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

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01351805
• Collaborator: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)
• Enrollment: 25,871
• Location: 1
• Arms: 4
• Anticipated Duration (Months): 125
• Patients Per Site Per Month: 207

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Autoimmune Diseases; Systemic Inflammatory Process; Knee Pain Chronic; Osteoarthritis; Rheumatoid Arthritis	Drug: Fish Oil; Dietary Supplement: Vitamin D; Other: placebo pill	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 25871 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Vitamin D and Fish Oil for Autoimmune Disease, Inflammation and Knee Pain
• Actual Study Start Date: Nov 1, 2011
• Anticipated Primary Completion Date: Apr 1, 2022
• Anticipated Study Completion Date: Apr 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fish Oil Subjects will receive marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]).	Drug: Fish Oil; Subjects will receive marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]).; Other Names: eicosapentaenoic acid (EPA) docosahexaenoic acid (DHA) marine fatty acids omega-3 fatty acids fish oils ; Other: placebo pill; placebo
Experimental: Vitamin D Subjects will receive vitamin D3 (cholecalciferol) 2000 IU a day.	Dietary Supplement: Vitamin D; Subjects will receive vitamin D3 (cholecalciferol) 2000 IU a day.; Other Names: cholecalciferol vitamin D3 ; Other: placebo pill; placebo
Placebo Comparator: placebo Subjects will receive placebo pill.	Other: placebo pill; placebo
Experimental: Vitamin D and Fish Oil Subjects will receive marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]).	Drug: Fish Oil; Subjects will receive marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]).; Other Names: eicosapentaenoic acid (EPA) docosahexaenoic acid (DHA) marine fatty acids omega-3 fatty acids fish oils ; Dietary Supplement: Vitamin D; Subjects will receive vitamin D3 (cholecalciferol) 2000 IU a day.; Other Names: cholecalciferol vitamin D3

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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).

3. 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).

4. Incident Autoimmune Diseases [5 years (Data are not yet published. They are under review at journal and embargoed.)]

   All participants will be 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. Data are not yet published. They are under review at journal and embargoed.

Secondary Outcome Measures

1. Interactions Between the Effects of Vitamin D and Those of Fish Oils for Each of the Primary Outcomes. Reported With Main Results. [5 years (Data are not yet published. They are under review at journal and embargoed.)]

   We will test for interactions between the effects of vitamin D and those of fish oils for each of the primary outcomes above: (A) whether either or both supplements are associated with reduced numbers of new cases of autoimmune diseases; (B) whether either or both supplements are associated with reductions in biomarkers of systemic inflammation and; (C) whether either or both supplements are associated with reduced levels of knee pain at the end of the trial. Data are not yet published. They are under review at journal and embargoed.

2. Subgroup Analysis of Primary Outcomes. Reported With Main Results, Primary Outcomes. [5 years (Data are not yet published. They are under review at journal and embargoed.)]

   We will test for differential effects of and interactions between vitamin D and fish oils for each of the three primary outcomes, according to participant age, race, sex and BMI. We will test for these interactions for each of the primary aims above: (A) whether either or both supplements are associated with reduced numbers of new cases of autoimmune diseases; (B) whether either or both supplements are associated with reductions in biomarkers of systemic inflammation and; (C) whether either or both supplements are associated with reduced levels of knee pain at the end of the trial. Data are not yet published. They are under review at journal and embargoed.

3. Incident Autoimmune Disease [8 years (Data are not yet published. They are under review at journal and embargoed.)]

   Development of new autoimmune diseases through open-label extension beyond the randomized 5 years Data are not yet published. They are under review at journal and embargoed.

Other Outcome Measures

1. Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA [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. We tested whether n-3 FA supplements 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).

2. Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With 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 Vitamin D supplements compared to those taking placebo. We tested whether Vitamin D supplements were associated with reduced levels of WOMAC knee pain at the end of the trial (comparing knee pain outcomes in those receiving supplements to placebo).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

• Principal Investigator: Karen H Costenbader, MD, MPH, Brigham and Women's Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 9, 2009

More Information

Additional Information:

• Welcome to the VITAL Study Website

Publications

None provided.

