Trial to Assess Chelation Therapy (TACT)

Principal Investigator: Gervasio A. Lamas, MD

Mount Sinai Medical Center – Miami Heart Institute

Miami Beach FL

TACT Design

5-year randomized, double-blind, placebo-controlled;

2X2 factorial trial; Testing the standard chelation solution versus

placebo; Testing the effects of a high-dose antioxidant

vitamin and mineral supplementation, versus a low dose regimen.

Specific Aims

To determine whether chelation or high-dose supplements in patients with CHD will reduce the incidence of clinical cardiovascular events;

To determine whether chelation and high-dose supplements have acceptable safety profiles.

Substudy Specific Aims

Two substudies will be conducted whose specific aims are as follows:

To determine whether chelation or high-dose supplements improve quality of life;

To conduct an economic analysis of chelation therapy and high dose supplements.

Inclusion Criteria

Men or women age 50 and older MI >6 weeks prior to randomization

Definition of MI

Biomarkers + (symptoms or ECG changes) OR Imaging evidence of myocardial scar +

evidence of coronary disease on angiography.

This requires PI involvement, especially the decision that the CAD corresponds to an imaged scar. Remember that the CCC is always happy to help.

Major Exclusion Criteria Chelation within 5 years Known allergy to any components of solutions or

vitamins Carotid and coronary revascularization within 6

months, or planned revascularization Symptomatic HF, or HF hospitalization within 6 months Uncontrolled hypertension No venous access Creatinine >2.0mg/dL Baseline platelets <100,000 Cigarette smoking within 3 months

Primary Endpoint

Composite clinical endpoint including: all cause mortality myocardial infarction stroke coronary revascularization hospitalization for angina

Secondary Endpoints

Composite serious irreversible vascular events including: cardiovascular death, or non-fatal MI or non-fatal stroke.

Dr. Lee

Event Rate Assumptions

20% event rate (primary endpoint) in control arm after 2.5 years of follow-up

Chelation therapy will reduce event rate by 25% (if patients comply)

7% of patients per year will discontinue the infusions (20% over 3 years)

3% loss to follow-up

Statistical Power of TACT

With these assumptions, 2,372 patients will provide:

85% power for detecting a 25% in the primary endpoint, taking into account non-compliance and loss to follow-up

The Clinical Unit Principal Investigator (PI) with NIH Clinical

Investigator training module completed Research coordinator with NIH Clinical

Investigator training module completed Commitment to follow protocol FWA IRB approval Training in chelation Training in evidence-based cardiology Internet access Infusion area Patient base

Study Overview

Infusion Visits Initial - Weekly X 30 wks Maintenance - Every 5 – 8 weeks Enter data into internet data collection system

during or immediately post visit

Study Overview

Patient Follow-up: 3 phone calls/year (average 2.5 years f/u) 1 annual clinic visit Clinic visit at end of study

Pharmacy – Delivery of Study Drugs

Infusion Kits – UPS delivery the morning before scheduled visit 500 ml bag IV solution 2 - 20ml syringes

Vitamins – Initial supply shipped with first kit Subsequent shipments on 1st each month Subsequent shipments contain 2-month supply (360

tablets in a bottle; 60 gel-caps in blister packs)

Pharmacy – Security and Storage

Infusion Kit refrigerated (2-8 degrees C) Vitamins at room temperature Store study drugs in secure location with

limited access

Pharmacy – Simple Mixing Instructions

Prepare infusion just prior to administration Inject 2 syringes of solution into IV bag using

21 g needles Allow solution to reach room temp prior to

infusing (30 minutes) Administer within 24 hrs of mixing

Potential Toxicity

Nephrotoxicity Hypocalcemia Hypoglycemia Hypotension Trace metal and vitamin deficiencies Venous access problems Clotting parameters Febrile episodes ECG changes Fluid overload

Subject Safety

EDTA dose is adjusted based on estimated creatinine clearance (Jan 15, 2003 section 6.2)

Kidney. Doubling of the creatinine from baseline or increase to a level of 2.5 mg/dLwill lead to cessation of infusions and continuation of the vitamin regimen. We will also look for signs of hematuria and/or proteinuria, which will prompt further evaluation.

