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5-Methyltetrahydrofolate Survival and Inflammation in ESRD Patients

This study has been completed.
Sponsor:
Collaborator:
University of Bologna
Information provided by:
St. Orsola Hospital
ClinicalTrials.gov Identifier:
NCT00626223
First received: February 4, 2008
Last updated: February 28, 2008
Last verified: February 2008
  Purpose

A randomized prospective study was done to determine whether i.v. 5-methyltetrahydrofolate vs oral folate improved survival in ESRD patients. Homocysteine, CRP, Lp(a), albumin, folates, vitamin B6 and B12 were checked. The 5-MTHF treated group was associated with lowered C reactive protein and higher survival than the folate treated group.


Condition Intervention
Mortality
Hyperhomocysteinemia
Inflammation
Drug: 5-MTHF (5-methyltetrahydrofolate)
Drug: folic acid

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 5-Methyltetrahydrofolate Survival and Inflammation in ESRD Patients

Resource links provided by NLM:


Further study details as provided by St. Orsola Hospital:

Primary Outcome Measures:
  • survival [ Time Frame: 55 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Risk factors for cardiovascular disease in ESRD patients [ Time Frame: 55 months ] [ Designated as safety issue: Yes ]
  • Homocysteine levels after 6, 12, 24 and 55 months [ Time Frame: 55 months ] [ Designated as safety issue: Yes ]
  • CRP levels after 6, 12, 24 and 55 months [ Time Frame: 55 months ] [ Designated as safety issue: Yes ]
  • Gene polymorphisms analysis on C677T and A1298C loci and differences in polymorphisms distribution in both groups [ Time Frame: basal ] [ Designated as safety issue: No ]
  • Differences at baseline between the groups concerning age, dialysis age, CRP, albumin, haemoglobin, Lp(a), homocysteine, folate, B6 and B12 baseline levels [ Time Frame: basal ] [ Designated as safety issue: No ]

Enrollment: 341
Study Start Date: January 1998
Study Completion Date: July 2007
Primary Completion Date: July 2001 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
patients treated with intravenous 5-MTHF (Prefolic®, Knoll, Milan, Italy) 50 mg at the end of each hemodialysis session; The group will receive supplementation with vitamin B6 300 mg (Benadon®, Roche, Milan, Italy) and vitamin B12 1000 mcg (Dobetin®, A.C.R.A.F, Rome, Italy) administered by intravenous injection at the end of the hemodialysis session three times per week
Drug: 5-MTHF (5-methyltetrahydrofolate)
50 mg intravenous at the end of each hemodialysis session
Active Comparator: B

treated with 5 mg per day of oral folic acid (Folina® Schwarz Pharma, Milan, Italy).

The group will receive supplementation with vitamin B6 300 mg (Benadon®, Roche, Milan, Italy) and vitamin B12 1000 mcg (Dobetin®, A.C.R.A.F, Rome, Italy) administered by intravenous injection at the end of the hemodialysis session three times per week

Drug: folic acid
5 mg per day of oral folic acid

Detailed Description:

BACKGROUND Hemodialysis patients show a 20-fold increase in CVD mortality in comparison to the general population.

Although hyperhomocysteinemia has been implicated as an important independent risk factor in both the general population2, as well as for ESRD patients, several studies have questioned the benefit of lowering homocysteine in ESRD patients. Paradoxically, two recent studies showed that patients with very low homocysteine plasma levels had worse outcomes including a higher incidence of hospitalization and mortality. This raises the question as to whether elevated homocysteine in uremic patients is consequential rather than causal in the role of cardiovascular complications.

Despite this uncertainty, many ESRD and pre-ESRD patients receive treatment to lower homocysteine. Elevated homocysteine is frequently reported for ESRD patients with a prevalence ranging from 85 to 100%.

There are two basic strategies that can be used to lower homocysteine. Both attempt to increase levels of biologically active folate which is essential in the remethylation pathway of homocysteine metabolism via its active metabolite 5-methyltetrahydrofolate (5-MTHF), thus lowering homocysteine efflux from tissues into the plasma compartment.

The first, and most common approach, is by oral administration of folic acid. Folic acid is not biologically active, however it is more stable than folate, and is often used in tablets and food fortification. The second approach is to supplement 5-MTHF, the natural circulating form of folate. In addition to folate, both vitamin B6 and vitamin B12 are necessary co-factors in homocysteine metabolism. ESRD patients are often resistant to homocysteine lowering by administration of both folic acid and 5-MTHF.