• Responsible Party: Karen H. Costenbader, Associate Physician, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01351805
• Other Study ID Numbers: R01AR059086; R01AR059086
• First Posted: May 11, 2011
• Last Update Posted: Apr 12, 2021
• Last Verified: Mar 1, 2021

• Keywords provided by Karen H. Costenbader, Associate Physician, Brigham and Women's Hospital: 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
• Additional relevant MeSH terms: Arthritis; Osteoarthritis; Arthritis, Rheumatoid; Autoimmune Diseases; Inflammation; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins

Study Results

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.
Pre-assignment Detail	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.

Arm/Group Title	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
Arm/Group Description	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 = Vitamin D3, one 2000 IU capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day	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, one capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day
Period Title: Overall Study
STARTED	6463	6464	6470	6474
Knee Pain Cohort Within VITAL Trial	342	332	353	371
Biomarkers of Systemic Inflammation Cohort Within VITAL Trial	392	392	392	385
COMPLETED	6463	6464	6470	6474
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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 = Vitamin D3, one 2000 IU capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day	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, one capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day	Total of all reporting groups
Overall Participants	6463	6464	6470	6474	25871
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2458 38%	2462 38.1%	2461 38%	2467 38.1%	9848 38.1%
>=65 years	4005 62%	4002 61.9%	4009 62%	4007 61.9%	16023 61.9%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.1 (7.1)	67.1 (7.0)	67.2 (7.1)	67.1 (7.1)	67.1 (7.1)
Sex/Gender, Customized (Count of Participants)
Female	3276 50.7%	3271 50.6%	3271 50.6%	3267 50.5%	13085 50.6%
Male	3187 49.3%	3193 49.4%	3199 49.4%	3207 49.5%	12786 49.4%
Race/Ethnicity, Customized (Count of Participants)
Non-Hispanic white	4515 69.9%	4498 69.6%	4529 70%	4504 69.6%	18046 69.8%
African American	1278 19.8%	1275 19.7%	1271 19.6%	1282 19.8%	5106 19.7%
Hispanic (not African American)	246 3.8%	270 4.2%	245 3.8%	252 3.9%	1013 3.9%
Asian/Pacific Islander	102 1.6%	86 1.3%	98 1.5%	102 1.6%	388 1.5%
Native American/ Alaskan Native	62 1%	56 0.9%	58 0.9%	52 0.8%	228 0.9%
Other/ unknown	126 1.9%	133 2.1%	123 1.9%	141 2.2%	523 2%
Region of Enrollment (participants) [Number]
United States	6463 100%	6464 100%	6470 100%	6474 100%	25871 100%

Outcome Measures

1. Primary Outcome

Title	Serum Levels of Biomarkers of Systemic Inflammation: Interleukin-6 (IL-6)
Description	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).
Time Frame	Baseline and 1 year

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Vitamin D	Placebo Vitamin D	Active n-3 FA	Placebo n-3 FA
Arm/Group Description	Vitamin D3, one 2000 IU capsule/day	Vitamin D placebo, one 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).	Omega-3 fatty acids placebo, one capsule/day
Measure Participants	784	777	784	777
Baseline ln (IL-6) pg/ml, geometric mean (95% Cl)	1.71	1.68	1.69	1.70
Year 1 ln (IL-6) pg/mL, geometric mean (95% CI)	1.80	1.63	1.70	1.72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Vitamin D, Placebo Vitamin D
	Comments	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.
	Type of Statistical Test	Other
	Comments	Test of change from baseline as above. Test for interaction on multiplicative scale between vitamin D and fish oil.
Statistical Test of Hypothesis	p-Value	0.02
	Comments	1. IL-6 from baseline to one year: overall % change= 8.19% (95%CI 1.52-15.31).
	Method	as above
	Comments	p above adjusted for age, sex, race and n-3 fatty acid randomized treatment group. p for interaction between vitamin D and fish oil= 0.12
Method of Estimation	Estimation Parameter	Percent change in means
	Estimated Value	8.19
	Confidence Interval	(2-Sided) 95%; 1.52 to 15.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	p for interaction on multiplicative scale

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active n-3 FA, Placebo n-3 FA
	Comments	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.
	Type of Statistical Test	Other
	Comments	Test of change from baseline as above. Test for interaction on multiplicative scale between vitamin D and fish oil.
Statistical Test of Hypothesis	p-Value	0.97
	Comments	4. IL-6 from baseline to one year: overall % change= -0.73% (95%CI -6.87 to 5.81).
	Method	as above
	Comments	p above adjusted for age, sex, race and vitamin D randomized treatment group. p for interaction between fish oil and vitamin D= 0.22
Method of Estimation	Estimation Parameter	Percent change in means
	Estimated Value	-0.73
	Confidence Interval	(2-Sided) 95%; -6.87 to 5.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Serum Levels of Biomarkers of Systemic Inflammation: C-reactive Protein (CRP)
Description	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).
Time Frame	Baseline and 1 year

