Clinical trial NCT02733185
Conditions: Diabetes Myocardial Infarction
Keywords: chelation
Sponsor: Mt. Sinai Medical Center, Miami
Start date: 2016-10-01; Completion date: 2023-06-30
Enrollment: 1000 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
Trial to Assess Chelation Therapy 2 (TACT2) is a randomized, double blind controlled factorial clinical trial of edetate disodium-based chelation and high-dose oral vitamins and minerals to prevent recurrent cardiac events in diabetic patients with a prior myocardial infarction (MI).

Detailed description:
The primary objective of TACT2, therefore, is to determine if the chelation-based strategy increases the time to the first occurrence of any of the components of the TACT2 primary endpoint: all-cause mortality, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina compared to the placebo chelation strategy.

TACT2 is a 2x2 factorial trial testing 40-weekly edetate disodium-based chelation infusions and twice daily high-dose oral multivitamins and multiminerals (OMVM) in a placebo-controlled design.

TACT2 is being carried out to replicate the findings of TACT1, which found a striking reduction of recurrent cardiovascular events in post-MI diabetic patients receiving edetate disodium-based chelation therapy.

Arms: arm 1: Active disodium EDTA (chelation) + Active Oral Multi Vitamins/Minerals (OMVM) arm 2: Active disodium EDTA (chelation) + Placebo Oral Multi Vitamins/Minerals (OMVM) arm 3: Placebo disodium EDTA (chelation) + Active Oral Multi Vitamins/Minerals (OMVM) arm 4: Placebo disodium EDTA (chelation) + Placebo Oral Multi Vitamins/Minerals (OMVM)
Interventions: intervention 1: disodium EDTA intervention 2: Oral Multi Vitamins/Minerals (OMVM) intervention 3: Placebo disodium EDTA intervention 4: Placebo Oral Multi Vitamins/Minerals (OMVM)
Intervention descriptions: intervention 1: IV Disodium Ethylene diamine tetra acetic acid in 500 cc intervention 2: 6 tablets of Multi-vitamin/Multimineral daily intervention 3: IV Placebo comparator- 500 normal saline intervention 4: 6 tablets of a placebo Multi-vitamin/Multimineral daily

Protocol documents:
ICF_000.pdf: 
Trial to Assess Chelation Therapy- 2 
(TACT2) 
 
NCT02733185 
 
Informed Consent Form 
Version Date: 05.01.2019 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 1 of 15 
Version: 4 Date: 01 May 2019 
PARTICIPANT INFORMED CONSENT FORM AND 
AUTHORIZATION TO USE AND DISCLOSE MEDICAL INFORMATION 
 
STUDY TITLE: 
A randomized, double blind controlled factorial clinical trial of edetate 
disodium-based chelation and high-dose oral vitamins and minerals to 
prevent recurrent cardiac events in diabetic patients with a prior 
myocardial infarction. 
 
PROTOCOL NO: 
TACT2 
 
STUDY DOCTOR: 
«First_Name» «Middle_Name» «Last_Name», «Suffix» 
 
STUDY SITE: 
«Company_Name» 
 
 
 
«Address» 
 
 
 
«City_State_ZIP» 
 
TELEPHONE: 
«Telephone» 
 
 
 
«Telephone_2_if_applicable» 
 
SPONSOR: 
 
National Institutes of Health 
 
INTRODUCTION 
 
You are being asked to take part in TACT2, a research study funded by the National Institutes 
of Health (NIH), because you have diabetes and had a heart attack. Mount Sinai Medical Center 
and Duke Clinical Research Institute (DCRI) are the research centers that received funding from 
NIH. As the Data Coordinating Center, DCRI is responsible for data collection, analysis of 
results, and monitoring the participating sites. The clinical coordinating center, Mount Sinai, is 
responsible for the clinical and medical management of the study activities with the study doctor 
and staff.  
 
Your participation in this research study is strictly voluntary, meaning that you may or may not 
choose to take part. To decide whether or not you want to be part of this research, the risks and 
possible benefits of the study are described in this form so that you can make an informed 
decision. This process is known as informed consent. This consent form describes the purpose, 
procedures, possible benefits and risks of the study. This form explains how your medical 
information will be used and who may see it. You may have a copy of this form to review at your 
leisure or to ask advice from others. 
 
The study doctor or study staff will answer any questions you may have about this form or about 
the study. Please read this document carefully and do not hesitate to ask anything about this 
information. This form may contain words that you do not understand. Please ask the study 
doctor or study staff to explain the words or information that you do not understand. After 
reading the consent form, if you would like to participate, you will be asked to sign this form. You 
will be given a signed copy of your consent form to take home and keep for your records. You 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
Page 2 of 15 
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will also be asked to complete and sign a medical release form and a form authorizing the study 
staff to receive your study vitamins and minerals. 
PURPOSE OF THE STUDY 
The purpose of this study is to find out if chelation therapy (a chemical process in which a 
synthetic solution is infused into the bloodstream to remove heavy metals and/or minerals from 
the body) and oral vitamins and minerals help decrease the risk of new heart events (including 
another heart attack, death, chest pains, or heart surgery to open blood vessels) in research 
participants with diabetes who have already survived a heart attack. This study is being carried 
out because a prior study suggested benefit with chelation therapy when given to research 
participants with diabetes who had had a heart attack. The study drug, chelation, is a drug given 
by vein that that sticks to heavy metals in the blood, like lead and cadmium. These metals can 
then come out of the body in the urine. Lead and cadmium may lead to heart disease. 
We will also collect and store blood and urine samples to determine: 

whether other metals or blood changes account for the effect of chelation

whether we can predict cardiac events like heart attacks based on your body metal levels

for future analyses that we have not thought of yet

You will be 1 of about 1,200 people in this study

There are about 120 research sites in North America

You will be in this study for up to 5 years

The study requires:
o
40 weekly IV’s (through a vein in your arm) and taking vitamins and minerals or inactive
placebo (identical in appearance to vitamins and minerals but contain no active
ingredient) twice a day by mouth
o
up to 48 months of follow-up and taking pills twice a day by mouth
BACKGROUND 
The study drug, chelation therapy, consists of a drug in a solution of dissolved materials that 
bind to heavy metals, including lead and cadmium, and allow them to come out in the urine. 
These metals may lead to heart disease. 
The drug in the solution used in this study is edetate disodium (also called disodium EDTA or 
EDTA). The United States Food and Drug Administration (FDA) has not approved EDTA for 
treating heart disease in heart attack survivors, making its use in this study investigational. The 
drug under use in this study is not the same drug approved by the FDA for use in cases of lead 
poisoning (calcium EDTA or edetate calcium disodium). The FDA is aware of this study and 
receives regular reports. 
This infusion is given over 3–4 hours, through a needle placed into your arm by medical staff. 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 3 of 15 
Version: 4 Date: 01 May 2019 
This study is funded by the US government (NIH), and receives no support from pharmaceutical 
or other commercial drug companies. 
 
PROCEDURES 
 
You will be asked to have a study screening visit, which will take about 1 hour. At the visit, we 
will: 
 
 
Review and ask you to sign this Participant Informed Consent Form and Authorization To 
Use and Disclose Medical Information and a Pharmacy Designation Form after all of your 
questions are answered. 
 
Review the study inclusion and exclusion criteria 
 
Ask you to provide contact information for follow-up 
 
Ask you to complete medical history forms 
 
Ask you questions about your health, activities, and how you are feeling emotionally 
 
Perform a brief physical exam. The physical exam will not include a breast, pelvic, or rectal 
exam 
 
Get a blood sample (3 tablespoons) to check your blood cell counts and kidney and liver 
function. 
 
If you have been hospitalized with fluid in your lungs due to a weak heart within the last 6 
months, you will not be permitted to participate in the study. 
 
Your blood test results and medical history will confirm if you are eligible to participate in the 
study. 
 
You will be assigned by chance (like a coin toss) to a study group. You will be assigned to one 
of the following 4 study groups: 
 
 
Chelation solution + oral multivitamins and multiminerals 
 
Chelation placebo solution + oral multivitamins and multiminerals 
 
Chelation solution + placebo oral multivitamins and multiminerals 
 
Chelation placebo solution + placebo oral multivitamins and multiminerals 
 
Placebo is identical in appearance to the active solution or multivitamins and multiminerals but 
contains no active ingredients. 
 
All participants will also take an additional low-dose vitamin and mineral pill each day while they 
are receiving infusions, to replace essential vitamins and minerals (in addition to the ones 
mentioned above). 
 
You have an equal chance of being assigned to any of the 4 study groups. Neither you, nor the 
study doctor and study staff will know to which study group you have been assigned. Your 
assigned study group will be available to your study doctor in the event of a medical emergency. 
 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 4 of 15 
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Your first infusion visit will be scheduled. 
 
Infusion Visits (40 visits over 52 weeks, about 4 hours for each visit) 
 
At each infusion visit: 
 
 
We will check your blood pressure, pulse, weight, and listen to your heart and lungs 
 
You will have your blood collected at screening and infusions 5, 10, 20, 30, and 40 (or at 1 
year, whichever is first), to check for kidney function, control of your diabetes, calcium, and 
blood counts 
 
Additional blood and urine samples are collected at Visits 1, 5, 20, and 40 (or at 1 year) to 
see if long-term EDTA chelation infusions can reduce lead and cadmium levels. These are 
harmful metals that when removed or decreased may be related to lowering the risk for 
heart disease These specimens will be shipped to the central metals laboratory for 
processing and the results will be in the study database at DCRI 
 
Each sample will require about 3 tablespoons of blood, and 2 ounces of urine 
 
Trained medical staff will use a needle to insert a catheter into a vein in your arm 
 
The chelation infusion will be given slowly, over at least 3 hours 
 
We will ask you how you are feeling and whether you have any new health problems, new 
heart problems, or hospital visits 
 
Follow-up Contacts (beginning 6 and 12 months after randomization, and every 4 months 
until the study ends, for about 15–20 minutes) 
 
 
You will be contacted by phone by trained research staff from the Economics and Patient 
Reported Outcomes Center at Duke Clinical Research Institute (the DCRI Call Center). 
 
If the research staff cannot reach you, they will call the people you have listed as your 
contacts and ask how to get in touch with you. If you have chosen a person who is allowed 
to answer questions for you in your absence, the interview team may call this person and 
ask questions about how you are doing. 
 
These interviews will take place every 4 months for up to 5 years. 
 
You will continue taking your assigned multivitamins and multiminerals or oral placebo. 
 
You will be asked about changes in how you feel, in your ability to perform your daily 
activities, if you have had any hospital visits, medications, vitamin use, questions related to 
your diabetes and your working status. 
 
