Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT)

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00064753
• Collaborator: Office of Dietary Supplements (ODS) (NIH)
• Enrollment: 4,110
• Locations: 30
• Arms: 2
• Duration (Months): 113
• Patients Per Site: 137
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this randomized clinical trial is to determine if lowering homocysteine levels in renal transplant recipients with a multivitamin will reduce the occurrence of cardiovascular disease outcomes.

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease; Cardiovascular Disease; Death	Drug: High Dose Multivitamin; Device: Low Dose Multivitamin	Phase 2/Phase 3

Detailed Description

The hypothesis of the trial is as follows: Treatment with a high dose combination of folic acid, vitamin B6, and vitamin B12 will reduce the rate of pooled arteriosclerotic cardiovascular disease outcomes (i.e., pooled occurrence of non-fatal and fatal arteriosclerotic outcomes, including coronary heart, cerebrovascular, and peripheral vascular disease events) relative to treatment with an identical multivitamin containing no folic acid, and Estimated Average Requirement amounts of vitamin B6, vitamin B12, among chronic, stable renal transplant recipients

Study Design

• Study Type: Interventional
• Actual Enrollment: 4110 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT)
• Study Start Date: May 1, 2002
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High Dose Multivitamin Multivitamin with increased folic acid, vitamin B6 and vitamin B12	Drug: High Dose Multivitamin; Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg; Other Names: multivitamin
Active Comparator: Low Dose Multivitamin Multivitamin devoid of folic acid and with estimated average requirement amounts of vitamin B6 and vitamin B12	Device: Low Dose Multivitamin; Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg; Other Names: multivitamin

Outcome Measures

Primary Outcome Measures

1. Recurrent or de Novo Arteriosclerotic Cardiovascular Disease (CVD) Defined as the Occurrence of Non-fatal or Fatal Arteriosclerotic Outcomes Including Coronary Heart, Cerebrovascular, and Peripheral Vascular Disease Events [Up to 6 years (mean 4 years)]

Secondary Outcome Measures

1. Renal Graft Failure [Up to 6 years (mean 4 years)]

2. Mortality (All-cause) [Up to 6 years (mean 4 years)]

   censored at 3 months after return to dialysis

3. Fatal/Non-fatal Myocardial Infarction (MI) [Up to 6 years (mean 4 years)]

   censored at 3 months after return to dialysis

4. Fatal/Non-fatal Stroke [Up to 6 years (mean 4 years)]

   censored at 3 months after return to dialysis

5. Resuscitated Sudden Death (RSD) [Up to 6 years (mean 4 years)]

   censored at 3 months after return to dialysis

6. CVD Death [Up to 6 years (mean 4 years)]

   censored at 3 months after return to dialysis

7. Coronary Artery Revascularization [Up to 6 years (mean 4 years)]

   censored at 3 months after return to dialysis

8. Lower Extremity Peripheral Arterial Disease (PAD) [Up to 6 years (mean 4 years)]

   censored at 3 months after return to dialysis

9. Carotid Endarterectomy or Angioplasty [Up to 6 years (mean 4 years)]

   censored at 3 months after return to dialysis

10. Abdominal Aortic Aneurysm Repair [Up to 6 years (mean 4 years)]

    censored at 3 months after return to dialysis

11. Renal Artery Revascularization [Up to 6 years (mean 4 years)]

    censored at 3 months after return to dialysis

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 35 - 75 years old

• Had kidney transplant at least 6 months

• Calculated Creatinine Clearance must be 25 mL/min or greater

• Must be willing to stop supplements (B6, B12, folic acid) for 4-6 weeks prior to visit

Exclusion Criteria:

• If pregnant or lactating

• If of child bearing potential and not on birth control

• If any of the following will limit life expectancy to less than 2 yrs:

• Cancer

• Congestive heart failure (CHF) (end stage)

• Liver disease (end stage)

• Severe pulmonary disease

• Progressive HIV

• Any other chronic wasting illness

• If patient had myocardial infarction (MI), stroke, lower extremity amputation above ankle or percutaneous revascularization procedure (coronary, cerebrovascular, lower extremity) in past 2months

