Clinical trial NCT00032435: Homocysteine Study (HOST)
Official title: CSP #453 - Homocysteinemia in Kidney and Endstage Renal Disease Study (HOST)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: End Stage Renal Disease
Renal Failure
Keywords: folate
pyridoxine
vitamin B6
cyanocobalamin
homoc
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Pan American Laboratories
name: Abbott Diagnostics Division
First posted: 2002-03-22
Enrollment: 2003
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no

Brief summary: The primary objective of this study is to test the hypothesis that administration of folate, pyridoxine (vitamin B6) and cyanocobalamin (vitamin B12) in high doses to patients with advanced chronic renal failure or end stage renal disease and abnormally high plasma homocysteine levels will lower the homocysteine levels and the death rate compared to patients who receive placebo. The secondary objective is to test the hypothesis that intake of the vitamins compared to placebo decreases the incidence of myocardial infarction, disabling stroke, and amputation of a lower extremity and, in hemodialysis patients, thrombosis of the vascular access.

Detailed description: Primary Hypothesis:

The primary objective of this proposal is to test the hypothesis that administration of folate, pyridoxine (vitamin B6) and cyanocobalamin (vitamin B12) in high doses to patients with advanced chronic renal failure or end-stage renal disease and abnormally high plasma homocysteine levels will lower the homocysteine levels and increase survival.

Secondary Hypotheses:

The secondary objectives are to test the hypotheses that intake of the vitamins decreases: 1) MI, 2) stroke, 3) amputation of lower extremity, 4) combination death, MI, stroke and amputation of lower extremity, 5) thrombosis of the vascular access in hemodialysis patients.

Primary Outcome: Death

Interventions: A treated group that receives a daily tablet containing 40mg of folic acid, 100mg of pyridoxine and 2mg of B12 versus a control group that receives a placebo.

Study Abstract:

The experimental design is a prospective, two-arm, randomized, double blind study, stratified for medical center and whether the patient has chronic renal failure or end-stage renal disease. In each arm 1003 patients will ingest daily a capsule containing either 40mg of folic acid, 100mg of pyridoxine and 2mg of vitamin B12, or placebo. We will use stratified randomization to ensure that the treatment is balanced within the end-stage renal disease patients and chronic renal failure patients.

This 6 year study will require an accrual phase of 2 years and a treatment phase lasting a minimum of 4 years. Patients will be screened by their plasma homocysteine concentration. They must have a level of at least 15 uM/L to be enrolled in the study. The study nurse will evaluate each patient at 3 months. Thereafter, patients will be contacted by phone, or mail if they prefer, at 3-month intervals by coordinators at a central location. Secondary endpoint events, hospitalization, onset of dialysis, and death or other reason for exit from the study will be recorded on standard forms. Plasma homocysteine levels will be obtained at 3 months in all patients.

Patients will be excluded if: age less than 21 years, expected life span less than 6 months, pregnancy, metastatic cancer, AIDS-related infection, end-stage liver disease, vitamin B12 deficiency, treatment with methotrexate, or anticonvulsants, unreliable or likely non-compliant, participation in other long-term trial, or unwilling or unable to give informed consent.

For a relative treatment effect of 17% (that is reducing the 3-year death rate from 28% to 23.2%) and 80% power, 2006 patients and 36 VA medical centers are required.

An abundance of published reports has shown a strong correlation between homocysteinemia and the incidence of cardiovascular death. Authors of these papers have unanimously recommended a study be undertaken to determine if folate, pyridoxine, and vitamin B12 can lower the incidence.

The study is to be conducted in patients with chronic renal failure and end-stage renal disease whose plasma homocysteine levels and incidence of cardiovascular death and disease are among the highest of all patient populations. By screening for patients with high plasma homocysteine concentrations and measuring the levels after 3 months, we will be able to determine if the hypothetical reduction in death and cardiovascular event rate is associated with a decrease in plasma homocysteine concentration.

Eligibility criteria: Inclusion Criteria:

Patients will be screened by their plasma homocysteine concentration. They must have a level of at least 15 mM/L to be enrolled in the study.

Patients will be excluded by any of the following criteria: age less than 21 years, expected life span less than 6 months, pregnancy, metastatic cancer, end-stage liver disease, treatment with methotrexate, other anti-folate medication or anticonvulsants, unreliable or likely noncompliant, participation in another long-term trial, or unwilling or unable to give informed consent.