If you had a hospital visit during the follow-up period, you will be asked to sign a medical 
release. This will give the study access to any medical records related to that hospital visit. 
 
The DCRI Call Center will also receive a copy of your signed Participant Informed Consent 
Form and Authorization to Use and Disclose Medical Information. This will be used to obtain 
copies of your medical records, tests, and bills during the study. This information will help 
determine the details of any hospitalizations related to your heart disease and the cost effects of 
the study chelation infusion. At the conclusion of the study, your contact information will be 
destroyed. 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 5 of 15 
Version: 4 Date: 01 May 2019 
YOUR RESPONSIBILITIES 
 
Taking part in this research study is voluntary. If you choose to take part in this study, your 
major responsibilities will include: 
 
 
Telling the study staff of any changes in your health. 
 
Telling the study staff if there is any change in your contact information. 
 
Telling study staff if you need to reschedule an infusion visit. 
 
Allowing at least 5 hours for each infusion visit. 
 
On the day of your infusion visit, taking your vitamins after the infusion  
 
Allowing the study pharmacy to send your multivitamins and multiminerals or oral placebo, 
to your home through the mail. 
 
Taking all other medications for your heart disease, diabetes, and other conditions as 
prescribed by your physician. 
 
Completing the interviews over the phone. 
  
RISKS AND SIDE EFFECTS 
 
Of the 1,708 people who were in the prior chelation study, there were no more serious study 
drug complications, including death, in the group that received chelation study drugs when 
compared to those who received the inactive, or placebo, study drug. 
 
The side effects that other doctors have reported are listed below. In addition, there may be 
other side effects.  
 
IV Chelation Side Effects 
 
Low Blood Calcium 
 
The IV chelation can cause calcium in the blood to be too low. This can cause tingling, muscle 
cramps, lightheadedness, severe muscular spasms, low blood pressure, and even heart rhythm 
problems that could cause death. These symptoms may be seen when the IV chelation is given 
too quickly. They are hardly ever seen when the IV is given correctly. 
 
Low Blood Pressure 
 
Giving the IV chelation too quickly may cause your blood pressure to drop. Your blood pressure 
will be checked before and after the IV. 
 
Heart Problems 
 
If your heart is weak, you may be at risk of building water in your lungs, in your ankles, or having 
rapid weight gain. These symptoms may happen because your heart cannot tolerate the amount 
of water in the IV. 
 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 6 of 15 
Version: 4 Date: 01 May 2019 
We will check your weight to make sure you are not retaining fluid. Chelation infusions may be 
stopped for a short time if your study doctor determines that your weight gain is related to the 
infusions. Your study doctor may decide to give you a diuretic (water pill) to help prevent any 
further fluid in your lungs that may lead to shortness of breath. 
 
Low Kidney Function 
 
If your kidneys get worse during the infusions, then the dose will be reduced, or the IV will be 
stopped. 
 
Flu-like Symptoms 
 
You may develop flu-like symptoms, such as low-grade fevers, sneezing, muscle and joint 
aches, headaches and watery eyes. These symptoms may occur 4 to 8 hours after receiving the 
IV. 
 
Death 
 
Death is a very rare complication of IV chelation. 
 
Diabetes 
 
The IV chelation may cause low blood sugar. You should eat a snack before your study visits, 
and we will watch for symptoms of low blood sugar. 
 
Some participants using continuous glucose monitors (CGMs) may have incorrect readings. 
This could result in either not giving insulin when it is needed or giving too much insulin. To 
avoid insulin dosing errors as a result of an incorrect CGM reading you should do the following: 
 
 
Do not depend on the results of CGM for insulin dosing while you are receiving an infusion 
and for 12 hours from the beginning of the infusion. 
 
If you have a closed loop insulin pump system, you should put your pump into manual mode 
for 24 hours starting at the time of the infusion. 
 
If, during the above time periods, you note a low or high reading on your CGM, you should 
perform a fingerstick measurement to determine if you need insulin. 
 
IV site problems 
 
You might have some discomfort at the needle puncture site. There is also a risk of bruising, 
swelling, and redness developing at the needle puncture site. Infection at the needle site is a 
rare risk. 
 
You may also experience these discomforts when having your blood drawn. 
 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 7 of 15 
Version: 4 Date: 01 May 2019 
During the IV you may experience a “burning-like” sensation at the site of the infusion, or 
through the vein.  
 
Certain vitamins and minerals that are needed by your body may be excreted (come out in the 
urine) after chelation. This can cause symptoms such as feeling tired, dry skin, tingling in your 
hands and feet, a skin rash, diarrhea, and constipation. You will be provided with oral 
multivitamins and multiminerals to replace these elements. 
 
The effectiveness of some of the medications you are taking may decrease during chelation. 
You must tell your study doctor about any medications, including prescription, over-the-counter, 
and herbal supplements, that you are taking while in this study. 
 
Vitamins B1, B6, pantothenic acid, and vitamin C also are included in the IV. These vitamins 
have no significant side effects. However, vitamin C is being used at a higher dose than usual, 
and at this dose may be associated with kidney stones. 
 
Procaine is a numbing medicine that will help with discomfort at the needle puncture site. The 
main side effect of procaine is the possibility of allergy. 
 
Any component in the chelation solution could possibly cause allergies. Please tell your doctor if 
you have any allergies. Symptoms of any allergic reaction can include a rash, hives, itching, 
and/or difficulty breathing, closing of the throat, or swelling of the lips, tongue, or face. Rarely it 
can cause death. You will be monitored carefully after administration of the IV solution for signs 
of an allergic reaction. There are trained medical staff and emergency equipment and medicines 
available at the study site to treat you in the event of an allergic reaction. If you think you are 
having a severe allergic reaction after you leave the study site, dial 9-1-1 and seek 
medical attention immediately. 
 
There could be additional side effects from the chelation solution that we cannot predict at this 
time. 
 
Side Effects of Vitamins and Mineral Pills 
 
Vitamin A, in doses much higher than those used in this study, may cause dizziness, nausea, 
vomiting, headache, skin damage, mental disturbances, and, in women, infrequent periods. 
 
Vitamin D, in doses much higher than those used in this study, may cause increased blood 
calcium levels, muscle weakness, anorexia, vomiting, diarrhea, and mental changes. 
 
Vitamin E, in doses much higher than those used in this study, may cause bleeding problems, 
mostly in people taking anti-clotting medications. 
 
Vitamin K, in doses much higher than those used in this study, may cause allergic-type 
responses, including rash and itching. If you are taking Coumadin (warfarin), a blood thinner, 
you should not take Vitamin K without checking with your physician. 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 8 of 15 
Version: 4 Date: 01 May 2019 
 
Beta-carotene has been related with cancer in participants who smoke. Do not start smoking 
while you are in this study. 
 
Any component of the oral multivitamins and multiminerals could possibly cause allergies. 
Please tell your doctor if you have any allergies. 
 
There could be additional side effects from the oral vitamins that we cannot predict at this time. 
 
There also may be other side effects or discomforts, especially to a fetus or embryo. Because 
the drug in this study is not approved for use in pregnancy, you should not become pregnant 
while on this study. Your study doctor will discuss this with you. You should not breast-feed a 
baby while on this study. 
 
There is a possible risk to your privacy. Every effort will be made to maintain your privacy, 
however this cannot be guaranteed 
 
Your treatment and medical care will not change because you are taking part in this study. Your 
doctor will continue to make all decisions regarding your proper care. 
 
If you have any questions about the risks or discomforts, contact Dr. «Last_Name» at 
«Telephone». 
 
NEW FINDINGS 
 
An independent group of medical experts will review the information from this research often 
throughout this study. You will be told in a timely manner if new information becomes available 
that may change your mind about participating in this study. 
 
BENEFITS 
 
You may or may not receive any medical benefit from being in this study. In the future, other 
people with a similar condition may benefit from the knowledge obtained from this study. 
 
ALTERNATIVE TREATMENTS 
 
If you choose not to take part in this study, it will not affect your other heart treatments as 
directed and recommended by your doctor. You should continue to use proven standard 
medicines for diabetes and heart attack patients whether or not you participate in this research 
study. You may be able to receive chelation therapy and oral multivitamins and multiminerals 
outside of the study. Ask your study doctor about the risks and benefits of alternative treatments 
before you take part in this study. 
 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 9 of 15 
Version: 4 Date: 01 May 2019 
COSTS TO YOU 
 
You or your insurance company will not be charged for the study chelation infusions or for tests 
required by the study. All the study drugs are provided at no charge to you. 
 
COMPENSATION TO YOU 
 
If you complete all study visits you will receive up to a total of «Total_Comp». If you withdraw 
from the study before it is completed, you will receive «Per_Visit» for each completed visit. A 
completed visit means all scheduled study procedures have been carried out. 
 
COMPENSATION FOR RESEARCH-RELATED INJURY 
 
In case of medical illness or injury related directly or indirectly to your participation in this study, 
you will receive all appropriate treatments. You or your insurance company will be billed for any 
research-related injury in the ordinary manner; however, you do not waive any of your legal 
rights or release anyone from liability for negligence by signing this document. 
 
In case of injury, contact Dr. «Last_Name» at telephone number «Telephone». 
 
RIGHT TO WITHDRAW 
 
Your decision to participate is entirely voluntary. You may elect to receive alternative treatment. 
You may refuse to participate without penalty or loss of benefits to which you are otherwise 
entitled. Your ongoing medical care will not be affected by your decision to be in this study or to 
withdraw from the study. 
 
If you decide to participate in this study, you can withdraw at any time. You have the right to 
change your mind to not have any of your information collected. You have the option to choose 
to withdraw from all or parts of the study. We ask that you contact Dr. «Last_Name» in writing 
and let him/her know which specific part of the study that you are withdrawing: 
 
 
chelation infusions 
 
oral multivitamins and multiminerals 
 
follow-up phone calls 
 
Your study doctor will ask to schedule one last visit with you. 
 
INVOLUNTARY WITHDRAWAL 
 
Your study doctor may ask you to leave this study if he/she decides it is appropriate or 
necessary. Your study doctor will notify you if this should occur. This in no way will affect your 
continued medical care and treatment by your physician. 
 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 10 of 15 
Version: 4 Date: 01 May 2019 
CONFIDENTIALITY 
 
Your study records will be kept private as required by law. Information that could identify you by 
name will not be used if the results of this study are published. You will be assigned a unique 
code number at the time of study entry, and your name will be available on a highly restricted 
basis to your clinical enrolling site, to the Central Pharmacy so you can get your study 
medicines to the DCRI Call Center, so they can reach you after the infusions are over and find 
out how you are doing, and to the Mount Sinai Clinical Coordinating Center. At each site, all 
your data will be kept in secure computers available by password only, and behind secure 
firewalls (high-security computer networks). Your personal health information (PHI) will be 
protected. 
 
