Transcript Powerpoint Presentation about TACT

Trial to Assess Chelation
Therapy (TACT)
Principal Investigator: Gervasio A. Lamas, MD
Mount Sinai Medical Center – Miami Heart Institute
Miami Beach FL
TACT Design
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5-year randomized, double-blind, placebocontrolled;
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
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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:
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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
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Men or women age 50 and older
MI >6 weeks prior to randomization
Definition of MI
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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
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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
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Composite clinical endpoint including:
all cause mortality
 myocardial infarction
 stroke
 coronary revascularization
 hospitalization for angina
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Secondary Endpoints
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Composite serious irreversible vascular
events including: cardiovascular death, or
non-fatal MI or non-fatal stroke.
Dr. Lee
Event Rate Assumptions
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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:
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85% power for detecting a 25%  in the
primary endpoint, taking into account noncompliance and loss to follow-up
The Clinical Unit
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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
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Infusion Visits
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Initial - Weekly X 30 wks
Maintenance - Every 5 – 8 weeks
Enter data into internet data collection system
during or immediately post visit
Study Overview
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Patient Follow-up:
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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
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Infusion Kits – UPS delivery the morning before
scheduled visit
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500 ml bag IV solution
2 - 20ml syringes
Vitamins – Initial supply shipped with first kit
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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
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Infusion Kit refrigerated (2-8 degrees C)
Vitamins at room temperature
Store study drugs in secure location with
limited access
Pharmacy – Simple Mixing
Instructions
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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
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Nephrotoxicity
Hypocalcemia
Hypoglycemia
Hypotension
Trace metal and vitamin deficiencies
Venous access problems
Clotting parameters
Febrile episodes
ECG changes
Fluid overload
Subject Safety
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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
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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 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%
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%
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
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Inositol
50 mg
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PABA (as para-amino benzoic acid)
50 mg
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Boron (as boron aspartate and boron citrate)
2 mg
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Vanadium (as vanadyl sulfate)
39 mcg
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Citrus Bioflavonoids
100 mg
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Selenium (as selenium amino acid chelate)
Safety Monitoring
Screen
Creatinine
Calcium
Magnesium
Glucose
CBC/platelets
LFT
Urine Dipstick
Inf.
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Quality of Life Endpoints
Data collected by structured interview
in 1000 randomly selected patients
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Cardiac physical functioning: Duke Activity
Status Index
Psychological well-being: SF-36 MHI5
Patient utilities: EuroQoL
Analysis by intention to treat
Economic Analysis
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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
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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