Design of the Trial to Assess Chelation Therapy (TACT)

Article Outline

• Abstract
• Methods
  • Design overview
  • Trial chronology
  • Trial administration
  • Clinical sites
  • Data collection
  • Patient safety oversight and adverse event
  • Patient population
  • Randomization
  • Treatment regimens
  • Blinding
  • Patient follow-up
  • Safety monitoring
  • Study end points
  • Cardiovascular event rates and statistical power
  • Statistical analysis
  • Subgroup analyses
• Discussion
• Conclusions
• Acknowledgements
• References
• Copyright

TACT is an National Institutes of Health–sponsored, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial testing the benefits and risks of 40 infusions of a multicomponent disodium EDTA chelation solution compared with placebo and of an oral, high-dose multivitamin and mineral supplement. TACT has randomized and will follow up 1,708 patients for an average of approximately 4 years. The primary end point is a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A 900-patient substudy will examine quality-of-life outcomes. The trial is designed to have >85% power to detect a 25% relative reduction in the primary end point for each treatment factor. Enrollment began in September 2003 and was completed in October 2010.

National surveys consistently show that more than one third of adult patients in the United States use alternative therapies,¹, ², ³ for which reliable evidence of net benefits is lacking. Chelation therapy with disodium EDTA (Na₂EDTA), a drug currently without indication in the United States,⁴ is one such therapy.

EDTA chelation of divalent and trivalent ions has been postulated to produce a favorable effect on atherosclerotic plaque, questionably leading to improvement in endothelial function, reductions in symptoms, and major vascular events.⁵, ⁶, ⁷ Thus, EDTA chelation is sometimes used for the treatment of coronary and peripheral artery disease, and the disodium salt has been favored because of the potential to decalcify atherosclerotic plaque.⁸ There is also ample evidence of potential harm. Disodium EDTA, particularly when infused rapidly may cause hypocalcemia and death.⁹ The available evidence for treatment effects of chelation therapy in patients with coronary heart disease or peripheral arterial disease is mixed and limited to case series¹⁰ and 3 small trials evaluating¹¹, ¹², ¹³ surrogate end points.

The ongoing use of a therapy with the potential for benefit as well as harm led to the release of a request for applications (RFA 01-004, April 2001) by the National Center for Complementary and Alternative Medicine (NCCAM), cofunded by NCCAM and the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health (NIH).

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Methods 

Design overview 

TACT, ClinicalTrials.gov identifier NCT00044213, is a randomized, double-blind, placebo-controlled, 2 × 2 factorial trial testing the benefits and risks of 40 infusions of a standard multicomponent Na₂EDTA chelation solution compared with placebo and of an oral, high-dose multivitamin and mineral supplement compared with placebo. The primary end point is a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. This trial is supported by grant number U01 HL92607 from the NHLBI and NCCAM.

The trial uses the components, route, and methods of administration of Na₂EDTA chelation recommended by the American College for Advancement in Medicine (ACAM),¹⁴ the largest organization of chelating physicians in North America. The ACAM Board approved the final Na₂EDTA dosage and frequency of infusions and all vitamin protocols.

Trial chronology 

A grant to conduct the trial was awarded to Mount Sinai Medical Center in August 2002. The US Food and Drug Administration (FDA) approved the Investigational New Drug application for the Akzo Nobel (Lima, OH) formulation of Na₂EDTA chelation in April 2003 (IND no. 66,743). The first patient was randomized in September 2003. The trial concluded enrollment of 1,708 patients in October 2010. The last TACT follow-up visit took place in October 2011.

Trial administration 

The Clinical Coordinating Center (CCC) is located at Mount Sinai Medical Center, Miami Beach, FL. The Duke Clinical Research Institute (Durham, NC) serves as the Data Coordinating Center (DCC), and the Economics and Quality of Life Coordinating Center. The TACT central pharmacy (Accu-Care Services Pharmacy, Miami, FL, September 10, 2003, to June 18, 2010, and Universal Arts Pharmacy from June 28, 2010 to the present) has mixed and delivered, to date, >50,000 bags of blinded chelation solution and the corresponding oral vitamin supplements to clinical sites.

Clinical sites 

Clinical sites complete TACT investigator and coordinator training. They meet all NIH, FDA, and Office for Human Research Protections (OHRP) requirements for participation in federally funded studies.

Data collection 

TACT data collection takes place through an Internet-based, electronic data capture system (TrialMaster; OmniComm Systems, Davie, FL). This permits real-time, patient-specific prescription of the EDTA dose of the active chelation solution, based on an individual patient's estimated glomerular filtration rate (eGFR). An unblinded physician not otherwise involved with the study at the CCC gives patient-specific prescription approval.