Government agencies, such as the Food and Drug Administration, may inspect the study 
records. This includes the information about you, collected for study purposes. 
 
AUTHORIZATION TO COLLECT, USE AND DISCLOSE MEDICAL INFORMATION 
 
If you sign this consent form, you are giving your permission for Dr. «Last_Name» and his/her 
study team to report your study-related test results and medical information to the following 
people or groups for research: 
 
 
National Institutes of Health (NIH) 
 
Department of Health and Human Services (DHHS) 
 
United States Food and Drug Administration (FDA) 
 
Other government agencies in other countries 
 
Sterling Institutional Review Board (IRB) 
 
Duke Clinical Research Institute (DCRI) 
 
Mount Sinai Clinical Coordinating Center 
 
The TACT2 Central Pharmacy 
 
The TACT2 Central Laboratory 
 
The TACT2 Central Metal Laboratory 
 
The TACT2 Biorepository Laboratory 
 
Your study information may be released to the groups listed above. If your study information is 
reviewed by these people, they may need to see your entire medical record; it is possible that 
your Social Security number may be included in the records reviewed. Because of this, it cannot 
be assured that your confidentiality will always be protected. It is possible that your information 
will be shared (re-disclosed) in a way that it would no longer be protected. However, this access 
to your records will be granted without violating your confidentiality to the extent permitted by 
applicable laws and regulations. By signing this form, you are authorizing this access to your 
records. 
 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 11 of 15 
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The health information about you that the people or groups listed above may give to the 
researchers to use in this research study includes: 
 
 
Medical History and current medications  
 
Blood pressure  
 
Heart rate  
 
Height and weight  
 
Hospitalizations, clinic visits, emergency department visits  
 
New and existing medical records  
 
Laboratory results  
 
Types, dates and results of various tests and procedures  
 
Research information collected about you might be put in your medical record. It’s possible that 
you may not be able to see the research study information that has become part of your medical 
record until the entire research study is over.  
 
A public data set that is not identifiable with your personal information will become available 
when the study has been completed. Other scientists may use the information to perform 
additional research that has not been thought of yet. 
 
This permission (also called an authorization) will have no end date. 
 
You may also take away (or withdraw) your permission for the use of your protected health 
information at any time. If you choose to withdraw your permission, you must write your study 
doctor a letter. 
 
The study doctor’s mailing address is «Company_Name», «Address», «City_State_ZIP». The 
study doctor will still be able to use the health information collected about you before you 
withdrew your permission. Information that has already been sent to the sponsor of the study 
cannot be taken back. 
 
If you withdraw your permission after you have entered the study, you cannot continue 
participating in the study. If you refuse to give permission or withdraw your permission, your 
medical care and your relationship with the health care providers at the study center will not be 
affected. 
 
QUESTIONS 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
If you have questions, concerns or complaints about the research study or you experience a 
research-related injury, please contact Dr. «Last_Name» or the study staff at «Telephone» or 
«Telephone_2_if_applicable». 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
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If you have questions regarding your rights as a research participant, or if you have questions, 
concerns, complaints about the research, would like information, or would like to offer input, you 
may contact the Sterling Institutional Review Board Regulatory Department, 6300 Powers Ferry 
Road, Suite 600-351, Atlanta, Georgia 30339 (mailing address) at telephone number 1-888-
636-1062 (toll free). 
 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 13 of 15 
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STATEMENT OF CONSENT 
 
The purpose of this study, procedures to be followed, risks and benefits have been explained to 
me. I have received answers to any questions. I have been told whom to contact if I have 
additional questions.  
 
I voluntarily consent to participate in this research study and I understand that I may withdraw 
my consent at any time without penalty or prejudice to my subsequent care. I give my 
permission to the study doctor to use and disclose my protected health information as described 
in this consent form. 
 
I will receive a signed copy of this form, which has 15 pages. 
 
I have not waived any of my legal rights by signing this document. 
 
 
_________________________________________ 
Printed Name of Participant 
 
 
_________________________________________ 
________________ 
Signature of Participant 
 
 
 
 
Date 
 
 
_________________________________________ 
Printed Name of Person Obtaining Consent 
 
 
_________________________________________ 
________________ 
Signature of Person Obtaining Consent 
 
 
Date 
 
 
_________________________________________ 
Printed Name of Witness (if applicable) 
 
 
_________________________________________ 
________________ 
Signature of Witness (if applicable)  
 
 
Date 
 
*A witness is not required unless the participant is unable to read (such as blind or illiterate). If a witness is present, 
however, the witness must observe the entire informed consent process, including participant signature. 
 
 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 14 of 15 
Version: 4 Date: 01 May 2019 
INFORMED CONSENT FORM FOR BLOOD AND URINE BIOREPOSITORY 
 
The National Institutes of Health (NIH) would like to keep in storage some of the blood and urine 
specimens that are taken during the study. If you agree, the blood and urine will be kept and 
may be used in future research to learn more about heart attacks and other diseases. These 
specimens will be stored at the study central metal and biorepository laboratory and will be used 
for research studies in the future. You have the right to not have your samples placed in the 
biorepository and/or removed from the biorepository. 
 
Any research study using your blood and urine must be approved by an Institutional Review 
Board (IRB) that provides oversight for human subject rights in research studies. The research 
that may be done with your blood and urine is not designed to help you specifically. It might help 
people who have heart attacks and other diseases in the future. Reports about research done 
with your blood and urine will not be given to you or your doctor. These reports will not have any 
information that could identify you by name and will not be put in your health records. The 
research using your blood and urine will not affect your care. 
 
The choice to let the NIH keep the blood and urine for future research is up to you. No matter 
what you decide to do, it will not affect your care in this study. If you decide now that your blood 
and urine can be kept for research, you can change your mind at any time. Just contact your 
study doctor and let him or her know that you do not want NIH to use your samples and they will 
no longer be used for research. Otherwise, the blood and urine may be kept until it is used up, 
or until NIH decides to destroy it. 
 
In the future, people who do research may need to know more about your health. While NIH 
may give them reports about your health, they will not give them your name, address, phone 
number, or any other information that will let the researchers know who you are. Sometimes 
blood is used for genetic research (about diseases that are passed on in families). Even if your 
blood is used for this kind of research, the results will not be told to you. You are not consenting 
to have these results put in your health records. Your blood and urine will be used only for 
research and will not be sold. The research done with your blood and urine may help to develop 
new products in the future, but you will not get paid. 
 
The possible benefits of research from your blood and urine include learning more about what 
causes heart attacks and other diseases, how to prevent them, and how to treat them. The 
greatest risk to you is the release of information from your health records. NIH will protect your 
records so that your name, address, and phone number will be kept private. The chance that 
this information will be given to someone else is very small. There will be no cost to you for any 
blood and urine collected and stored by NIH. 
 
Please read the following sentence and think about your choice. After reading the sentence, 
indicate "yes" or "no." If you have questions, please talk to your doctor or nurse. Remember, no 
matter what you decide to do about the storage and use of your blood and urine, you may still 
take part in this study. 
 


STUDY: TACT2 
PROTOCOL NO:  TACT2 
STERLING IRB ID:  «IRB_ID» 
DATE OF IRB REVIEW: 
DATE REVISED: 05/07/19 
 
 
Page 15 of 15 
Version: 4 Date: 01 May 2019 
I agree to the use of my blood and urine for other research studies: _____Yes _____No 
 
_________________________ 
_____________________ 
Participant’s Signature 
 
Date 

SAP_002.pdf: 
TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 1 of 28 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
Protocol Version: 
Amendment 3 
 
Protocol Date: 
November 1, 2019 
 
Analysis Plan Version: 
2.0 
 
Analysis Plan Date: 
September 12, 2023 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 2 of 28 
 
 
 
TABLE OF CONTENTS 
1 
Introduction .......................................................................................................................................... 6 
1.1 
Study Design .................................................................................................................................. 6 
1.2 Study Objectives ................................................................................................................................. 6 
1.2.1 Primary Objective ......................................................................................................................... 6 
1.2.2 Secondary Objectives ................................................................................................................... 6 
1.2 
Sample size Considerations ........................................................................................................... 7 
2 
General Considerations for Data Analyses............................................................................................ 9 
2.1 
Analysis Populations ..................................................................................................................... 9 
2.1.1 
Intention-to-treat Population (ITT) ....................................................................................... 9 
2.1.2 
Modified Intention-to-treat Infusion Population (mITT) ...................................................... 9 
2.2 
Data Sources ................................................................................................................................. 9 
2.3 
General Analysis Conventions ....................................................................................................... 9 
2.4 
Disposition of Participants .......................................................................................................... 10 
2.5 
Demographic and Baseline Characteristics ................................................................................. 10 
2.6 
Handling of Missing Data ............................................................................................................ 10 
3 
Analysis of Clinical Endpoints .............................................................................................................. 11 
3.1 
General ........................................................................................................................................ 11 
3.1.1 
Estimands and Censoring Scheme ...................................................................................... 11 
3.1.2 
Event Data ........................................................................................................................... 16 
3.1.3 
Assessment of Model Assumptions .................................................................................... 16 
3.1.4 
Multiple Comparisons and Composite Endpoints ............................................................... 17 
3.2 
Primary Endpoint Analysis .......................................................................................................... 17 
3.2.1 
Primary Analysis .................................................................................................................. 17 
3.2.2 
Sensitivity Analyses of the Primary Outcome ..................................................................... 18 
3.3 
Analysis of the Secondary Endpoints .......................................................................................... 19 
3.3.1 
Recurrent-event analysis of the primary endpoint ............................................................. 19 
3.3.2 
Time to Event Analysis of the Secondary Endpoints ........................................................... 20 
3.3.3 
Sensitivity Analyses of the Secondary Outcomes ............................................................... 21 
3.4 
Subgroup Analyses ...................................................................................................................... 21 
3.5 
Safety Analyses ........................................................................................................................... 22 
4 
References .......................................................................................................................................... 23 
5 
SAP Revision ........................................................................................................................................ 24 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 3 of 28 
 
 
6 
Appendices .......................................................................................................................................... 25 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 4 of 28 
 
 
Signature page 
Prepared by: 
Electronically signed by: Hayley Nemeth 
Reason: Approved 
………………………………………….. 
Hayley Nemeth, MS 
DCRI Statistics Representative 
Biostatistician III 
Duke Clinical Research Institute 
Date: Sep 19…
, 2…02…3…1…
3:…
06…E…D…
T …………… 
Date 
 