Liver. Doubling of the ALT, AST, alkaline phosphatase or bilirubin will be lead to interruption of infusions and a potential re-challenge.

Hematology. Platelet count < 100,000, or a 50% decrease from baseline will lead to elimination of heparin.

Study Interventions

ACAM protocol EDTA chelation vs placebo High dose antioxidant vitamins and

minerals vs placebo

Low-Dose Regimen

Low-Dose Regimen

(Taken once daily)Amount % Daily Value

Vitamin B6 (as pyridoxine hydrochloride) 25 mg 1250%

Zinc (as zinc gluconate) 25 mcg 167%

Copper (as copper gluconate) 2 mg 100%

Manganese (as manganese gluconate) 15 mg 750%

Chromium (as chromium picolinate) 50 mg 42%

These supplements, produced by OleoMed S.A., Madrid, Spain, are administered in an olive oil based gel capsule.

High Dose RegimenHigh Dose Regimen

(Taken twice daily)Amount per

Serving% Daily Value

Vitamin A (as fish liver oil and beta-carotene) 25,000 IU 500%

Vitamin C (as calcium ascorbate, magnesium ascorbate and potassium ascorbate

1,200 mg 2000%

Vitamin D3 (as cholecalciferol) 100 IU 25%

Vitamin E (as d-alpha tocopheryl succinate and

d-alpha tocopheryl acetate) 400 IU 1333%

Vitamin K1 (as phytonadione) 60 mcg 75%

Thiamin (vitamin B1) (as thiamin mononitrate) 100 mg 6667%

Niacin (as niacinamide and niacin) 200 mg 1000%

Vitamin B6 (as pyridoxine hydrochloride) 50 mg 2500%

Folate (as folic acid) 800 mcg 200%

Vitamin B12 (as cyanocobalamin) 100 mcg 1667%

Biotin 300 mcg 100%

Pantothenic acid (as d-calcium pantothenate) 400 mcg 4000%

Calcium (as calcium citrate and calcium ascorbate) 500 mcg 50%

Iodine (from kelp) 150 mcg 100%

High Dose Regimen (cont.)

High Dose Regimen

(Taken twice daily)Amount per

Serving% Daily Value

Magnesium (as magnesium aspartate, magnesium ascorbate and magnesium amino acid chelate)

500 mg 125%

Zinc (as zinc amino acid chelate) 20 mg 133%

Selenium (as selenium amino acid chelate) 200 mcg 286%

Copper (as copper amino acid chelate) 2 mg 100%

Manganese (as manganese amino acid chelate) 20 mg 1000%

Chromium (as chromium polynicotinate) 200 mcg 167%

Molybdenum (as molybdenum amino acid chelate) 150 mcg 200%

Potassium (as potassium aspartate and potassium ascorbate)

99 mg 3%

Choline (as choline bitartrate) 150 mg *

Inositol 50 mg *

PABA (as para-amino benzoic acid) 50 mg *

Boron (as boron aspartate and boron citrate) 2 mg *

Vanadium (as vanadyl sulfate) 39 mcg *

Citrus Bioflavonoids 100 mg *

Safety MonitoringScreen Inf.

#1Inf. #2

Inf. #5

Inf. #10

Inf. #15

Inf. #20

Inf. #25

Inf. #30

Inf. #36

Inf. #40

CreatinineX X X X X X X X X X

CalciumX X X X X X X X X X

MagnesiumX X X X X X X X X X

GlucoseX X X X X X X X X X

CBC/platelets X X X X X X X X X X

LFT X X X X X X X XX X

Urine Dipstick X X X X

Quality of Life Endpoints

Cardiac physical functioning: Duke Activity Status Index

Psychological well-being: SF-36 MHI5 Patient utilities: EuroQoL Analysis by intention to treat

Data collected by structured interview Data collected by structured interview in 1000 randomly selected patientsin 1000 randomly selected patients

Economic Analysis

Medical resource consumption on CRF Compared by intention to treat Cost weights assigned from 2º sources CEA if 1º study endpoint positive for

experimental arms

Dr. Lee

Statistical Analysis - Overview

Treatment comparisons performed according to “intention to treat”

Treatments compared using “two-sided” statistical tests

Analysis will incorporate not only how many events occur, but also when they occur