Specific steps with regard to training, site visits by the DCC, and TrialMaster programming are taken to assure the integrity of the patient data collected in TACT.

Patient safety oversight and adverse event 

The NIH, FDA, and local or central institutional review boards (IRBs) oversee TACT. A Data and Safety Monitoring Board (DSMB) reviews unblinded outcome and safety data approximately every 6 months and recommends whether to continue the trial. The members of the DSMB include experts in clinical trial design and interpretation, bioethics, cardiology, pharmacology, chelation therapy, and biostatistics.

The site investigator documents all adverse events and serious adverse events (SAEs) that occur from initiation of study drug through 30 days after the final study infusion. The site investigator assigns causality to each SAE. The DCC medical monitor or designee determines which SAEs meet the “unexpected” criteria (not labeled in the investigator's brochure) and makes an independent assessment of causality. A blinded clinical events committee performs clinical event adjudication.

Patient population 

Patients are eligible if they are at least 50 years of age and have had an acute myocardial infarction >6 weeks before enrollment and are ineligible if they have abnormal renal function or other exclusions (Table I, Table II).

Table I. Inclusion criteria

All of the following inclusion criteria must be present

1. Men or postmenopausal women age ≥50 y

2. MI over 6 wk before evaluation, defined by criteria A, B, or C

A. Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of cardiac biomarkers with at least one of the following:

1) Ischemic symptoms,

2) Pathologic Q waves, or

3) ECG changes of ischemia;

or

B. Imaging evidence of myocardial scar and angiographic evidence of coronary disease in that distribution,

or

C. Past ischemic symptoms, MI on ECG, and segmental wall motion abnormality or scar on an imaging study, with review and agreement by the CCC.

CK-MB, Creatine kinase-MB; ECG, electrocardiogram.

Table II. Exclusion criteria

None of the following exclusion criteria may be present

▪Chelation therapy within 5 years

▪Allergy to any study drug

▪Coronary or carotid revascularization within 6 months

▪Planned revascularization

▪Symptomatic or clinically evident heart failure

▪Heart failure hospitalization within 6 months

▪Blood pressure >160/100

▪No venous access

▪Serum creatinine >2.0 mg/dL

▪Platelet count <100000/mm3

▪Cigarette smoking within the last 3 months

▪Liver disease or ALT or AST >2.0 times the upper limit of normal

▪Diseases of copper, iron, or calcium metabolism

▪Inability to tolerate 500 mL of fluids weekly

▪Inability to keep to study schedules

▪Medical condition likely to affect patient survival within 4 years

▪Women of child-bearing potential

ALT, Alanine aminotransferase; AST, aspartate aminotransferase.

Randomization 

Randomization is carried out on the TACT TrialMaster System. Patients are randomly assigned in equal proportions to 1 of the 4 treatment arms defined by the 2 × 2 factorial design.

Treatment regimens 

All eligible consenting patients are randomized to receive 40 infusions of either chelation solution (Table III) or placebo, consisting of 500 mL of normal saline and 1.2% dextrose. The first 30 infusions occur weekly. The final 10 infusions may occur between 2 weeks and up to 8 weeks apart. Each patient is also randomized to receive either an oral high-dose vitamin and mineral supplement or identical-appearing placebo pills (Table IV). The dosing and components of the high-dose oral vitamins were developed with the collaboration of ACAM and represent the typical multi-intervention treatment offered by chelation therapy practitioners. Finally, during the infusion phase of the trial, all study patients receive a daily low-dose regimen consisting of vitamin B6 25 mg, zinc 25 mg, copper 2 mg, manganese 15 mg, and chromium 50 μg, to prevent depletion by the chelation regimen.

Table III. Chelation infusion contents

The dose of EDTA changes based on eGFR; the maximum dose is 3 g.

Table IV. High-dose oral contents

RDA, Recommended daily allowance.

Blinding 

The chelation solution is blinded using a previously piloted method.¹⁵ The shipped and refrigerated infusion pack contains an ascorbic acid syringe (or ascorbic acid placebo), 1 syringe with EDTA (or EDTA placebo) and a bag for intravenous infusion with all the other components already mixed (or a bag containing only normal saline if the patient is assigned to the placebo arm). At the time of infusion, the site coordinator injects the contents of the syringe into the infusion bag. The placebo oral high-dose vitamins are identical appearing to the active therapy.

Patient follow-up 

Patients are seen at baseline and at each of the 40 infusion visits. After the infusion phase of the trial, patients are contacted quarterly by telephone, have annual clinic visits, and are seen at the end of the trial or at the 5-year follow-up, whichever occurs first. TACT study procedures recommend evidence-based concomitant care for post–myocardial infarction (MI) patients.