• If patient had coronary artery bypass graft (CABG) or abdominal aortic aneurysm (AAA) in past 5 months

• If patient has conditions that prevent reliable study participation e.g., depression, alcohol or drug abuse, other cardiovascular disease (CVD) studies

• If patient has had multi-organ transplant, except kidney/pancreas

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham School of Medicine	Birmingham	Alabama	United States	35233
2	Banner Good Samaritan Transplant	Phoenix	Arizona	United States	85004-1608
3	Cedars-Sinai Health System/Center for Kidney Diseases and Transplantation	Los Angeles	California	United States	90048
4	University of California at Los Angeles	Los Angeles	California	United States	90095-7306
5	University of California at San Francisco	San Francisco	California	United States	94143-0780
6	Northwestern University	Chicago	Illinois	United States	60611
7	Southern Illinois University	Springfield	Illinois	United States	62794-9638
8	Indiana University	Indianapolis	Indiana	United States	46202
9	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
10	Maine Medical Center	Portland	Maine	United States	04102
11	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
12	Brigham and Women's Hospital	Boston	Massachusetts	United States	02120
13	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109-0364
14	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55404
15	Faireview University Medical Center	Minneapolis	Minnesota	United States	55455
16	Mayo Clinic	Rochester	Minnesota	United States	55905
17	Washington University	Saint Louis	Missouri	United States	63110
18	Albany Medical Center	Albany	New York	United States	12208
19	State University of New York Downstate Medical Center	Brooklyn	New York	United States	11203
20	Duke University Medical Center	Durham	North Carolina	United States	27710
21	East Carolina University	Greenville	North Carolina	United States	27834
22	The Ohio State University Medical Center	Columbus	Ohio	United States	43210-1228
23	Oregon Health Sciences University	Portland	Oregon	United States	97201-2940
24	Drexel University	Philadelphia	Pennsylvania	United States	19102-1192
25	Rhode Island Hospital	Providence	Rhode Island	United States	02903
26	University of Wisconsin at Madison	Madison	Wisconsin	United States	53792
27	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
28	Universidade Federal de Sao Paulo	Sao Paulo	SP	Brazil	04023-900
29	London Health Sciences Center	London	Ontario	Canada	N6A 5A5
30	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2N2

Sponsors and Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Office of Dietary Supplements (ODS)

Investigators

• Study Director: Andrew Levey, M.D., Tufts Medical Center
• Principal Investigator: Myra A Carpenter, PhD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• FAVORIT website

Publications

• Bostom AG, Carpenter MA, Kusek JW, Hunsicker LG, Pfeffer MA, Levey AS, Jacques PF, McKenney J; FAVORIT Investigators. Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial. Am Heart J. 2006 Sep;152(3):448.e1-7.
• Carpenter MA, John A, Weir MR, Smith SR, Hunsicker L, Kasiske BL, Kusek JW, Bostom A, Ivanova A, Levey AS, Solomon S, Pesavento T, Weiner DE. BP, cardiovascular disease, and death in the Folic Acid for Vascular Outcome Reduction in Transplantation trial. J Am Soc Nephrol. 2014 Jul;25(7):1554-62. doi: 10.1681/ASN.2013040435. Epub 2014 Mar 13.
• Carpenter MA, Weir MR, Adey DB, House AA, Bostom AG, Kusek JW. Inadequacy of cardiovascular risk factor management in chronic kidney transplantation - evidence from the FAVORIT study. Clin Transplant. 2012 Jul-Aug;26(4):E438-46. doi: 10.1111/j.1399-0012.2012.01676.x. Epub 2012 Jul 9.
• Troen AM, Scott TM, D'Anci KE, Moorthy D, Dobson B, Rogers G, Weiner DE, Levey AS, Dallal GE, Jacques PF, Selhub J, Rosenberg IH; FACT Study Investigators. Cognitive dysfunction and depression in adult kidney transplant recipients: baseline findings from the FAVORIT Ancillary Cognitive Trial (FACT). J Ren Nutr. 2012 Mar;22(2):268-276.e3. doi: 10.1053/j.jrn.2011.07.009. Epub 2011 Dec 6.
• Weiner DE, Carpenter MA, Levey AS, Ivanova A, Cole EH, Hunsicker L, Kasiske BL, Kim SJ, Kusek JW, Bostom AG. Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial. Am J Transplant. 2012 Sep;12(9):2437-45. doi: 10.1111/j.1600-6143.2012.04101.x. Epub 2012 May 17.
• Weir MR, Gravens-Muller L, Costa N, Ivanova A, Manitpisitkul W, Bostom AG, Diamantidis CJ; FAVORIT Study Investigators. Safety events in kidney transplant recipients: results from the folic Acid for vascular outcome reduction in transplant trial. Transplantation. 2015 May;99(5):1003-8. doi: 10.1097/TP.0000000000000454.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00064753
• Other Study ID Numbers: FAVORIT dk61700 IND; U01DK061700
• First Posted: Jul 15, 2003
• Last Update Posted: Oct 18, 2017
• Last Verified: Oct 1, 2015

