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

November 4, 2015 updated by: Ottar Kjell Nygård, Haukeland University Hospital

Combined Analyses and Long-term Follow-up in the Two Norwegian Homocysteine-Lowering B-Vitamin Trials NORVIT and WENBIT

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 trials 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.

Thus, the main objective of the combinded NORVIT-WENBIT study will will be to evaluate the long-term effect of the B-vitamin intervention on incident life-style diseases including cardiovascular disease, diabetes, osteoporotic fractures and cancer.

A secondary object will be the identification of risk phenotypes or genotypes, and if such risk associations are midified by the B-vitamin intervention

Study Overview

Status

Unknown

Conditions

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. However, the treatment with folic acid / B12 was associated With a more rapid progression of angiographic coronary atenoses {Løland, 2010}. Thus, the "homocysteine-hypothesis" of vascular disease has been attenuated through the emergence of these negative trial results, whereas a potential harmful effect of the B-vitamin intervention has been revealed.

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.

The effect of the B-vitamin intervention will also be studied in relation to other life-style diseases like diabetes and osteoprosis.

Additionally, the combined NORVIT-WENBIT cohort will used for observational studies evaluating new risk phenotypes or genotypes and their potential effect modification by the B-vitamin interventions.

Study Type

Observational

Enrollment (Anticipated)

6839

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Norway
      • Bergen, Norway, 5021
        • Department of Heart Disease, Haukeland University Hospital
      • Tromsø, Norway, 9037
        • University of Tromsø

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

27 years to 86 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
1
Participants in NORVIT and WENBIT allocated to daily oral treatment with folic acid 0.8 mg and vitamin B12 0.4 mg
2
Participants in NORVIT and WENBIT allocated to daily oral treatment with folic acid 0.8 mg, vitamin B12 0.4 mg and B6 40 mg.
3
Participants in NORVIT and WENBIT allocated to daily oral treatment with vitamin B6 40 mg.
4
Participants in NORVIT and WENBIT allocated to daily oral treatment with placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
1998-2014

Secondary Outcome Measures

Outcome Measure
Time Frame
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
1998-2014

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Haukeland University Hospital

Collaborators

University of Tromso
Norwegian Foundation for Health and Rehabilitation

Investigators

  • Study Chair: Ottar Nygård, MD, PhD, Department of Heart Disease, Haukeland University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 1998

Primary Completion (Anticipated)

December 1, 2020

Study Completion (Anticipated)

January 1, 2021

Study Registration Dates

First Submitted

April 29, 2008

First Submitted That Met QC Criteria

April 29, 2008

First Posted (Estimate)

May 5, 2008

Study Record Updates

Last Update Posted (Estimate)

November 5, 2015

Last Update Submitted That Met QC Criteria

November 4, 2015

Last Verified

November 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NSD-17895
  • REK-267.07 (Other Identifier: REK vest)
  • DT-08/00230-2/RVB (Other Identifier: Datatilsynet)
  • Hdir-08/623- (Other Identifier: Helsedirektoratet)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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