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Vitamin D	Placebo Vitamin D	Active n-3 FA	Placebo n-3 FA
Arm/Group Description	Vitamin D3, one 2000 IU capsule/day	Vitamin D placebo, one 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).	Omega-3 fatty acids placebo, one capsule/day
Measure Participants	784	777	784	777
Baseline ln (hsCRP) mg/L, geometric mean (95% Cl)	1.48	1.51	1.57	1.43
Year 1 ln (hsCRP) mg/L, geometric mean (95% CI)	1.62	1.54	1.63	1.53

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Vitamin D, Placebo Vitamin D
	Comments	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.
	Type of Statistical Test	Other
	Comments	Test of change from baseline as above. Test for interaction on multiplicative scale between vitamin D and fish oil.
Statistical Test of Hypothesis	p-Value	0.16
	Comments	3. HsCRP from baseline to one year: overall % change= 7.12% (95%CI -1.81-16.78).
	Method	as above
	Comments	p above adjusted for age, sex, race and n-3 fatty acid randomized treatment group. p for interaction between vitamin D and fish oil= 0.38
Method of Estimation	Estimation Parameter	Percent change in means
	Estimated Value	7.12
	Confidence Interval	(2-Sided) 95%; -1.81 to 16.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active n-3 FA, Placebo n-3 FA
	Comments	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.
	Type of Statistical Test	Other
	Comments	Test of change from baseline as above. Test for interaction on multiplicative scale between vitamin D and fish oil.
Statistical Test of Hypothesis	p-Value	0.44
	Comments	6. HsCRP from baseline to one year: overall % change= -3.89% (95%CI -11.92-4.86).
	Method	as above
	Comments	p above adjusted for age, sex, race and vitamin D randomized treatment group. p for interaction between fish oil and vitamin D= 0.38
Method of Estimation	Estimation Parameter	Percent change in means
	Estimated Value	-3.89
	Confidence Interval	(2-Sided) 95%; -11.92 to 4.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Serum Levels of Biomarkers of Systemic Inflammation: Tumor Necrosis Factor-receptor 2 (TNFR2)
Description	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).
Time Frame	Baseline and 1 year