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): homocysteine; multi-vitamin; cardiovascular disease; renal transplant recipients
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Cardiovascular Diseases

Study Results

Participant Flow

Recruitment Details	Trial enrolled 4110 participants from August 2002 through January 2007 at 20 clinical sites in the US, Canada, and Brazil.

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with estimated average requirement (EAR) amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Period Title: Overall Study
STARTED	2056	2054
COMPLETED	1382	1406
NOT COMPLETED	674	648

Baseline Characteristics

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin	Total
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Total of all reporting groups
Overall Participants	2056	2054	4110
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52 (9.4)	52 (9.5)	52 (9.4)
Sex: Female, Male (Count of Participants)
Female	767 37.3%	761 37%	1528 37.2%
Male	1289 62.7%	1293 63%	2582 62.8%
Region of Enrollment (participants) [Number]
Canada	249 12.1%	249 12.1%	498 12.1%
United States	1500 73%	1500 73%	3000 73%
Brazil	307 14.9%	305 14.8%	612 14.9%
Graft vintage (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	6 (5.1)	5 (5.0)	5 (5.0)
History of CVD (participants) [Number]
History of CVD	406 19.7%	414 20.2%	820 20%
No History of CVD	1650 80.3%	1640 79.8%	3290 80%
History of diabetes mellitus (participants) [Number]
History of diabetes mellitus	813 39.5%	850 41.4%	1663 40.5%
No history of diabetes mellitus	1243 60.5%	1204 58.6%	2447 59.5%
Prevalent hypertension (participants) [Number]
Prevalent hypertension	1879 91.4%	1899 92.5%	3778 91.9%
Non-prevalent hypertension	177 8.6%	155 7.5%	332 8.1%
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29 (6.2)	29 (6.3)	29 (6.2)
Current smoker (participants) [Number]
Current smoker	230 11.2%	221 10.8%	451 11%
Not current smoker	1826 88.8%	1833 89.2%	3659 89%
Total cholesterol (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	4.8 (1.2)	4.8 (1.1)	4.8 (1.1)
High-density lipoprotein cholesterol (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	1.2 (0.4)	1.2 (0.4)	1.2 (0.4)
Calculated or direct low-density lipoprotein cholesterol (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	2.6 (0.9)	2.6 (0.9)	2.6 (0.9)
Triglycerides levels (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	2.3 (2.5)	2.2 (1.6)	2.2 (2.1)

Outcome Measures

1. Primary Outcome

Title	Recurrent or de Novo Arteriosclerotic Cardiovascular Disease (CVD) Defined as the Occurrence of Non-fatal or Fatal Arteriosclerotic Outcomes Including Coronary Heart, Cerebrovascular, and Peripheral Vascular Disease Events
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

Censored at 3 months after return to dialysis

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2029	2029
Number [participants]	269 13.1%	278 13.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments	P was calculated with stratified proportional hazards models stratified by country
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Renal Graft Failure
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