 
Reviewed by: 
Kevin J. Anstrom 
………………………………………….. 
Kevin J. Anstrom, PhD 
Co-Principal Investigator, DCC 
 
Electronically signed by: Kevin J. Anstrom 
Reason: Approved 
Date: Sep 19, 2023 18:29 EDT 
…………………………………… 
Date 
University of North Carolina Gillings 
School of Global Public Health 
 
Approved by: 
Gervasio Lamas 
………………………………………….. 
Gervasio A. Lamas, MD, 
Principal Investigator, CCC 
Electronically signed by: Gervasio Lamas 
Reason: Approved 
Date: Sep 21, 2023 16:42 EDT 
…………………………………… 
Date 
Mount Sinai Medical Center and Columbia 
University Medical Center 
 
Electronically signed by: Daniel Mark 
Reason: Approved 
………………………………………….. 
Daniel B. Mark, MD, MPH, 
Co-Principal Investigator, DCC 
Duke Clinical Research Institute 
Date: Sep 23, 2023 18:08 EDT 
…………………………………… 
Date 
 
Electronically signed by: Mario Stylianou 
Reason: Approved 
Date: Sep 25, 2023 12:07 EDT 
………………………………………….. 
Mario Stylianou, PhD 
NIH Representative 
National Heart, Lung, and Blood 
Institute/National Institutes of Health 
…………………………………… 
 
Date 
Hayley Nemeth 
Daniel Mark 
Mario Stylianou 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 5 of 28 
 
 
 
Abbreviations 
 
Abbreviation 
Definition 
CEC 
Clinical Events Committee 
CI 
Confidence Interval 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DCRI 
Duke Clinical Research Institute 
EDC 
Electronic Data Capture 
FU 
Follow-Up 
HR 
Hazard Ratio 
ITT 
Intention-To-Treat 
MI 
Myocardial Infarction 
mITT 
Modified Intention-To-Treat 
NDI 
National Death Index 
OMVM 
Oral MultiVitamins and Multiminerals 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TACT2 
Trial to Assess Chelation Therapy 2 
WLW 
Wei, Lin, and Weissfeld 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
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1 Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to describe the analyses and data presentations that 
will be used for the creation of the primary manuscript of the study which will focus on the comparison 
of active chelation vs. placebo chelation. 
1.1 Study Design 
The Trial to Assess Chelation Therapy 2 (TACT2) is a randomized, double blinded, placebo- 
controlled 2x2 factorial clinical trial. The study treatments are edetate disodium-based 
chelation (weekly infusion for 40 weeks) and high-dose oral multivitamins and multi-minerals 
(OMVM) (twice daily for up to 5 years). Subjects with diabetes mellitus with a prior myocardial 
infarction (MI) are recruited from participating sites in the US and Canada and randomized in a 
1:1:1:1 fashion to 4 groups: 
i. Active chelation + active OMVM 
ii. Active chelation + placebo OMVM 
iii. Placebo chelation + active OMVM 
iv. Placebo chelation + placebo OMVM. 
 
Patients will be followed for clinical events until the earlier of database lock or five years from 
randomization. Clinical outcomes will be collected by study sites at each infusion visit and by 
the DCRI Call Center at month 6 and 12, and every 4 months afterwards with the last 
assessment at month 60. 
TACT2 is an event driven trial with a plan to continue until at least 282 primary endpoint events 
are identified. The original planned sample size was 1200 participants. The sample size was 
later modified to 1100. The final enrollment is 1000, but with an increased follow-up time to 
preserve statistical power. More details on sample size and power calculation are included later 
in the SAP. 
1.2 Study Objectives 
TACT2 seeks to replicate TACT, which found a reduction of recurrent cardiovascular events 
most prominent in the subgroup of post-MI diabetic patients receiving edetate disodium-based 
chelation therapy. 
1.2.1 Primary Objective 
The primary objective of TACT2 is to determine if the chelation-based strategy increases the 
time to the first occurrence of any of the components of the primary composite endpoint of all- 
cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina 
compared with the placebo chelation strategy. 
1.2.2 Secondary Objectives 
The secondary objectives of TACT2 are to determine: 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 7 of 28 
 
 
 
i. 
if the chelation-based strategy reduces the overall rate of occurrence of the events 
which define the primary composite endpoint of all-cause mortality, MI, stroke, 
coronary revascularization, or hospitalization for unstable angina events compared with 
the placebo chelation strategy. 
ii. 
to determine if the chelation-based strategy increases the time to the first occurrence of 
a secondary composite endpoint of cardiovascular mortality, MI, or stroke compared 
with the placebo chelation strategy. 
iii. 
to determine if the chelation-based strategy increases the time to all-cause mortality 
compared with the placebo chelation strategy. 
 
 
1.2 Sample size Considerations 
The study was originally designed to enroll 1200 participants with a minimum follow-up of 12 
months. Since the enrollment was slower than projected, the DSMB conducted a blinded 
review of enrollment aggregate event rates, and projected event rates in July 2019. The study 
team proposed a new sample size based on the updated projected event rate, an assumed 
hazard ratio of 0.7 comparing chelation and placebo, and a dropout rate of 5% (Table 1). While 
the sample size was reduced to 1100 with an extended enrollment time by December 2020, the 
follow-up (FU) period was extended to 2 years to ensure to have the targeted power of 85%. 
The final study enrollment was 1000. The study team evaluated the study power with a newly 
extended FU period of 2.5 years assuming various dropout rates (Table 2). Even with a dropout 
rate of 10%, the study power exceeds the targeted power of 85% with 1000 participants and 
2.5 years of follow-up. 
The full details around sample size adjustment and study power are included in Appendix I. 
Table 1. Original and modified sample size and study power 
Sample 
size 
Note 
Power 
Overall 
event rate 
(%/pt-yr) 
Assumed 
event rate 
in EDTA 
(%/pt-yr) 
Assumed 
event rate 
in Placebo 
(%/pt-yr) 
Dropout 
rate 
Enrollment 
year 
FU 
year 
Total # 
events 
1200 
Original 
sample size 
85% 
10.9% 
8.97% 
12.81% 
2% 
3 
1 
282 
1100 
Modified 
sample size 
88% 
9.2% 
7.56% 
10.82% 
5% 
4.25 
2 
308 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 8 of 28 
 
 
 
Table 2. Study power with the final 1000 participants enrolled 
 
Scenario 
Overall event 
rate (%/pt-yr) 
Assumed event rate 
in EDTA (%/pt-yr) 
Assumed event rate 
in Placebo (%/pt-yr) 
Overall 
dropout rate 
Mean 
power 
Mean # 
events 
Projected 
8.8 
7.2 
10.4 
5% 
89% 
299 
7% 
88% 
295 
10% 
87% 
288 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 9 of 28 
 
 
 
 
 
2 General Considerations for Data Analyses 
2.1 Analysis Populations 
2.1.1 Intention-to-treat Population (ITT) 
The ITT population will include all randomized participants, including those who are later found 
not to meet study eligibility criteria. There were two participants who mistakenly “re-joined” 
the trial after infusions ended and were re-randomized in a second site, near their original site. 
The detail for the two participants is in Appendix II. They will only be counted once in the ITT 
population. Their data from the 2nd randomization will not be included the analysis. 
2.1.2 Modified Intention-to-treat Infusion Population (mITT) 
All participants in the ITT population who have completed at least one infusion will be included 
in the modified intention-to-treat population. The mITT population will be the primary analysis 
population. 
2.2 Data Sources 
The data used for analysis will come from 5 sources: the randomization data from the 
Interactive Voice/Web System (IXRS), the e-CRF data collected by the iMedidata Rave electronic 
data capture system (RAVE), the adjudicated endpoint data from the clinical events committee 
database (CEC), the site-level information stored in the Clinical Trial Management System 
(CTMS) database, and the CDC National Death Index (NDI). 
Masked-source NDI search results will be used to focus a search for supporting clinical and 
other documentation. If supporting documentation is obtained, the data will be submitted to 
the CEC process prior to being used in the analysis. If needed, a Mortality Review Committee 
will be assigned to classify potential death events when there are insufficient/incomplete or 
contradictory NDI and/or Call Center data to make a reliable determination. Additional details 
will be described in a separate charter. 
2.3 General Analysis Conventions 
Statistical comparisons will be performed using two-sided significance tests. An alpha level of 
0.05 will determine significance unless otherwise specified. 
Continuous variables will be presented in terms of percentiles (e.g., median, 25th percentile, 
and 75th percentiles) along with means and standard deviations. Categorical variables will be 
summarized in terms of frequencies and percentages. 
All programs written to create analysis datasets or perform analyses will be validated according 
to SOPs by the Statistical Programming group. 
All statistical analysis will be performed using SAS® v9.4 or higher (Cary, NC USA) and/or other 
proper software, e. g. R. 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 10 of 28 
 
 
 
2.4 Disposition of Participants 
Disposition of participants (number randomized, number who received treatment, number of 
infusions received per patient, number of withdrawals and dropouts from the study, number 
lost to follow-up, length of follow-up, time since last contact, number unmasked) will be 
summarized by active chelation vs placebo chelation groups using a CONSORT flow diagram and 
subject disposition table. 
Lost to follow-up among alive and non-withdrawn participants will be reported in the CONSORT 
diagram as described above. The number of participants lost to follow-up with a primary 
endpoint will be included in the total and also reported separately. Participants alive and not 
withdrawn or lost to follow-up will be defined as completing the study. 
The definition for lost to follow-up will be: 
No contact within 12 months of the end of study. End of study is defined as the 5-year informed 
consent expiration date or administrative end of study date (June 30, 2023). Last contact is 
defined as the last known alive date. 
2.5 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by active and placebo chelation 
groups and for the overall mITT population. These include cardiovascular risk factors, 
comorbidities, relevant descriptors from the history, concomitant medical care including post- 
MI medications, treatments for diabetes, over-the-counter supplements and herbal remedies. 
Physical examination, laboratory data, cardiopulmonary symptoms, and past clinical events. 
Blood and urine metals pre- and post-chelation are discussed in the SAP for the Trave Metals 
Biorepository Core Lab. 
2.6 Handling of Missing Data 
Every effort will be made to obtain complete data during the course of the trial. If missing data 
remains despite all the efforts, rules on how to handle the missing data will be implemented. 
If the proportion of subjects with missing values in any of the covariates for the primary 
analysis, i.e. age, sex, and baseline insulin use, is greater than 1%, then the missing values will 
be imputed to the mode. 
Since the clinical endpoints are adjudicated by the CEC, we don’t anticipate missing values for 
positively adjudicated outcomes. In the very rare occasion where the event day is missing, it will 
be imputed as the last day of the month. If missing day and month, then December 31st of the 
provided year will be used. If the year is missing, no imputation will be performed. 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 11 of 28 
 
 
 
3 Analysis of Clinical Endpoints 
3.1 General 
3.1.1 Estimands and Censoring Scheme 
Summaries of the descriptions of the estimand attributes and censoring schemes are shown in 
Table 3. Like TACT, the primary analysis will include all identified events obtained as part of the 
planned follow-up from infusion visits and call center interviews. 
Table 3. Key Study Estimands and Censoring Scheme. 
 
