NORVIT and WENBIT - Long-term Follow-up (NORVIT-WENBIT)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
University of Tromso
Norwegian Foundation for Health and Rehabilitation
Information provided by (Responsible Party):
Marta Ebbing, Haukeland University Hospital
ClinicalTrials.gov Identifier:
NCT00671346
First received: April 29, 2008
Last updated: March 17, 2013
Last verified: March 2013
  Purpose

Two large homocysteine-lowering B-vitamin intervention trials have been performed in Norway during the period 1998 to 2005, NORVIT and WENBIT. The main objective in these was to study the clinical effects of homocysteine-lowering therapy with folic acid and vitamin B12 in patients with established coronary artery disease. Follow-up was terminated for NORVIT on Marc 31st 2004 and for WENBIT October 5th 2005, and none of the two trials proved any protective effect of the B-vitamin intervention on cardiovascular outcomes.

There is so far no data on possible long-term effects following years of such B-vitamin treatment.

Current data indicate that folic acid and other B-vitamins prevents cancer. However, during the last few years several reports have challenged this assumption. A new hypothesis has been launched that folate may prevent the transformation from normal cells to cancer cells, but may enhance the growth of cancer once it has been established.

Our main objective is to estimate possible cancer preventive or promotional effects by the B-vitamin treatment given to participants in NORVIT and WENBIT during trial follow-up and through long-term follow-up years after the intervention was terminated. Our second objective is to estimate possible preventive or harmful long-term effects of the B-vitamin treatment on cardiovascular outcomes.


Condition
Cancer
Myocardial Infarction
Cerebrovascular Stroke

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Combined Analyses and Long-term Follow-up in the Two Norwegian Homocysteine-Lowering B-Vitamin Trials NORVIT and WENBIT

Resource links provided by NLM:


Further study details as provided by Haukeland University Hospital:

Primary Outcome Measures:
  • Possible effects of B-vitamin treatment on risk of developing cancer during the trial periods (completed by 2004 and 2005) and during post-trial follow-up. [ Time Frame: 1998-2014 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • The possible effects of B-vitamin treatment on major cardiovascular events, all cause mortality and cause specific death during the trial periods (completed by 2004 and 2005) and during post-trial follow-up. [ Time Frame: 1998-2014 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 6839
Study Start Date: December 1998
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts
1
Participants in NORVIT and WENBIT allocated to treatment with folic acid and vitamin B12.
2
Participants in NORVIT and WENBIT allocated to no treatment with folic acid and vitamin B12.
3
Participants in NORVIT and WENBIT allocated to treatment with vitamin B6.
4
Participants in NORVIT and WENBIT allocated to no treatment with vitamin B6.

Detailed Description:

The "homocysteine-hypothesis" of vascular disease has attracted considerable interest, as total plasma homocysteine levels can be easily lowered by folic acid and vitamin B12, raising the prospect that cardiovascular disease could be lowered by such B-vitamin supplementation.

Two large B-vitamin intervention trials have been performed in Norway during the period 1998 to 2005, NORVIT and WENBIT, both registered at ClinicalTrials.gov, identifiers NCT00266487 and NCT00354081, respectively. The main objective in these trials was to study the effects of homocysteine-lowering therapy with folic acid and vitamin B12 to reduce the risk of cardiovascular events in patients with established coronary artery disease. The B-vitamin intervention, which included vitamin B6 in a 2x2 factorial design, was identical in the two trials. Follow-up was terminated for NORVIT on March 31st 2004 and for WENBIT October 5th 2005. Results from the NORVIT trial was published April 2006 {Bonaa, 2006} and preliminary results from the WENBIT trial were presented at the annual congress of the European Society of Cardiology September 4th 2007 {Zegers, 2007}. The WENBIT trial is completed and submitted for publication early in year 2008.

So far, none of the B-vitamin intervention trials have shown any statistically significant favourable effect of homocysteine-lowering therapy with folic acid with or without concomitant vitamin B12 on cardiovascular events {Bazzano, 2006}. In NORVIT there was even a trend towards an increased risk of cardiovascular events (myocardial infarctions) in patients receiving the combination of folic acid, vitamin B12 and vitamin B6. This trend was not observed in WENBIT. Thus, the "homocysteine-hypothesis" of vascular disease has been attenuated through the emergence of these negative trial results. There is still some evidence that folic acid might prevent strokes, and there has been a call for meta-analyses when several large ongoing trials are completed {Clarke, 2007}.