Intention-to-treat

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2029	2029
Number [participants]	181 8.8%	162 7.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments	P was calculated with stratified proportional hazards models stratified by country
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95%; 0.93 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mortality (All-cause)
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2054	2049
Number [participants]	217 10.6%	214 10.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments	P was calculated with stratified proportional hazards models stratified by country
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Fatal/Non-fatal Myocardial Infarction (MI)
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2056	2054
Number [participants]	90 4.4%	86 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.61
	Comments	P was calculated with stratified proportional hazards models stratified by country
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Fatal/Non-fatal Stroke
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2056	2054
Number [participants]	35 1.7%	32 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.64
	Comments	P was calculated with stratified proportional hazards models stratified by country
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Resuscitated Sudden Death (RSD)
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2056	2054
Number [participants]	7 0.3%	9 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.66
	Comments	P was calculated with stratified proportional hazards models stratified by country
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.30 to 2.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	CVD Death
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

P was calculated with stratified proportional hazards models stratified by country

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2056	2054
Number [participants]	75 3.6%	91 4.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Coronary Artery Revascularization
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2056	2054
Number [participants]	111 5.4%	120 5.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	Regression, Cox
	Comments	P was calculated with stratified proportional hazards models stratified by country
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Lower Extremity Peripheral Arterial Disease (PAD)
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2056	2054
Number [participants]	59 2.9%	53 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	Regression, Cox
	Comments	P was calculated with stratified proportional hazards models stratified by country
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Carotid Endarterectomy or Angioplasty
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2056	2054
Number [participants]	10 0.5%	9 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Regression, Cox
	Comments	P was calculated with stratified proportional hazards models stratified by country
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.46 to 2.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Abdominal Aortic Aneurysm Repair
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2056	2054
Number [participants]	3 0.1%	5 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.50
	Comments
	Method	Regression, Cox
	Comments	P was calculated with stratified proportional hazards models stratified by country
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.15 to 2.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Renal Artery Revascularization
Description	censored at 3 months after return to dialysis
Time Frame	Up to 6 years (mean 4 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Multivitamin	Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg	Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
Measure Participants	2	2054
Number [participants]	9 0.4%	7 0.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Multivitamin, Low Dose Multivitamin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	Regression, Cox
	Comments	P was calculated with stratified proportional hazards models stratified by country
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95%; 0.48 to 3.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	4 years
Arm/Group Title	High Dose Multivitamin		Low Dose Multivitamin
Arm/Group Description	Multivitamin with increased folic acid, vitamin B6 and vitamin B12 High Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 50 mg Folic acid: 5.0 mg Vitamin B12: 1.0 mg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg		Multivitamin devoid of folic acid and with EAR amounts of vitamin B6 and vitamin B12 Low Dose Multivitamin: Vitamin B6 (Pyridoxine HCl): 1.4 mg Folic acid: 0.0 mg Vitamin B12: 2.0 mcg Vitamin B1 (Thiamine HNO3): 1.5 mg Vitamin B2 (Riboflavin): 1.5 mg Vitamin C (Ascorbic Acid): 60 mg d-Biotin: 300 mcg Niacinamide: 20 mg Pantothenic Acid Calcium Pantothenate): 10 mg
All Cause Mortality
	High Dose Multivitamin		Low Dose Multivitamin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	High Dose Multivitamin		Low Dose Multivitamin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2056 (0%)		0/2054 (0%)
Other (Not Including Serious) Adverse Events
	High Dose Multivitamin		Low Dose Multivitamin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	121/2056 (5.9%)		114/2054 (5.6%)
Gastrointestinal disorders
Gastrointestinal disturbances	121/2056 (5.9%)		114/2054 (5.6%)

Limitations/Caveats

The B-vitamin pathway for reducing total homocysteine (tHcy) may not be the optimal one for reducing CVD risk. Also, the duration of follow-up may not have been sufficient to identify a lagged impact on modification of CVD risk.

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.