Objective Description 
/ Study Population 
Endpoint 
Summary 
statistics 
Events to be 
included in the 
endpoint 
derivation 
Censoring date 
Primary Objective/ 
mITT 
Time from 
randomization to 
the first 
occurrence of 
primary 
composite 
endpoint of all- 
cause mortality, 
MI, stroke, 
coronary 
revascularization, 
or hospitalization 
for unstable 
angina 
Hazard ratio 
estimate based on 
a Cox proportional 
hazards model. 
All positively 
adjudicated 
primary endpoint 
events post- 
randomization 
except those 
occurring after 
withdrawal of 
consent or ICF 
expiration. 
Events occurring 
after withdrawal 
consent or ICF 
expiration will be 
censored. Subjects 
with events after 
withdrawal or ICF 
expiration will be 
censored at the 
min(date withdrew 
consent, date of 
last contact with 
patient/proxy 
where event status 
was assessed). 
Among subjects not 
experiencing endpoint 
of interest: 
Censoring date = 
min(date withdraw 
consent, date of last 
contact with 
patient/proxy where 
event status was 
assessed) 
Date of last contact 
defined as: 
If the last contact 
occurred during the 
study infusion phase - 
use last infusion visit 
date where survival 
status and event status 
were assessed (yes or 
no to event). 
If last contact occurred 
during call center follow 
up period – use 
‘complete’/’incomplete’ 
status date by 
patient/proxy where 
survival status and 
hospitalization status 
were assessed (yes or 
no to hospitalization). 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
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For composite 
endpoints, date of last 
assessment = the 
earliest of the last 
assessment date among 
all components. 
Secondary Objective / 
mITT 
Overall rate of 
recurrent events 
due to all-cause 
mortality, MI, 
stroke, coronary 
revascularization, 
or hospitalization 
for unstable 
angina 
Hazard ratio 
estimate based on 
a proportional 
intensity model by 
Andersen-Gill and 
a marginal model 
by Wei, Lin and 
Weissfeld. 
*same as primary 
endpoint 
*same as primary 
endpoint 
Secondary Objective / 
mITT 
Time from 
randomization to 
the first 
occurrence of the 
secondary 
composite 
endpoint of 
cardiovascular 
mortality, MI, or 
stroke 
Cause specific 
hazard ratio 
estimate based on 
a cause-specific 
Cox proportional 
hazards model. 
All positively 
adjudicated 
endpoint events 
post- 
randomization 
except those 
occurring after 
withdrawal of 
consent or ICF 
expiration date. 
Among subjects not 
experiencing endpoint 
of interest or competing 
event: 
Censoring date = 
min(date withdraw 
consent, date of last 
contact with 
patient/proxy where 
event status was 
assessed) 
Non-CV death or 
undetermined 
cause of death is 
considered a 
competing risk. 
*Date of last contact 
defined in 1st row, 5th 
column (primary 
endpoint) 
Among subjects 
experiencing 
competing risk 
(non-CV death or 
undetermined 
death is a 
competing risk of 
CV death or 
MI/stroke if a 
subject died 
without having any 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 13 of 28 
 
 
 
of these events 
beforehand): 
Event date = non- 
CV or 
undetermined 
death date; 
Secondary Objective / 
mITT 
Time from 
randomization to 
all-cause 
mortality 
Hazard ratio 
estimate based on 
a Cox proportional 
hazards model. 
All deaths post- 
randomization 
(including 
adjudicated deaths 
obtained from the 
NDI search) 
A death date after 
withdrawn consent 
or ICF expiration 
(obtained from 
public data source) 
is considered an 
event. 
Among subjects who are 
alive: 
Censoring date = (date 
last known alive) 
Date of last known alive 
defined as: 
If the last contact 
occurred during the 
study infusion phase - 
use last infusion visit 
date. 
If last contact occurred 
during call center follow 
up period – use 
‘complete’/’incomplete’ 
status date by 
patient/proxy or (‘not 
done’ status date 
where source = patient) 
or last alive date from 
Call Center where death 
status was assessed. 
Secondary Objective / 
Total number of 
Number and 
Randomization to 
N/A 
mITT 
SAE and 
proportions by 
min(withdraw 
percentage of 
treatment group. 
consent, 30 days 
patients 
Confidence 
post final infusion) 
experiencing at 
intervals will be 
least 1 SAE. 
based on the 
Miettinen- 
Nurminen 
method. 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
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Sensitivity Analysis of 
the Primary Outcome 
/ Bayesian analysis 
using TACT results as 
one of the priors / 
mITT 
*Same as primary 
analysis 
Treatment effect 
mean posterior 
hazard ratio based 
on a Bayesian 
time to event 
model 
*Same as primary 
analysis 
*Same as primary 
analysis 
Sensitivity Analysis of 
the Secondary All- 
Cause Mortality 
Outcome / Bayesian 
analysis using TACT 
results as one of the 
priors / mITT 
*Same as primary 
analysis 
Treatment effect 
mean posterior 
hazard ratio based 
on a Bayesian 
time to event 
model 
*Same as primary 
analysis 
*Same as primary 
analysis 
Sensitivity Analysis of 
the Primary Outcome 
/ ITT 
*Same as primary 
analysis 
*Same as primary 
analysis 
*Same as primary 
analysis 
*Same as primary 
analysis 
Sensitivity Analysis of 
the Primary Outcome 
/ mITT with imputed 
event status for 
subjects withdrew 
/lost to follow up 
*Same as primary 
analysis 
*Same as primary 
analysis 
*Same as primary 
analysis except that 
the event status 
will be imputed for 
subjects who 
withdrew consent 
or lost to follow up 
before study 
completion 
*Same as primary 
analysis 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
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Sensitivity Analysis of 
the Primary 
Outcome/ mITT with 
the exclusion of 
positively adjudicated 
events > 1 year after 
the last contact 
where all components 
of the composite 
were assessed 
*Same as primary 
analysis 
*Same as primary 
analysis 
*Same as primary 
analysis but 
exclude positively 
adjudicated events 
more than 1 year 
from the most 
recent study 
contact where all 
components of the 
composite 
endpoint were 
assessed. 
Among subjects not 
experiencing endpoint 
of interest or 
experiencing first CEC 
event > 1 year after 
event assessment date: 
Censoring date = 
min(date withdraw 
consent, date of last 
contact with 
patient/proxy where 
event status was 
assessed) 
*Date of last contact 
defined in 1st row, 5th 
column (primary 
endpoint) 
Sensitivity Analysis of 
the Secondary 
Composite Outcome/ 
Where undetermined 
death is considered 
CV-death / mITT 
*same as 
secondary 
composite 
endpoint 
*same as 
secondary 
composite 
endpoint, where: 
Undetermined 
death is analyzed 
as CV-death. 
*same as 
secondary 
composite 
endpoint 
*same as secondary 
composite endpoint 
Sensitivity Analysis of 
the Secondary 
Composite Objective / 
Cause of death based 
on best available data 
(from CEC or CRF if 
CEC is unavailable) / 
mITT 
*Same as 
secondary 
composite 
analysis 
*Same as 
secondary 
composite 
analysis 
*Same as 
secondary 
composite analysis, 
where: 
Cause of death is 
determined based 
on best available 
data. If cause of 
death from CEC is 
available, use CEC 
cause of death. 
Otherwise, if CRF 
cause of death 
available, use CRF 
cause of death. 
*Same as secondary 
composite analysis 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
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If cause of death is 
unavailable in CEC 
and CRF, use NDI 
cause of death. 
Sensitivity Analysis of 
the Secondary All- 
Cause Mortality 
Outcome / Censor at 
the date of NDI 
assessment / mITT 
*Same as 
secondary all- 
cause mortality 
analysis 
*Same as 
secondary all- 
cause mortality 
analysis 
*Same as 
secondary all-cause 
mortality analysis 
Among subjects who are 
alive: 
Censoring date = 
max(date of NDI 
assessment, last known 
alive date) 
Date of NDI assessment 
is defined as: 
The last date that NDI 
results were assessed. 
This will be consistent 
for all participants 
without an event. 
*See section 2.1 for the definition of ITT and mITT. 
One participant who was randomized twice and received infusions from the second site will be 
censored at the second randomization. The other participant who was lost to follow-up at the 
first site and then was randomized at the second site will be censored at the time of lost to 
follow-up at the first site. 
 
 
3.1.2 Event Data 
Analyses of the clinical endpoints will use the CEC-adjudicated data for death, MI, stroke, 
coronary revascularization, or hospitalization for unstable angina. 
3.1.3 Assessment of Model Assumptions 
The validity of the proportional hazards assumption will be examined using a standard graphical 
method such as Schoenfeld residual plots. If the assumption holds, the survival curves should 
be approximately parallel to each other. An additional analytical method that includes the 
supremum test as implemented by using the ASSESS statement in PROC PHREG in SAS version 
9.4 may be utilized. A P-value of < 0.05 indicates violation of the proportional hazards 
assumption. If there is evidence of non-proportionality, a time dependent covariate will be 
included in the model, or a restricted mean survival time model will be performed. 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 17 of 28 
 
 
 
3.1.4 Multiple Comparisons and Composite Endpoints 
With the number of primary hypotheses and the various secondary endpoints to be analyzed 
and compared, there is an increased probability that at least one of the comparisons could be 
"significant" by chance. We have pre-specified the primary and secondary outcome variables to 
help avoid over-interpretation and to reduce the problems inherent with multiple testing. We 
will be conservative in the interpretation of these analyses, taking into account the degree of 
significance, and looking for consistency across endpoints. 
 