There is so far no data on possible long-term effects following years of B-vitamin supplementation. By combining analyses and follow-up in the NORVIT and WENBIT cohorts, we will probably have some more answers both considering possible subgroup and long-term effects of the B-vitamin intervention.

Current data indicate that folate prevents cancer, especially breast and colorectal cancer. However, during the last few years several reports have challenged this assumption. Swedish observational studies found increased risk of colorectal cancer at high blood folate levels {Van Guelpen, 2006} and increased risk of prostate cancer at high levels of folate and vitamin B12 {Hultdin, 2005}. In a randomised trial with folic acid versus placebo to prevent colorectal adenomas, one found increased risk of cancer in the group receiving folic acid, especially of prostate cancer {Cole, 2007}. In a long-term follow-up of women taking high doses of folic acid throughout pregnancy one found a doubled risk of deaths attributable to breast cancer {Charles, 2004}. Recently it has been hypothesized that the implementation of folic acid fortification of foods may have been wholly or partly responsible for the observed increase in colorectal cancer rates in the USA and Canada in the mid to late 1990s {Mason, 2007}. This has led to new hypotheses that folate may prevent carcinogenesis but may enhance the growth of established cancer cells {Ulrich, 2007}. The question of possible adverse effects of folic acid supplementation will be of major importance when public health administrations decide whether to implement or enhance programs folic acid fortification of foods.

  Eligibility

Ages Eligible for Study:   27 Years to 86 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

The study population for combined analyses consists of the of 3 749 + 3 090 = 6 839 men and women aged 27 - 86 years when randomised in the NORVIT and WENBIT trials between December 1998 and April 2004. All patients in NORVIT were randomised following an acute myocardial infarction, whereas patients in WENBIT were randomised following coronary angiography, of which 85% had stable angina pectoris, 10% had acute myocardial infarction and 5% had unstable angina pectoris at baseline.

Criteria

Inclusion Criteria:

  • Randomised in the Norwegian Vitamin Trial (NORVIT) or in the Western Norway B-Vitamin Intervention Trial (WENBIT)

Exclusion Criteria:

  • Withdrawn consent to participate in study cohort for post-trial observational follow-up
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00671346

Locations
Norway
Department of Heart Disease, Haukeland University Hospital
Bergen, Norway, 5021
University of Tromsø
Tromsø, Norway, 9037
Sponsors and Collaborators
Haukeland University Hospital
University of Tromso
Norwegian Foundation for Health and Rehabilitation
Investigators
Study Chair: Marta Ebbing, MD, PhD Department of Heart Disease, Haukeland University Hospital
  More Information

Additional Information:
Publications:
Ebbing M, Bønaa KH, Nygård O et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 302(19): 2119-2126, 2009.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Marta Ebbing, MD, PhD, Haukeland University Hospital
ClinicalTrials.gov Identifier: NCT00671346     History of Changes
Other Study ID Numbers: NSD-17895, REK-267.07, DT-08/00230-2/RVB, Hdir-08/623-
Study First Received: April 29, 2008
Last Updated: March 17, 2013
Health Authority: Norway: Norwegian Social Science Data Services (NSD)
Norway: Data Protection Authority
Norway: Norwegian Directorate of Health

Keywords provided by Haukeland University Hospital:
Cancer
Coronary artery disease
Myocardial infarction
Cerebrovascular stroke
Homocysteine
Vitamin B Complex
Folic acid
Vitamin B12
Vitamin B6
Pyridoxal phosphate

Additional relevant MeSH terms:
Cerebral Infarction
Infarction
Myocardial Infarction
Stroke
Brain Diseases
Brain Infarction
Brain Ischemia
Cardiovascular Diseases
Central Nervous System Diseases
Cerebrovascular Disorders
Heart Diseases
Ischemia
Myocardial Ischemia
Necrosis
Nervous System Diseases
Pathologic Processes
Vascular Diseases
Vitamin B Complex
Vitamins
Growth Substances
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 20, 2014