Safety monitoring 

The most important potential adverse events are hypocalcemia and renal toxicity. Nephrotoxicity has been encountered with far higher doses than TACT uses as well as more frequent administration¹⁶, ¹⁷ and in patients with underlying renal disease. Patients with a baseline creatinine >2.0 are excluded from the trial. Renal function is assessed at baseline and 9 additional times during the infusion regimen. Sites are issued an electronic alert, copied to the CCC, if there is a 25% decrease in eGFR, and infusions stop until creatinine levels return to baseline. Infusions are permanently stopped if there is either a doubling of serum creatinine or an increase to a level of 2.5 mg/dL, whichever is lower. Hematuria and proteinuria are assessed using urine dipstick.

Hypocalcemia due to rapid administration of Na₂EDTA is another potentially serious side effect.⁸ Patients receive infusions over a 3-hour period and over a longer time span if the calcium level, corrected for albumin concentration, is low. Short infusions are reported electronically to the site, the CCC, and the DCC.

Hypoglycemia in diabetic patients may occur. Diabetic patients on insulin snack before the infusion and sites are able to treat hypoglycemia if necessary.

Additional side effects include hypotension, trace metal and vitamin deficiency syndromes, febrile episodes, and heart failure due to fluid overload. During the trial, the patient consent and brochure were modified to include heart failure as a possible adverse event associated with the infusions. The FDA was notified of this finding. The trial also instituted weighing patients before all infusions and required a clinical evaluation if the patient had gained ≥5 lb since the baseline visit to rule out potential progression or new onset of heart failure.

Infusions are delayed in patients whose alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase or bilirubin double, or total white blood cell count falls below the normal limit. The development of thrombocytopenia to below 100,000 platelets or a 50% decrease from baseline leads to a delay of infusions until platelet count reverts to normal levels and an omission of unfractionated heparin from future infusions.

All SAEs are reported to the Data and Safety Monitoring Board, NIH, and FDA on a regular basis. Deaths and unexpected SAEs are reported in an expedited fashion to the above and to the IRBs. Hospitalizations for heart failure are reported to the DSMB and NIH in an expedited fashion.

Study end points 

The primary end point is a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A key secondary end point is the composite of cardiovascular death, nonfatal MI, or nonfatal stroke.

There are 4 other prespecified secondary end points: (1) quality of life, (2) cost-effectiveness of therapy, (3) high-sensitivity C-reactive protein, and (4) eGFR.

Baseline quality-of-life data include 8 scales from the Medical Outcomes Study Short Form,¹⁸ the Duke Activity Status Index,¹⁹ bed and disability day questions from the National Interview Survey,²⁰ job class and days lost from work and the Seattle Angina Questionnaire,²¹ the New York Heart Association congestive heart failure class, and the Canadian Cardiovascular Society class for angina. The EuroQol²² utility is collected at baseline. A random subset of 900 patients undergoes telephone interviews at 6, 12, and 24 months of follow-up. Economic analyses comparing costs between arms will be conducted if either of the experimental therapies demonstrates a reduction in the primary end point. The level of C-reactive protein will be compared between treatment groups in 600 patients. We will compare eGFR in patients receiving active EDTA treatment compared with those receiving placebo infusions.

Cardiovascular event rates and statistical power 

TACT originally planned to enroll 2,372 patients over 3 years. Difficulties in enrolling the requisite numbers of patients ultimately led to a reduction in the total sample size to 1,700 patients, with a counterbalancing extension in median follow-up to 4 years. The event rates in each control arm of TACT were estimated based on published data on similar post-MI patient populations participating in clinical trials,²³ namely, ≥20% after 2.5 years of follow-up. The level of noncompliance with EDTA (or placebo) infusion therapy and oral vitamin (or placebo) expected in TACT was estimated as 7.2% of patients per year or 22% over 3 years. We also assumed a loss to follow-up rate of up to 3% of patients in the trial. This statistical plan provides 85% power for detecting a 25% relative reduction in the primary end point for each treatment.