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active Vitamin D	Placebo Vitamin D	Active n-3 FA	Placebo n-3 FA
Arm/Group Description	Vitamin D3, one 2000 IU capsule/day	Vitamin D placebo, one 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).	Omega-3 fatty acids placebo, one capsule/day
Measure Participants	784	777	784	777
Baseline ln (TNFR2) pg/ml, geometric mean (95% Cl)	2546.5	2525.4	2571.3	2500.9
Year 1 ln (TNFR2) pg/mL, geometric mean (95% CI)	2604.7	2567.9	2605.3	2567.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Vitamin D, Placebo Vitamin D
	Comments	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.
	Type of Statistical Test	Other
	Comments	Test of change from baseline as above. Test for interaction on multiplicative scale between vitamin D and fish oil.
Statistical Test of Hypothesis	p-Value	0.57
	Comments	2. TNFR2 from baseline to one year: overall % change= 0.63% (95%CI -1.03 to 2.31).
	Method	as above
	Comments	p above adjusted for age, sex, race and n-3 fatty acid randomized treatment group. p for interaction between vitamin D and fish oil= 0.74
Method of Estimation	Estimation Parameter	Percent change in means
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; -1.03 to 2.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active n-3 FA, Placebo n-3 FA
	Comments	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.
	Type of Statistical Test	Other
	Comments	Test of change from baseline as above. Test for interaction on multiplicative scale between vitamin D and fish oil.
Statistical Test of Hypothesis	p-Value	0.13
	Comments	5. TNFR2 from baseline to one year: overall % change= -1.27% (95%CI -2.89 to 0.39).
	Method	as above
	Comments	p above adjusted for age, sex, race and vitamin D randomized treatment group. p for interaction between fish oil and vitamin D= 0.74
Method of Estimation	Estimation Parameter	Percent change in means
	Estimated Value	-1.27
	Confidence Interval	(2-Sided) 95%; -2.89 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Incident Autoimmune Diseases
Description	All participants will be 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. Data are not yet published. They are under review at journal and embargoed.
Time Frame	5 years (Data are not yet published. They are under review at journal and embargoed.)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Interactions Between the Effects of Vitamin D and Those of Fish Oils for Each of the Primary Outcomes. Reported With Main Results.
Description	We will test for interactions between the effects of vitamin D and those of fish oils for each of the primary outcomes above: (A) whether either or both supplements are associated with reduced numbers of new cases of autoimmune diseases; (B) whether either or both supplements are associated with reductions in biomarkers of systemic inflammation and; (C) whether either or both supplements are associated with reduced levels of knee pain at the end of the trial. Data are not yet published. They are under review at journal and embargoed.
Time Frame	5 years (Data are not yet published. They are under review at journal and embargoed.)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Subgroup Analysis of Primary Outcomes. Reported With Main Results, Primary Outcomes.
Description	We will test for differential effects of and interactions between vitamin D and fish oils for each of the three primary outcomes, according to participant age, race, sex and BMI. We will test for these interactions for each of the primary aims above: (A) whether either or both supplements are associated with reduced numbers of new cases of autoimmune diseases; (B) whether either or both supplements are associated with reductions in biomarkers of systemic inflammation and; (C) whether either or both supplements are associated with reduced levels of knee pain at the end of the trial. Data are not yet published. They are under review at journal and embargoed.
Time Frame	5 years (Data are not yet published. They are under review at journal and embargoed.)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Incident Autoimmune Disease
Description	Development of new autoimmune diseases through open-label extension beyond the randomized 5 years Data are not yet published. They are under review at journal and embargoed.
Time Frame	8 years (Data are not yet published. They are under review at journal and embargoed.)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With n-3 FA
Description	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. We tested whether n-3 FA supplements 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).
Time Frame	Baseline and 5 years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Active n-3 FA	Placebo n-3 FA
Arm/Group Description	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
Measure Participants	595	626
Baseline mean WOMAC Pain	36.5 (0.7)	35.4 (0.7)
Follow Up mean WOMAC pain	33.6 (0.9)	33.7 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Vitamin D, Placebo Vitamin D
	Comments	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.
	Type of Statistical Test	Other
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.77
	Comments	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.
	Method	Mixed Models Analysis
	Comments	Repeated measures model with censoring for total knee replacement.
Other Statistical Analysis		We assessed for effect modification between n-3 FA and vitamin D and tested for other pre-specified interactions. We again used a repeated measures model with censoring for TKR. We adjusted for age, sex and vitamin D treatment arm (in analyses in which vitamin D treatment arm was not investigated as a potential modifier).

9. Other Pre-specified Outcome

Title	Severity of Knee Pain in Subsample With Chronic, Frequent Knee Pain at Baseline- With Vitamin D
Description	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 Vitamin D supplements compared to those taking placebo. We tested whether Vitamin D supplements were associated with reduced levels of WOMAC knee pain at the end of the trial (comparing knee pain outcomes in those receiving supplements to placebo).
Time Frame	Baseline and 5 years

Outcome Measure Data

Analysis Population Description

Subsample of VITAL trial participants with chronic, frequent knee pain at baseline prior to randomization.

Arm/Group Title	Active Vitamin D	Placebo Vitamin D
Arm/Group Description	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
Measure Participants	591	630
Baseline mean WOMAC Pain	35.4 (0.7)	36.5 (0.7)
Follow Up mean WOMAC Pain	32.7 (0.9)	34.6 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Vitamin D, Placebo Vitamin D
	Comments	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.
	Type of Statistical Test	Other
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.41
	Comments	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.
	Method	Mixed Models Analysis
	Comments	Linear time by treatment interaction (comparing change in WOMAC pain over time in two randomized groups)
Other Statistical Analysis		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).