 
3.2 Primary Endpoint Analysis 
The primary endpoint is the composite of all-cause mortality, MI, stroke, coronary 
revascularization, or hospitalization for unstable angina. 
If two of the component events of the primary composite endpoint occur on the same day, the 
following hierarchy will be used when reporting the components of the primary endpoint. For 
example, a patient with stroke and all-cause mortality on the same date will be considered as 
having stroke when summarizing individual events within the primary composite outcome. This 
hierarchy will only be used for summarizing events within the primary composite outcome and 
will not affect the primary analysis. 
i. 
MI 
ii. 
Stroke 
iii. 
Hospitalization for unstable angina 
iv. 
Coronary revascularization 
v. 
All-cause mortality 
 
3.2.1 Primary Analysis 
The primary objective is to determine if the chelation-based strategy increases the time to 
composite endpoint compared with the placebo chelation strategy. The primary composite 
endpoint will be analyzed using a Cox proportional hazards regression model of time from 
randomization to the first occurrence of all-cause mortality, MI, stroke, coronary 
revascularization, or hospitalization for unstable angina. 
The primary analysis will be based on a Cox model which includes indicator variables for the 
active chelation as the primary variable of interest and active OMVM groups, age, sex, and 
baseline insulin use as covariates. Age will be included in the model in the form of cubic splines 
using three knots at 10th, 50th, and 90th percentiles. Two separate manuscripts will explore the 
effect of active OMVM and the effects of chelation by OMVM. 
The chelation treatment effect will be summarized using hazard ratios and associated 95% CIs. 
A hazard ratio of < 1 would suggest a benefit for the chelation-based therapy. Kaplan Meier 
survival estimates will be constructed based on the time from randomization to the first 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 18 of 28 
 
 
 
primary event occurrence. Events occurring after withdrawal of consent or informed consent 
expiration will be censored. 
The OMVM treatment effect from the Cox model will be estimated using the Cox model 
described above. A hazard ratio of < 1 would suggest a benefit for OMVM treatment. Given the 
focus on chelation therapy, the interpretation of the OMVM treatment effect will be 
considered exploratory. A full set of analyses of the 2x2 design will be reported in a separate 
manuscript. 
 
Four interim analyses were conducted at 25%, 40%, 60%, and 80% of expected information 
using a Haybittle-Peto-type boundary for efficacy (i.e. p<=0.001, Z=3). For this reason, the 
adjusted two-sided significance level for the final analysis is 0.05 (i.e., the corresponding critical 
value, Z = -1.96). 
 
Formal statistical hypothesis testing will follow a hierarchy based on statistical significance of 
the prior endpoint. If the prior endpoint is statistically significant at the 0.05 level, the next 
endpoint’s p-value will be tested for significance. The outcome hierarchy will be evaluated as 
follows: 
1) Primary composite outcome 
2) Secondary all-cause mortality outcome (with conservative censoring) 
3) Secondary composite outcome of cardiovascular mortality, MI, or stroke 
4) Secondary recurrent event analysis (Andersen & Gill method) 
 
 
3.2.2 Sensitivity Analyses of the Primary Outcome 
The primary hypothesis for the primary composite endpoint will be tested using the ITT 
population as a sensitivity analysis. 
A sensitivity analysis was initially planned to investigate the potential effect of the COVID-19 
outbreak on the primary analysis. Instead, the potential effect of COVID-19 may be explored in 
a separate manuscript. 
A sensitivity analysis will use Bayesian methods to estimate the primary outcome treatment 
effect posterior distribution using the first TACT trial results and other related information to 
develop a set of priors for the treatment effect (Zampieri, 2020). As suggested by Zampieri, 
these analyses will include at least one prior distribution for the effect of chelation vs. placebo 
in each of the following categories: skeptical, pessimistic, and optimistic. The priors will be 
assumed to follow a normal distribution and will represent the log hazard ratio from the Cox 
model. There will be two skeptical (non-informative) priors for the log hazard ratio with a mean 
of zero and differing standard deviations (e.g., one standard deviation will be 10 and the other 
will be 100). Two pessimistic priors for the log hazard ratio will also be included, both will be 
centered around zero and allow for low probability of a favorable treatment effect (e.g., 0.5% 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 19 of 28 
 
 
 
and 2.5% probability of the hazard ratio for chelation of 0.80 compared to placebo). The two 
optimistic priors will include the overall treatment effect from TACT (e.g., HR of 0.82 with a 95% 
CI of 0.69 to 0.99) and diabetes subgroup treatment effect from TACT (e.g., HR of 0.59 with a 
95% CI of 0.44 to 0.79). In all of the above models, the priors for the parameters associated 
with other model covariates will be non-informative with large standard deviations (e.g., 
standard deviation of 100) and center at zero for the associated log hazard ratios. The chelation 
treatment effect will be summarized using mean posterior hazard ratios and associated 95% 
highest posterior density credible intervals. A mean posterior hazard ratio of < 1 would suggest 
a benefit for the chelation-based therapy. 
 
Another sensitivity analysis is planned to assess how the primary analysis would be affected by 
various assumptions regarding the occurrence of primary endpoint events among those who 
withdrew consent or were lost to follow-up, as was performed and published in TACT. Baseline 
characteristics by treatment group will be assessed for the patients who did versus did not 
withdraw consent or were lost to follow-up. Events will be imputed by simulation only for the 
consent withdrawal or lost patients who did not have a documented occurrence of one of the 
primary events prior to the withdrawn consent/lost to follow-up. The different percentages of 
the withdrawn or lost patients will be assumed to have an event at their censoring time. The 
event rates among patients that withdrew or were lost to follow-up in each treatment group 
will be varied across a broad spectrum and include scenarios that were markedly unfavorable to 
chelation. The imputed event rates for patients who withdrew consent or were lost to follow- 
up will be combined with the observed event rates of patients who completed the study to 
assess the treatment effect via a hazard ratio. These analyses will focus on scenarios in which 
events among withdrawn or lost patients in the active arm are assumed to occur at a higher 
rate than withdrawn or lost patients in the placebo arm. 
Another sensitivity analysis is planned for the primary endpoint to censor, at the point of last 
contact, those deaths that were identified more than one year following the most recent study 
contact. 
3.3 Analysis of the Secondary Endpoints 
The three secondary endpoints are: 
i. 
Recurrent events of the primary composite endpoint 
ii. 
All-cause mortality 
iii. 
Composite of cardiovascular mortality, MI, or stroke 
 
3.3.1 Recurrent-event analysis of the primary endpoint 
Recurrent event analyses include all positively adjudicated primary endpoint events attributed 
to a participant: all-cause mortality, recurrent MI, stroke, coronary revascularization, or 
hospitalization for unstable angina events. The number of patients with a primary composite 
endpoint and the frequency of the primary composite endpoint per each component will be 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 20 of 28 
 
 
 
summarized by active chelation and placebo. We analyze this endpoint using two statistical 
techniques: 
i. 
The generalization of the Cox model to handle recurrent events developed by Andersen 
& Gill (1982) is the most frequently used approach to estimate treatment differences 
with total and recurrent events. This approach models gap time (time from enrollment 
to first event or from one event to the next) and assumes independence of observed 
event times within the same subject with the adjustment of the covariates. Our 
modeling will use robust standard errors to account for individual patients’ 
heterogeneity and covariance across event times. The treatment effect will be 
presented as a hazard ratio (EDTA vs. placebo) and associated 95% CIs and P-value. It 
will be the primary analysis for the total number of all-cause mortality, recurrent MI, 
stroke, coronary revascularization, or hospitalization for unstable angina events 
endpoint. 
ii. 
The stratified marginal Cox modeling approach developed by Wei, Lin, and Weissfeld 
(WLW) (1989) considers each event recurrence separately and models all the available 
data for the specific event. Therefore, each subject is considered to be at risk for all 
events, regardless of how many events each subject actually experienced. A different 
baseline hazard function is assumed for each event, through use of strata for each 
event. The WLW will model the marginal hazard of each event’s failure time. The time 
interval for each event for each subject starts at date of randomization and ends at the 
time of the specific event or censoring. A treatment effect will be presented as a hazard 
ratio (EDTA vs. placebo) and a 95% CI and P-value. This will be considered as a sensitivity 
analysis. 
 
Both analyses will be adjusted for age, sex, and baseline insulin use. In either analysis, a hazard 
ratio of < 1 would suggest a benefit for the chelation-based therapy. 
An event rate of the endpoint for each treatment group will be calculated as percentage per 
100 patient years, accounting for differential follow-up duration. A 95% CI for the event rates 
will be calculated as 
 
𝑟𝐶 
𝑟𝐶 
(𝑇  ) ± 1.96√𝑇2, 
𝐶 
𝐶 
where subscript C denotes the chelation arm, and r is the total number of event occurrences, 
and T is the total follow-up time among all participants. 
 
 
3.3.2 Time to Event Analysis of the Secondary Endpoints 
The analyses for the time to the first occurrence of secondary endpoints (1) time to the first 
occurrence of the composite of cardiovascular mortality, MI, or stroke; 2) time to all-cause 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 21 of 28 
 
 
 
mortality) will be performed in the same manner as the primary analysis in Section 4.1, 
replacing the primary composite endpoint with secondary endpoints. 
 
Competing risk of non-CV death or undetermined death will be taken into account for the 
secondary composite endpoint (time to the first occurrence of the composite of cardiovascular 
mortality, MI, or stroke). Follow-up will be censored at the time of non-CV or undetermined 
death if there is no prior composite event. For this endpoint, the treatment effect will be 
presented as a cause-specific hazard ratio. 
 
All deaths post-randomization will be included in the secondary all-cause mortality endpoint. 
For this endpoint, a death date after withdrawal of consent or ICF expiration (obtained from 
public data sources) is considered an event. 
 
3.3.3 Sensitivity Analyses of the Secondary Outcomes 
A sensitivity analysis is planned for the secondary composite endpoint where undetermined 
death will be classified as CV-death. 
Another sensitivity analysis is planned for the secondary composite endpoint where cause of 
death is determined based on the best available data. Cause of death will first be determined 
based on the data from the CEC. If cause of death from the CEC is unavailable, cause of death 
will be determined from the CRF data. If cause of death from the CEC and CRF is unavailable, 
cause of death will be determined based on the NDI data. 
A sensitivity analysis is planned for the secondary all-cause mortality endpoint where 
participants with no event will be censored at the last date that NDI results were assessed. The 
censoring date will be consistent for all participants without an event. 
 
A sensitivity analysis will use Bayesian methods to estimate the secondary all-cause mortality 
outcome treatment effect posterior distribution. These analyses will be performed in an 
analogous manner as the Bayesian analysis of the primary outcome (section 3.2.2). 
 
3.4 Subgroup Analyses 
To examine the heterogeneity of the treatment effect, subgroup analyses for the primary and 
secondary endpoints will be performed using interaction terms within the Cox proportional 
hazards model. The pre-specified key subgroups of interest are following. 
 
