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

NCT01351805 | Completed Results DMC

• 1 other identifier: R01AR059086
• Study Type: interventional
• Target: 25,871
• Locations: 1 country
• Sites: 1

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.

Conditions

Autoimmune Diseases; Systemic Inflammatory Process; Knee Pain Chronic; Osteoarthritis; Rheumatoid Arthritis

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

Outcome Measures

Primary Outcomes (5)

• 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

• 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

Secondary Outcomes (1)

• Incident Autoimmune Disease

  extension of follow-up through 2 years post trial closure, up to 7 years

Study Arms (4)

Fish Oil

EXPERIMENTAL

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

Drug: Fish Oil; Other: placebo pill

Vitamin D

EXPERIMENTAL

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

Dietary Supplement: Vitamin D; Other: placebo pill

placebo

PLACEBO COMPARATOR

Subjects will receive placebo pill.

Other: 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 \[DHA\]).

Drug: Fish Oil; Dietary Supplement: Vitamin D

Interventions

Fish Oil DRUG

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

Also known as: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), marine fatty acids, omega-3 fatty acids, fish oils

Fish Oil; Vitamin D and Fish Oil

Vitamin D DIETARY_SUPPLEMENT

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

Also known as: cholecalciferol, vitamin D3

Vitamin D; Vitamin D and Fish Oil

placebo pill OTHER

placebo

Fish Oil; Vitamin D; placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

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

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (5)

• 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.

  PMID: 38518540 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.

  PMID: 38272846 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.

  PMID: 31699704 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.

  PMID: 32583982 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.

  PMID: 35082139 RESULT

Related Links

• Welcome to the VITAL Study Website

MeSH Terms

Conditions

Autoimmune Diseases; Osteoarthritis; Arthritis, Rheumatoid; Psoriasis

Interventions

Fish Oils; Eicosapentaenoic Acid; Docosahexaenoic Acids; Fatty Acids, Omega-3; Vitamin D; Cholecalciferol

Condition Hierarchy (Ancestors)

Immune System Diseases; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Papulosquamous; Skin Diseases

Intervention Hierarchy (Ancestors)

Oils; Lipids; Dietary Fats, Unsaturated; Dietary Fats; Fats; Eicosanoids; Fatty Acids, Unsaturated; Fatty Acids; Secosteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Cholestenes; Cholestanes; Sterols; Membrane Lipids

Results Point of Contact

• Title: Karen Costenbader
• Organization: Brigham and Women's Hospital/ Harvard Medical School

kcostenbader@bwh.harvard.edu

16177326088

Study Officials

• Karen H Costenbader, MD, MPH

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Physician

Study Record Dates

• First Submitted: May 4, 2011
• First Posted: May 11, 2011
• Study Start: July 1, 2010
• Primary Completion: November 10, 2018
• Study Completion: February 1, 2025
• Last Updated: December 3, 2025
• Results First Posted: January 8, 2021

Record last verified: 2025-11

Locations

US (1)