Adverse Events

Time Frame	5 years
Adverse Event Reporting Description	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
Arm/Group Title	Active Vitamin D		Placebo Vitamin D		Active Omega-3 Fatty Acids		Omega-3 Fatty Acids Placebo
Arm/Group Description	Vitamin D3, one 2000 IU capsule/day		Vitamin D placebo, one 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).		Omega-3 fatty acids placebo, one capsule/day
All Cause Mortality
	Active Vitamin D		Placebo Vitamin D		Active Omega-3 Fatty Acids		Omega-3 Fatty Acids Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	485/12927 (3.8%)		493/12944 (3.8%)		493/12933 (3.8%)		485/12938 (3.7%)
Serious Adverse Events
	Active Vitamin D		Placebo Vitamin D		Active Omega-3 Fatty Acids		Omega-3 Fatty Acids Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1673/12927 (12.9%)		1659/12944 (12.8%)		1613/12933 (12.5%)		1619/12938 (12.5%)
Blood and lymphatic system disorders
Gastrointestinal bleeding	341/12927 (2.6%)		403/12944 (3.1%)		370/12933 (2.9%)		374/12938 (2.9%)
Endocrine disorders
Hypercalcemia	147/12927 (1.1%)		143/12944 (1.1%)		151/12933 (1.2%)		139/12938 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive cancer of any type	793/12927 (6.1%)		824/12944 (6.4%)		820/12933 (6.3%)		797/12938 (6.2%)
Death from cancer	154/12927 (1.2%)		187/12944 (1.4%)		168/12933 (1.3%)		173/12938 (1.3%)
Breast cancer (in women)	124/12927 (1%)		122/12944 (0.9%)		117/12933 (0.9%)		129/12938 (1%)
Prostate cancer (in men)	192/12927 (1.5%)		219/12944 (1.7%)		219/12933 (1.7%)		192/12938 (1.5%)
Colorectal cancer	51/12927 (0.4%)		47/12944 (0.4%)		54/12933 (0.4%)		44/12938 (0.3%)
Vascular disorders
Major cardiovascular event	396/12927 (3.1%)		409/12944 (3.2%)		386/12933 (3%)		419/12938 (3.2%)
Myocardial infarction	169/12927 (1.3%)		176/12944 (1.4%)		145/12933 (1.1%)		200/12938 (1.5%)
Stroke	141/12927 (1.1%)		149/12944 (1.2%)		148/12933 (1.1%)		142/12938 (1.1%)
Death from cardiovascular causes	152/12927 (1.2%)		138/12944 (1.1%)		142/12933 (1.1%)		148/12938 (1.1%)
Other (Not Including Serious) Adverse Events
	Active Vitamin D		Placebo Vitamin D		Active Omega-3 Fatty Acids		Omega-3 Fatty Acids Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10086/12927 (78%)		10098/12944 (78%)		10094/12933 (78%)		10090/12938 (78%)
Blood and lymphatic system disorders
Easy bruising	3434/12927 (26.6%)		3408/12944 (26.3%)		3443/12933 (26.6%)		3399/12938 (26.3%)
Frequent nosebleeds	466/12927 (3.6%)		490/12944 (3.8%)		465/12933 (3.6%)		491/12938 (3.8%)
Blood in urine	911/12927 (7%)		882/12944 (6.8%)		919/12933 (7.1%)		874/12938 (6.8%)
Endocrine disorders
Parathyroid condition	50/12927 (0.4%)		62/12944 (0.5%)		52/12933 (0.4%)		60/12938 (0.5%)
Gastrointestinal disorders
Stomach upset or pain	4860/12927 (37.6%)		4870/12944 (37.6%)		4887/12933 (37.8%)		4843/12938 (37.4%)
Nausea	3519/12927 (27.2%)		3589/12944 (27.7%)		3558/12933 (27.5%)		3550/12938 (27.4%)
Constipation	5133/12927 (39.7%)		5162/12944 (39.9%)		5184/12933 (40.1%)		5111/12938 (39.5%)
Diarrhea	5511/12927 (42.6%)		5668/12944 (43.8%)		5599/12933 (43.3%)		5580/12938 (43.1%)
Increased burping	2168/12927 (16.8%)		2207/12944 (17.1%)		2217/12933 (17.1%)		2158/12938 (16.7%)
General disorders
Bad taste in mouth	2195/12927 (17%)		2290/12944 (17.7%)		2240/12933 (17.3%)		2245/12938 (17.4%)
Renal and urinary disorders
Kidney stones	477/12927 (3.7%)		426/12944 (3.3%)		430/12933 (3.3%)		473/12938 (3.7%)
Kidney failure or dialysis	85/12927 (0.7%)		88/12944 (0.7%)		85/12933 (0.7%)		88/12938 (0.7%)
Skin and subcutaneous tissue disorders
Skin rash	3268/12927 (25.3%)		3430/12944 (26.5%)		3331/12933 (25.8%)		3367/12938 (26%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.