC pain over time mean (Standard error - SE). Report only in final year. Differences in WOMAC pain scores in cross-classified groups. |