Although supplementation with folic acid, B6 and B12 usually decreases homocysteine in patients with vascular disease, it often remains elevated in ESRD patients despite supplementation of folic acid, B6 and B12. Several studies have reported only moderate effects, even with very high doses of folic acid (up to 15 mg/daily).

AIM OF THE STUDY The aim of this study is to investigate whether supplementation with 5MTHF vs. folic acid treatment affects patient survival. Homocysteine blood levels and MTHFR genetic polymorphisms will also be evaluated to determine if they can be considered as independent cardiovascular risk factors.

STUDY DESIGN Single center, randomised, prospective study. Two groups of stable ESRD patients treated with intravenous 5-MTHF or with 5 mg per day of oral folic acid.

Patient selection Period of selection : 4 years Start selection : 1 January 1998 End selection: 30 June 2001 Follow-up: 55 months.

STATISTICAL ANALYSIS Statistical analysis will be performed by the Statistical Package for the Social Sciences (SPSS).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Hemodialysis patients with age > 18 years on regular bicarbonate hemodialysis or hemodiafiltration treatment three times a week
  • Clinical stability at least three months before the study started
  • Cardiovascular disease assessment as presence/absence of hypertension, ischemic cardiac disease, cerebral and peripheral vascular disease, diabetes.

    • We will investigate coronary artery disease by determination of at least one of the following parameters:

      • previous documentation of acute myocardial infarction (laboratory or ECG modifications);
      • symptomatic CVD events in the clinical history confirmed by a positive treadmill test;
      • coronary artery stenosis more than 50% in one of the three major coronary vessels documented by an angiographic study. All patients with coronary artery disease will be examined by a treadmill test (thallium scan) or coronary angiographic exam before entering the study.
    • We will investigate cerebrovascular disease by one of the following criteria:

      • a previous ictus (ongoing clinical evidence of neurological deficit in the three months before the study beginning, confirmed by a TC scan, a nuclear magnetic resonance or a physician's record of clinical history);
      • carotid vessels stenosis more than 50% documented by a Doppler exam.
    • Peripheral vascular disease will be assessed by the evidence of claudication intermittence, previous vascular surgical procedure (including amputation for ischemic limb or by angiographic/Doppler documentation of atherosclerotic plaques in abdominal, iliac and femoral vessels). The vascular surgical procedure will be carried out at least three months before the study started.

Exclusion Criteria:

  • Diagnosis of one of the following clinical conditions in the last three months:

    • acute infection
    • vascular access thrombosis
    • ictus cerebri
    • myocardial infarction
    • hemorrhage
    • recent relevant surgery
  • Malignancy
  • Participation in other clinical trials
  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: NCT00626223

Locations
Italy
Nephrology Dialysis and Renal Transplantation Unit, S.Orsola University Hospital
Bologna, Italy, 40138
Sponsors and Collaborators
St. Orsola Hospital
University of Bologna
Investigators
Study Chair: Sergio Stefoni, Professor Nephrology Dialysis and Renal Trasnplantation Unit S.Orsola University Hospital Bologna Italy
  More Information

Publications:

Responsible Party: Professor Sergio Stefoni, Nephrology Dialysis and Renal Transplantation Unit, S.Orsola University Hospital
ClinicalTrials.gov Identifier: NCT00626223     History of Changes
Other Study ID Numbers: FCRB 2007/0234, ndtso 00025/2007
Study First Received: February 4, 2008
Last Updated: February 28, 2008
Health Authority: Italy: National Monitoring Centre for Clinical Trials - Ministry of Health

Keywords provided by St. Orsola Hospital:
ESRD patients
C-reactive protein
homocysteine
5-MTHF
survival
Hemodialysis patients

Additional relevant MeSH terms:
Hyperhomocysteinemia
Inflammation
Amino Acid Metabolism, Inborn Errors
Avitaminosis
Deficiency Diseases
Genetic Diseases, Inborn
Malabsorption Syndromes
Malnutrition
Metabolic Diseases
Metabolism, Inborn Errors
Nutrition Disorders
Pathologic Processes
Vitamin B Deficiency
Folic Acid
Vitamin B Complex
Growth Substances
Hematinics
Hematologic Agents
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Vitamins

ClinicalTrials.gov processed this record on November 24, 2014