Intervention With Vitamin D and Omega-3 Supplements and Incident Heart Failure

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02271230
• Collaborator: (none)
• Enrollment: 25,871
• Location: 1
• Arms: 4
• Duration (Months): 64
• Patients Per Site Per Month: 404.2

Study Details

Study Description

Brief Summary

This study will examine whether an intervention with vitamin D or fish oil supplements can reduce the risk of heart failure among adult men and women during a follow up period of up to five years (starting from the time of randomization into the parent VITAL trial). The investigators hypotheses are that both vitamin D and fish oil supplements will each reduce the risk of heart failure.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Vitamin D and fish oil; Dietary Supplement: Fish oil (EPA/DHA) alone; Drug: Vitamin D alone; Other: Placebo	Phase 3

Detailed Description

For this ancillary study of the ongoing parent VITAL trial, we will adjudicate incident heart failure cases occurring during a time period of up to five years starting from randomization of subjects in the parent VITAL study. Intention-to-treat analysis will be used to assess the efficacy of vitamin D as well as omega-3 fatty acids.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25871 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Intervention With Vitamin D and Omega-3 Supplements and Incident Heart Failure
• Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Dec 1, 2019
• Actual Study Completion Date: Dec 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vitamin D and fish oil 2000 IU per day and 1 g per day of fish oil	Drug: Vitamin D and fish oil; 2000 IU vitamin D and 1g/d fish oil
Placebo Comparator: Vitamin D alone 2000 IU Vitamin D and fish oil placebo	Drug: Vitamin D alone; 2000 IU vitamin D
Experimental: Fish oil (EPA/DHA) alone 1 g per day of fish oil and vitamin D placebo	Dietary Supplement: Fish oil (EPA/DHA) alone; 1 g/d fish oil
Placebo Comparator: Fish oil and vitamin D placebo Placebo for both vitamin D and fish oil	Other: Placebo; Vitamin D placebo and fish oil placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants With New Heart Failure Hospitalization [5 years]

   We will consider any hospitalization for heart failure among participants enrolled in the parent VITAL trial for this ancillary study. Incident heart failure are initially captured through annual questionnaires with subsequent validation by a team of physicians with expertise in cardiovascular medicine and epidemiology. We excluded 36 participants with prevalent heart failure at the time of randomization for the primary analysis.

Secondary Outcome Measures

1. Number of Recurrent Heart Failure Hospitalization [5 years]

   Recurrent heart failure hospitalizations ascertained either by review of medical records and/or use of CMS (Center for Medicare and Medicaid Services) data.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men aged 50 or older or women aged 55 or older

• Be consuming no more than 800 IU of vitamin D from all supplemental sources combined (individual vitamin D supplements, calcium+vitamin D supplements, medications with vitamin D [e.g., Fosamax Plus D], and multivitamins), or, if taking, willing to decrease or forego such use during the trial;

• Be consuming no more than 1200 mg/d of calcium from all supplemental sources combined, or, if taking, willing to decrease or forego such use during the trial;

• Not be taking fish oil supplements, or, if taking, willing to forego their use during the trial

Exclusion Criteria:

• prevalent heart failure

• History of cancer (except non-melanoma skin cancer), heart attack, stroke, transient ischemic attack, angina pectoris, CABG, or PCI

• History of renal failure or dialysis, hypercalcemia, hypo- or hyperparathyroidism, severe liver disease (cirrhosis), or sarcoidosis or other granulomatous diseases such as active chronic tuberculosis or Wegener's granulomatosis;

• Allergy to fish or soy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02120

Sponsors and Collaborators

• Brigham and Women's Hospital

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 31, 2020

More Information

Additional Information:

• Link to published results at Circulation

Publications

None provided.

• Responsible Party: Luc Djousse, Director of Research, Associate Professor of Medicine, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT02271230
• Other Study ID Numbers: 2014P001206
• First Posted: Oct 22, 2014
• Last Update Posted: Mar 18, 2022
• Last Verified: Feb 1, 2022

• Additional relevant MeSH terms: Heart Failure; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins

Study Results

Participant Flow

Recruitment Details	A total of 401605 adults were initially screened; 39430 eligible to enter run-in; 25871 eligible for randomization; 2x2 factorial design: 12927 assigned to active vit D (of these, 6463 were assigned to active omega-3 FAs and 6464 to placebo omega-3 FAs) & 12944 assigned to placebo vit D (of these, 6470 were assigned to active omega-3 FAs and 6474 to placebo omega-3 FAs)
Pre-assignment Detail	The trial included a 3-month placebo run-in period to select participants likely to have excellent compliance. Only individuals who reported taking at least 2/3 of their study pills during the run-in and met other eligibility criteria were randomized into the trial.

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
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 (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: Female, Male (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	Number of Participants With New Heart Failure Hospitalization
Description	We will consider any hospitalization for heart failure among participants enrolled in the parent VITAL trial for this ancillary study. Incident heart failure are initially captured through annual questionnaires with subsequent validation by a team of physicians with expertise in cardiovascular medicine and epidemiology. We excluded 36 participants with prevalent heart failure at the time of randomization for the primary analysis.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Vitamin D	Vitamin D Placebo	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
Measure Participants	12904	12931	12912	12923
Count of Participants [Participants]	240 3.7%	259 4%	244 3.8%	255 3.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Vitamin D, Vitamin D Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Omega-3 Fatty Acids, Omega-3 Fatty Acids Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Recurrent Heart Failure Hospitalization
Description	Recurrent heart failure hospitalizations ascertained either by review of medical records and/or use of CMS (Center for Medicare and Medicaid Services) data.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Each participant is allowed to have multiple heart failure hospitalizations.

Arm/Group Title	Active Vitamin D	Vitamin D Placebo	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
Measure Participants	12927	12944	12933	12938
Number [hospitalizations for heart failure]	341	364	326	379

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Vitamin D, Vitamin D Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Omega-3 Fatty Acids, Omega-3 Fatty Acids Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.74 to 0.998
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	5 years
Adverse Event Reporting Description	Conditions monitored for Vit D: kidney stones, hypercalcemia, parathyroid disease, kidney failure or dialysis; Other symptoms/side effects: gastrointestinal (GI) bleed, easy bruising; stomach upset or pain; nausea; constipation, diarrhea, skin rash Conditions monitored for omega-3: GI bleed; blood in urine; easy bruising; nosebleeds; kidney failure or dialysis; Other side effects: stomach upset or pain; nausea; constipation; diarrhea; skin rash; bad taste in mouth; increased burping
Arm/Group Title	Active Vitamin D		Vitamin D Placebo		Active Omega-3 Fatty Acids		Omega-3 Fatty Acids Placebo
Arm/Group Description	Vitamin D3, one capsule of 2,000 IU/day		Vitamin D placebo, 1 capsule/day		Omacor, 1 g capsule/day Each capsule of Omacor contains 465 mg of eicosapentaenoic acid (EPA) and 375 mg of docosahexaenoic acid (DHA)		Omega-3 fatty acids placebo, one capsule/day
All Cause Mortality
	Active Vitamin D		Vitamin D Placebo		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		Vitamin D Placebo		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	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 events	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		Vitamin D Placebo		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.