Statistical analysis 

All major treatment comparisons will be performed according to the principle of intention to treat. Statistical comparisons will be performed using 2-sided significance tests. The primary statistical assessments will compare EDTA chelation with placebo infusions and oral high-dose vitamins with oral placebo. The log-rank test²⁴ will be used for the adjusted comparisons of each treatment factor. Cumulative event rates will be calculated according to the Kaplan-Meier method.²⁵ Hazard ratios with associated CIs will be derived from the Cox proportional hazards model.²⁶ The Cox model will also be used to assess whether there is an interaction of EDTA chelation therapy with high-dose vitamins. Interim treatment comparisons are monitored with the use of 2-sided, symmetric O'Brien-Fleming boundaries generated with the Lan-DeMets α-spending function approach to group sequential testing.²⁷, ²⁸

Subgroup analyses 

A limited number of prespecified subgroup analyses of the primary outcome and selected secondary outcomes will test the efficacy of chelation therapy and/or high-dose vitamins. Treatment comparisons will be performed within subgroups defined by:

Subgroup differences in treatment effects will be assessed with the Cox model, by testing for interactions between the randomized treatment factor and the specific baseline variables listed above.

The authors are solely responsible for the design and conduct of this study, the drafting and editing of the manuscript, and its final contents.

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Discussion 

National surveys have documented widespread use of Complementary and Alternative Medicine (CAM) by patients across a broad spectrum of diagnoses.¹, ² American College for Advancement in Medicine and other organizations train chelation practitioners annually. The Centers for Disease Control and Prevention estimates that approximately 111,000 US adults used chelation therapy in 2007,³ a 66% increase since the previous survey in 2002.²⁹ The need to accumulate sufficient randomized evidence of a CAM therapy such as EDTA chelation goes beyond the need to identify a new therapy for patients with coronary disease. The labeled and possible toxicities, which include renal insufficiency, cardiac arrhythmias, hypocalcemia, hematologic problems, respiratory arrest, and death, must be assessed in the context of a therapy with potential but unproven benefits. This fair and balanced assessment can be carried out only in the context of a randomized trial.

The interpretation of any benefit or harm of chelation therapy as used in the community would be confounded by the concomitant use of high-dose oral supplements, a common clinical practice. Moreover, the use of high-dose supplements may not be innocuous.³⁰, ³¹, ³² Thus, the vitamin-treatment comparison, like the chelation comparison, stands alone as important for the assessment of efficacy as well as safety.

Besides challenges typical of large multisite trials, TACT was faced with several additional hurdles. Substantial recruitment difficulties led NIH to organize a review of trial progress carried out by a panel of experts in cardiovascular research independent of NIH, of the trial DSMB, and of trial investigators. Despite estimates that trial completion would be delayed several years, this independent committee concluded that TACT should continue with a reduced sample size. Concerns about the informed consent process and about trial conduct at several clinical sites also prompted investigations by OHRP and FDA, respectively. Following their reviews, each federal agency recommended that the trial could continue after corrective steps were taken. All sites met NIH, FDA, and OHRP requirements for participation in federally funded studies, including ethics review by a local or central IRB with a Federal-Wide Assurance. Details on these implementation issues will be presented in a subsequent article.

At this time, TACT has finished enrollment, has delivered the final infusions and vitamins, and is expected to present final results in 2012.

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Conclusions 

TACT has been designed to test whether EDTA chelation therapy and high-dose oral vitamin and mineral therapy offer clinical, quality of life, and economic benefits for patients with a prior MI.

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Acknowledgements 

The authors wish to acknowledge the valuable contributions of the following individuals: Ronald Hoffman, MD and Charles Hennekens, MD, DrPh, for protocol design; the CCC project directors (Ana Mon, MPH; Jacqueline Arciniega, MPH; Jaime Zimmerman, MPH; and Danielle Hollar, PhD); the CCC trial managers (Esteban Escolar, MD; Faisal Shamshad, MD; Pablo Guala, MD; Kayvan Amini, DO; Steven Hussein, MD; Alan Ackermann, DO); the project managers at the DCC (Sandra Tourt-Uhlig, RN, MSN; Joyce Good, RN, CCRC; Lindsay Lambe, BA, CNMT; Wanda Parker, RN, MSN; Nancy Clapp-Channing, BSN, MPH; Diane Minshall-Liu, CCRP); the NHLBI team members (Yves Rosenberg, MD; Mario Stylaniou, PhD; and Erin Iturriaga, RN, BS) and DSMB members (Howard Hodis, MD- Chair; Stephen Buckley, PharmD; Barry Davis, MD, PhD; Theodore Ganiats, MD; Robert Nash, MD; D. George Wyse, MD, PhD; and Gail Geller, ScD, MHS); the project directors at Omnicomm Systems (Chris Droz, Brandon Diaz) and the central pharmacy team (Eric M. Alvarez, PharmD; Juan Mora RPh; Marcia Perez); the NCCAM Office of Communication and Outreach (Alyssa Cotler, MPH); the NHLBI Office of Communications (Susan Dambrauskas, NHLBI press team leader); and the Florida Heart Research Foundation for funding the pilot study.

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