Sex: female vs. male 
 
Race: White vs. Black vs. Other 
 
Ethnicity: Hispanic vs. non-Hispanic (unknown ethnicity is considered missing) 
 
Age: ≤ 70 years vs. > 70 years 
 
MI location: anterior MI vs. non-anterior MI 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 22 of 28 
 
 
 
 
Pharmacologic treatment of diabetes (two subgroups analyses: no insulin vs. insulin, 
SGLT2i or GLP-1a vs. neither) 
 
Known peripheral artery disease at baseline: yes vs. no 
 
Tertiles of lead (in blood) and cadmium (in urine) 
 
For categorical variables, if the proportional hazards assumption is violated, we will include the 
subgroup factor as a stratification variable within the Cox regression model. This model 
structure will decrease the reliance on the proportional hazards assumption. Event rates by 
treatment and HRs with 95% CIs will be reported for each subgroup. Forest plots will be 
generated displaying the estimated hazard ratios and 95% CIs for each subgroup. For subgroups 
defined using continuous variables, the analysis based on the continuous form will be 
considered primary but for display purposes these variables can also be categorized. 
 
To further analyze the heterogeneity of treatment effects at the patient level, a separate 
manuscript will use the PATH statement approach for subgroup analyses. 
 
The use of statin treatment at baseline will be evaluated as a subgroup analysis in the OMVM 
manuscript. 
 
3.5 Safety Analyses 
Using the mITT population, the total number of serious adverse events (SAEs) and percentage 
of participants experiencing at least one SAE from randomization to 30 days post final infusion 
in each patient group will be compared with confidence intervals based on the Miettinen- 
Nurminen method. Whether SAEs were associated with treatment and required hospitalization 
(inpatient hospitalization or prolongation of existing hospitalization) will be summarized per 
Body System or Organ Class and Dictionary-Driven Term. 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 23 of 28 
 
 
 
4 References 
Andersen, P. K., & Gill, R. D. (1982). Cox's regression model for counting processes: a large 
sample study. The Annals of Statistics, 1100-1120. 
Finkelstein, D. M., & Schoenfeld, D. A. (1999). Combining mortality and longitudinal measures in 
clinical trials. Statistics in Medicine, 18(11), 1341-1354. 
Lamas GA, Anstrom KJ, Navas-Acien A, Boineau R, Kim H, Rosenberg Y, Stylianou M, Jones TLZ, 
Joubert BR, Santella RM, Escolar E, Aude YW, Fonseca V, Elliott T, Lewis EF, Farkouh ME, Nathan 
DM, Mon AC, Gosnell L, Newman JD, Mark DB; TACT2 Investigators. The trial to assess chelation 
therapy 2 (TACT2): Rationale and design. Am Heart J. 2022 Oct;252:1-11. doi: 
10.1016/j.ahj.2022.05.013. Epub 2022 May 19. PMID: 35598636. 
Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, Drisko JA, Lee KL. Design of the 
Trial to Assess Chelation Therapy (TACT). Am Heart J. 2012 Jan;163(1):7-12. doi: 
10.1016/j.ahj.2011.10.002. 
Luo, X., Tian, H., Mohanty, S., & Tsai, W. Y. (2015). An alternative approach to confidence 
interval estimation for the win ratio statistic. Biometrics, 71(1), 139-145. 
TACT Final Study SAP. (NCT00044213) https://classic.clinicaltrials.gov/ct2/show/NCT00044213 
https://biolincc.nhlbi.nih.gov/studies/tact/#:~:text=Design,regimen%20or%20an%20oral%20pl 
acebo. 
Wei, L. J., Lin, D. Y., & Weissfeld, L. (1989). Regression analysis of multivariate incomplete 
failure time data by modeling marginal distributions. Journal of the American Statistical 
Association, 84(408), 1065-1073. 
Zampieri FG, Casey JD, Shankar-Hari M; Harrell Jr. FE, and Harhay MO (2021). “Using Bayesian 
Methods to Augment the Interpretation of Critical Care Trials: An Overview of Theory and 
Example Reanalysis of the Alveolar Recruitment Trial.” Am J Respir Crit Care Med; 203(5): 543- 
552. 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 24 of 28 
 
 
 
5 SAP Revision 
Revision Date 
MMM dd, yyyy 
 
 
Section 
Summary of Revision 
Reason for Revision 
SEP 12, 2023 
2.2 Data sources, 
2.6 Missing data, 
3.1.1 Estimands and 
censoring, 
3.2.1 Primary 
Analysis, 
3.2.2, Sensitivity, 
3.3.1 Recurrent 
events, 
3.4 Subgroup 
analyses, 
Appendix III 
Added NDI as a data 
source. Updated 
imputation for 
missing data. Added 
sensitivity analyses. 
Added hierarchy for 
formal hypothesis 
testing. Added event 
rate equation for 
recurrent event 
analysis. Updated 
subgroup analyses. 
Added Bayesian 
sensitivity analysis. 
Additional 
information on NDI. 
Missing dates in the 
data. Additional 
sensitivity analyses 
requested. Requests 
from PIs. 
 
 
 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 25 of 28 
 
 
 
6 Appendices 
Appendix I. TACT2 Sample size and study power projections as of March 1, 2021 
 
1. Enrollment and timeline 
a. 1000 patients enrolled. 
 
Last rand subject infusion Last rand subject Follow-up Last endpoint adjudicated Database lock 
December 2021 
June 2023 
August 2023 
October 2023 
 
2. Event rate in the TACT diabetic cohort (n=633) 
a. EDTA: 7.8%/pt-yr = 80 events / 1031 patient-years 
b. Placebo: 13.2%/pt-yr = 117 events / 886 patient-years 
c. Hazard ratio: 0.59 
 
3. Original and modified sample size and power 
 
Sample 
size 
Enrollment 
FU 
Power 
Hazard ratio 
(EDTA/placebo) 
Overall 
event 
rate 
(%/pt- 
yr) 
Assumed 
event 
rate 
in EDTA 
(%/pt-yr) 
Assumed 
event 
rate 
in 
Placebo 
(%/pt-yr) 
Total # 
events 
1200 
3 years 
1 
year 
85% 
0.7 
10.9 
8.97 
12.81 
282 
1100 
3 years + 
15 months 
2 
years 
88% 
0.7 
9.2 
7.56 
10.82 
308 
 
4. Statistical power with 1000 enrolled participants as of March 1, 2021 
a. As of February 23, 2021, 137 patients with at least one adjudicated primary endpoint, 
1990 patient-years from 1000 enrolled patients 
i. Proportion of reported events adjudicated as primary endpoints = 69% 
ii. Projected overall event rate: If 39 patients had an adjudicated primary endpoint 
out of 57 additional patients with at least one reported event, 176/1990 = 
8.8%/pt-yr 
iii. Minimum overall event rate: 137/1990 = 6.9%/pt-yr 
iv. Optimistic overall event rate: If 45 patients had an adjudicated primary endpoint 
out of 57 additional patients with at least one reported event, 182/1990 = 
9.1%/pt-yr 
b. Assumptions for simulations with 10K iterations per scenario 
i. No re-consent for those who run out 5 years from the initial consent 
ii. Constant parameters: a two-sided alpha=0.05, hazard ratio of EDTA to 
placebo=0.7, sample size=1000, FU=2.5 years 
iii. Overall dropout rate: 5, 7, 10% 
iv. Overall event rate: 6.9, 8.8, 9.1%/pt-yr 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 26 of 28 
 
 
 
 
 
Scenario 
Overall 
event rate 
(%/pt-yr) 
Assumed 
event rate 
in EDTA 
(%/pt-yr) 
Assumed 
event rate 
in Placebo 
(%/pt-yr) 
Overall 
dropout rate 
Mean 
power 
Mean # 
events 
Projected 
8.8 
7.2 
10.4 
5% 
89% 
299 
7% 
88% 
295 
10% 
87% 
288 
Minimum 
6.9 
5.7 
8.1 
5% 
78% 
244 
7% 
77% 
240 
10% 
76% 
235 
Optimistic 
9.1 
7.5 
10.7 
5% 
88% 
307 
7% 
87% 
303 
10% 
86% 
297 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 27 of 28 
 
 
 
Appendix II. Details of two participants who were randomized from two different sites 
Double randomization case 1 
One participant was randomized again in a neighboring site right after completing 40 infusions 
from the first site where randomized for the first time. The study team found out the second 
randomization after the participant finished 35 infusions at the second site. This participant has 
been actively followed up by the Call Center. This participant will be censored at the time of the 
second randomization for any analyses using the ITT or mITT populations. 
Double randomization case 2 
The other participant was lost to follow up after the third infusion at the first site and then 
randomized again in a neighboring site after a break of longer than a year. The participant did 
not receive any infusion from the second site. The Call Center was not able to locate the 
participant for any follow-up calls. This participant will be censored at the time of lost to follow- 
up at the first site for any analyses using the ITT or mITT populations. 


TACT2 Statistical Analysis Plan, v 2.0; September 12, 2023 
Page 28 of 28 
 
 
 
Appendix III. TACT2 Statistical Team 
 
Team 
Name 
Email 
Attends DSMB 
Meetings 
Blinded Statistical 
Team 
Hayley Nemeth 
Hayley.nemeth@duke.edu 
X 
Jun Wen 
Jun.Wen@duke.edu 
X 
Zhen Huang 
zhen.huang@duke.edu 
X 
Hwasoon Kim 
hwasoon.kim@duke.edu 
X (left DCRI in June, 
2022) 
Kevin Anstrom 
kevin.anstrom@unc.edu 
X 
Unblinded 
Statistical Team 
Yuliya Lokhnygina 
yuliya.lokhnygina@duke.edu 
X 
Dianne Gallup 
dianne.gallup@duke.edu 
X 
Peter Merrill 
Peter.merrill@duke.edu 
X (left DCRI in October, 
2022 
Metals Manuscript 
Zhen Huang 
zhen.huang@duke.edu 
X 
Steve McNulty 
steven.mcnulty@duke.edu 
Peter Merrill 
Peter.merrill@duke.edu 
X (left DCRI in October, 
2022) 
Yuliya Lokhnygina 
yuliya.lokhnygina@duke.edu 
X 
NHLBI 
Biostatistician 
Mario Stylianou 
stylianm@nhlbi.nih.gov 
X 
TACT2 Project 
Leaders 
Shelby Morgan 
Shelby.morgan@duke.edu 
X 
Anne-Marie Elliott 
Ann.elliott@duke.edu 
X 
Ana Mon 
Ana.Mon@msmc.com 
X 
Leigh Gosnell 
Leigh.gosnell@duke.edu 
X (Prior Project Leader) 
Wanda Parker 
Wanda.parker@duke.edu 
X (Prior Project Leader) 


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Agreement completed. 