Exclusion Criteria:

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: VA Medical Center, Birmingham
state: Alabama
city: Menlo Park
country: United States
facility: Health Economics Resource Center (HERC), Menlo Park
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System, San Diego
state: California
city: Denver
country: United States
facility: VA Eastern Colorado Health Care System, Denver
state: Colorado
city: West Haven
country: United States
facility: VA Connecticut Health Care System (West Haven)
state: Connecticut
city: Washington
country: United States
facility: VA Medical Center, DC
state: District of Columbia
city: Bay Pines
country: United States
facility: VA Medical Center, Bay Pines
state: Florida
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System
state: Florida
city: Miami
country: United States
facility: VA Medical Center, Miami
state: Florida
city: West Palm Beach
country: United States
facility: West Palm Beach VA Medical Center
state: Florida
city: Hines
country: United States
facility: Edward Hines, Jr. VA Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Richard Roudebush VA Medical Center, Indianapolis
state: Indiana
city: New Orleans
country: United States
facility: Southeast Veterans Healthcare System, New Orleans
state: Louisiana
city: Boston
country: United States
facility: VA Medical Center, Jamaica Plain Campus
state: Massachusetts
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System
state: Michigan
city: Detroit
country: United States
facility: John D. Dingell VA Medical Center, Detroit
state: Michigan
city: Minneapolis
country: United States
facility: VA Medical Center, Minneapolis
state: Minnesota
city: Jackson
country: United States
facility: G.V. (Sonny) Montgomery VA Medical Center, Jackson
state: Mississippi
city: Kansas City
country: United States
facility: VA Medical Center, Kansas City MO
state: Missouri
city: Bronx
country: United States
facility: VA Medical Center, Bronx
state: New York
city: Buffalo
country: United States
facility: VA Western New York Healthcare System at Buffalo
state: New York
city: New York
country: United States
facility: New York Harbor HCS
state: New York
city: Northport
country: United States
facility: VA Medical Center, Northport
state: New York
city: Syracuse
country: United States
facility: VA Medical Center, Syracuse
state: New York
city: Cleveland
country: United States
facility: VA Medical Center, Cleveland
state: Ohio
city: Dayton
country: United States
facility: VA Medical Center, Dayton
state: Ohio
city: Portland
country: United States
facility: VA Medical Center, Portland
state: Oregon
city: Pittsburgh
country: United States
facility: VA Pittsburgh Health Care System
state: Pennsylvania
city: Charleston
country: United States
facility: Ralph H Johnson VA Medical Center, Charleston
state: South Carolina
city: Memphis
country: United States
facility: VA Medical Center, Memphis
state: Tennessee
city: Dallas
country: United States
facility: VA North Texas Health Care System, Dallas
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center (152)
state: Texas
city: Richmond
country: United States
facility: Hunter Holmes McGuire VA Medical Center
state: Virginia
city: Seattle
country: United States
facility: VA Puget Sound Health Care System, Seattle
state: Washington
city: Milwaukee
country: United States
facility: Zablocki VA Medical Center, Milwaukee
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: VA Medical Center, San Juan
Study officials:
affiliation: VA Palo Alto Health Care System
name: Rex L. Jamison
role: STUDY_CHAIR
References:
citation: Brady CB, Gaziano JM, Cxypoliski RA, Guarino PD, Kaufman JS, Warren SR, Hartigan P, Goldfarb DS, Jamison RL. Homocysteine lowering and cognition in CKD: the Veterans Affairs homocysteine study. Am J Kidney Dis. 2009 Sep;54(3):440-9. doi: 10.1053/j.ajkd.2009.05.013. Epub 2009 Jul 23.
citation: Jamison RL, Shih MC, Humphries DE, Guarino PD, Kaufman JS, Goldfarb DS, Warren SR, Gaziano JM, Lavori P; Veterans Affairs Site Investigators. Effect of the MTHFR C677T and A1298C polymorphisms on survival in patients with advanced CKD and ESRD: a prospective study. Am J Kidney Dis. 2009 May;53(5):779-89. doi: 10.1053/j.ajkd.2008.12.023. Epub 2009 Mar 9.
citation: Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, Gaziano JM; Veterans Affairs Site Investigators. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2007 Sep 12;298(10):1163-70. doi: 10.1001/jama.298.10.1163.