Trial to Assess Chelation Therapy (TACT)

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Trial to Assess Chelation Therapy (TACT)

• Principal Investigator Gervasio A. Lamas, MD
• Mount Sinai Medical Center Miami Heart
  Institute
• Miami Beach FL

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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.

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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.

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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.

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Inclusion Criteria

• Men or women age 50 and older
• MI gt6 weeks prior to randomization

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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.

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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 gt2.0mg/dL
• Baseline platelets lt100,000
• Cigarette smoking within 3 months

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Primary Endpoint

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

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Secondary Endpoints

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

Dr. Lee
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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

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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

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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

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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

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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

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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)

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Pharmacy Security and Storage

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

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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

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Potential Toxicity

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

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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 lt 100,000, or a 50
  decrease from baseline will lead to elimination
  of heparin.

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Study Interventions

• ACAM protocol EDTA chelation vs placebo
• High dose antioxidant vitamins and minerals vs
  placebo

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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.
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High Dose Regimen
High 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
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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
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Safety Monitoring
Screen Inf. 1 Inf. 2 Inf. 5 Inf. 10 Inf. 15 Inf. 20 Inf. 25 Inf. 30 Inf. 36 Inf. 40
Creatinine X X X X X X X X X X
Calcium X X X X X X X X X X
Magnesium X X X X X X X X X X
Glucose X 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 X X X
Urine Dipstick X X X X
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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

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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
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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