Trial to Assess Chelation Therapy (TACT)

1. Trial to Assess Chelation Therapy (TACT) Principal Investigator: Gervasio A. Lamas, MD Mount Sinai Medical Center – Miami Heart Institute Miami Beach FL

2. 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.

3. 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.

4. 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.

5. Inclusion Criteria • Men or women age 50 and older • MI >6 weeks prior to randomization

6. 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.

7. 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

8. Primary Endpoint • Composite clinical endpoint including: • all cause mortality • myocardial infarction • stroke • coronary revascularization • hospitalization for angina

9. Secondary Endpoints • Composite serious irreversible vascular events including: cardiovascular death, or non-fatal MI or non-fatal stroke. Dr. Lee

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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)

16. Pharmacy – Security and Storage • Infusion Kit refrigerated (2-8 degrees C) • Vitamins at room temperature • Store study drugs in secure location with limited access

17. 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

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

19. 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.

20. Study Interventions • ACAM protocol EDTA chelation vs placebo • High dose antioxidant vitamins and minerals vs placebo

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

22. High Dose Regimen

23. High Dose Regimen (cont.)

24. Safety Monitoring

25. Quality of Life Endpoints Data collected by structured interview in 1000 randomly selected patients • Cardiac physical functioning: Duke Activity Status Index • Psychological well-being: SF-36 MHI5 • Patient utilities: EuroQoL • Analysis by intention to treat

26. 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

27. 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