Prot_001.pdf: 
 
A randomized, double-blind, controlled factorial clinical trial of edetate disodium-based 
chelation and high-dose oral vitamins and minerals to prevent recurrent cardiac events 
in diabetic patients with a prior myocardial infarction. 
  
 
Principal Investigators:   
 
Gervasio A. Lamas, MD, PI CCC 
Mount Sinai Medical Center and Columbia University Medical Center 
 
Kevin J. Anstrom, PhD, Co-PI DCC and  
Daniel B. Mark, MD, MPH, Co-PI DCC 
Duke Clinical Research Institute 
 
Scientific PI for toxic metals analysis:   
Ana Navas-Acien MD PhD MPH 
Columbia University Mailman School of Public Health 
 
 
Supported by:  
 
National Institutes of Health 
 
Study Intervention Provided by: 
 
Edetate disodium is manufactured by Akzo Nobel Pharmaceuticals, Netherlands 
 
Sponsor of IND: 
 
Gervasio A. Lamas, MD, PI CCC 
IND 66,743 
 
REVISION HISTORY 
 
February 8, 2016 (Original Version Date) 
July 1, 2016 
May 18, 2017 
November 1, 2019 
May 6, 2021 
 
 


TACT2 Protocol 
May 6, 2021 
2 
TABLE OF CONTENTS 
 
PRÉCIS ........................................................................................................................... 4 
1. STUDY OBJECTIVES ................................................................................................. 6 
1.1 
Primary Objective .................................................................................. 6 
1.2 
Secondary Objectives ............................................................................ 6 
2. BACKGROUND AND RATIONALE ............................................................................. 7 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ...... 7 
2.2 
Study Rationale ..................................................................................... 9 
3. STUDY DESIGN ....................................................................................................... 12 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ........................................... 14 
4.1 
Inclusion and Exclusion Criteria ........................................................... 14 
4.2 
Study Enrollment Procedures .............................................................. 15 
5. STUDY INTERVENTIONS ........................................................................................ 16 
5.1 
Interventions, Administration, and Duration ......................................... 16 
5.2 
Handling of Study Interventions ........................................................... 18 
5.3 
Concomitant Interventions ................................................................... 20 
5.3.1 Optimal Concomitant Interventions ............................................... 20 
5.3.2 Prohibited Interventions Following randomization ........................ 21 
5.4 
Adherence Assessment ....................................................................... 21 
6.2 
Description of Evaluations ................................................................... 23 
6.2.1 Screening Evaluation .................................................................... 23 
6.2.3 Subsequent Infusion Visits (2-40) ................................................. 24 
6.2.4 Blinding ......................................................................................... 25 
6.2.5 Completion/Final Evaluation ......................................................... 26 
7. SAFETY ASSESSMENTS ........................................................................................ 26 
7.1 
Specification of Safety Parameters ...................................................... 26 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters .......................................................................................... 27 
7.3 
Adverse Events and Serious Adverse Events...................................... 28 
7.4 
Reporting Procedures .......................................................................... 30 
7.5 
Follow-up for Serious Adverse Events ................................................. 32 
7.6 
Safety Monitoring ................................................................................. 32 
8. INTERVENTION INTERRUPTION ............................................................................ 33 
9. STATISTICAL CONSIDERATIONS .......................................................................... 33 
9.1 
General Design Issues ........................................................................ 33 
9.2 
Sample Size and Randomization ......................................................... 33 
9.3  
Definition of ITT Population .................................................................. 35 
9.4 
Interim Analyses and Stopping Rules .................................................. 35 
9.5 
Outcomes ............................................................................................ 36 
9.5.1 Primary Outcome .......................................................................... 36 
9.5.2 Secondary Outcomes ................................................................... 36 
9.6 
Data Analyses ...................................................................................... 36 
10. DATA COLLECTION AND QUALITY ASSURANCE ............................................... 39 
10.1 
Data Collection Forms ......................................................................... 39 
10.2 
Data Management ............................................................................... 39 


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3 
10.3 
Quality Assurance ................................................................................ 40 
10.3.1 Training ....................................................................................... 41 
10.3.2 Quality Control ............................................................................ 41 
10.3.3 Metrics ........................................................................................ 41 
10.3.4 Protocol Deviations ..................................................................... 41 
10.3.5 Monitoring ................................................................................... 41 
10.4 
Medical Information Coding ................................................................. 42 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................. 42 
11.1 
Institutional Review Board (IRB) Review ............................................. 42 
11.2 
Informed Consent Forms ..................................................................... 42 
11.3 
Participant Confidentiality .................................................................... 42 
11.4 
Study Discontinuation .......................................................................... 43 
12. COMMITTEES ........................................................................................................ 43 
13. PUBLICATION OF RESEARCH FINDINGS ........................................................... 44 
14. REFERENCES ........................................................................................................ 44 
 
 
 


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4 
PRÉCIS  
Study Title  
Trial to Assess Chelation Therapy 2 (TACT2). 
A randomized, double-blind, controlled factorial clinical trial of edetate disodium-based 
chelation and high-dose oral vitamins and minerals to prevent recurrent cardiac events 
in diabetic patients with a prior myocardial infarction (MI). 
Objectives  
TACT2 is being carried out to replicate TACT, which found a reduction of recurrent 
cardiovascular events in post-MI diabetic patients receiving edetate disodium-based 
chelation therapy.  
 
The primary objective of TACT2, therefore, is to determine if the chelation-based 
strategy increases the time to the first occurrence of any of the components of the 
TACT2 primary endpoint: all-cause mortality, myocardial infarction, stroke, coronary 
revascularization, or hospitalization for unstable angina compared to the placebo 
chelation strategy.  
 
The secondary objectives of TACT2 are to determine: 
  
1. if the chelation-based strategy reduces the overall rate of occurrence of the 
events which define the primary TACT2 endpoint: all-cause mortality, myocardial 
infarction, stroke, coronary revascularization, or hospitalization for unstable 
angina events compared to placebo chelation strategy.  
2. if the chelation-based strategy increases the time to the first occurrence of a 
composite endpoint: cardiovascular mortality, recurrent myocardial infarction, or 
stroke compared to placebo chelation strategy. 
3. if the chelation-based strategy increases the time to all-cause mortality compared 
to placebo chelation strategy. 
  
Design and Outcomes  
TACT2 is a 2x2 factorial trial testing 40 weekly edetate disodium-based chelation 
infusions and twice-daily high-dose oral multivitamins and multiminerals (OMVM) in a 
placebo-controlled design.  
 
The primary endpoint is a composite of all-cause mortality, myocardial infarction, stroke, 
coronary revascularization, or hospitalization for unstable angina. All randomized 
patients will be followed until the end of the trial.  
 
The secondary endpoints for TACT2 include the following: 
 
Total number of CV events: This endpoint will include all CV events from 
randomization to the end of the study. 


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May 6, 2021 
5 
All-cause mortality: All-cause mortality is a secondary endpoint for the trial, based 
upon its importance and the observed 43% relative risk mortality reduction by chelation 
alone (P=0.011) in the diabetic subgroup of TACT. 
 
Composite of cardiovascular mortality, recurrent myocardial infarction, or stroke: 
This composite secondary endpoint captures serious, irreversible, ischemic events. 
Chelation treatment led to a 40% relative reduction in risk (P=0.017) in this endpoint in 
the diabetic subgroup of TACT. 
 
Exploratory analyses, defined as those seeking to confirm a signal of benefit observed 
in TACT, or to develop mechanistic hypotheses for benefits of chelation expected in 
TACT2, include: 
i. 
Analysis of the primary endpoint in patients receiving OMVM compared with oral 
placebo 
ii. 
Analysis of the primary endpoint in patients receiving active chelation + active 
OMVM, compared with placebo chelation + placebo OMVM 
iii. 
Analysis of markers of severity of diabetes (fasting glucose, HbA1c, 
microalbuminuria) throughout the infusion regimen 
iv. 
Analysis of lead and cadmium levels at multiple times during the infusion regimen  
v. 
Collection of biospecimens for the constitution of a biorepository to permit future 
analyses yet to be conceived 
Sample Size and Population  
TACT2 has enrolled 1000 diabetic patients 50 years of age or older with a prior MI and 
a serum creatinine of 2.0 mg/dL or less. Patients will be randomly allocated (1:1:1:1) to 
4 factorial groups, each with approximately 250 patients. TACT2 will use a simple 
randomization scheme. The four treatment groups are: 
 
1. 
Active chelation + active OMVM 
2. 
Active chelation + placebo OMVM 
3. 
Placebo chelation + active OMVM 
4. 
Placebo chelation + placebo OMVM 
 
The study is targeting a population consisting of 40% women and 18% minority 
subjects.  
 
 
 


TACT2 Protocol 
May 6, 2021 
6 
1. STUDY OBJECTIVES 
TACT2 is being carried out to replicate TACT, which found a reduction of recurrent 
cardiovascular events in post-MI diabetic patients receiving edetate disodium-based 
chelation therapy.  
1.1 
Primary Objective 
The primary objective of TACT2, therefore, is to determine if the chelation-based 
strategy increases the time to the first occurrence of any of the components of the 
TACT2 primary endpoint: all-cause mortality, myocardial infarction, stroke, coronary 
revascularization, or hospitalization for unstable angina compared to the placebo 
chelation strategy.  
1.2 
Secondary Objectives 
The secondary objectives of TACT2 are to determine: 
  
1. if the chelation-based strategy reduces the overall rate of occurrence of the events 
which define the primary TACT2 endpoint: all-cause mortality, myocardial infarction, 
stroke, coronary revascularization, or hospitalization for unstable angina events 
compared to placebo chelation strategy.  
2. if the chelation-based strategy increases the time to the first occurrence of a 
combined secondary endpoint: cardiovascular mortality, myocardial infarction, or 
stroke compared to placebo chelation strategy. 
3. if the chelation-based strategy increases the time to all-cause mortality compared to 
placebo chelation strategy. 
 
Exploratory analyses, defined as those seeking to confirm a signal of benefit observed 
in TACT, or to develop mechanistic hypotheses for benefits of chelation expected in 
TACT2, include: 
i. 
Analysis of the primary endpoint in patients receiving OMVM compared with oral 
placebo 
ii. 
Analysis of the primary endpoint in patients receiving active chelation + active 
OMVM, compared with placebo chelation + placebo OMVM 
iii. 
Analysis of markers of severity of diabetes (fasting glucose, HbA1c, 
microalbuminuria) throughout the infusion regimen 
iv. 
Analyses of lead and cadmium in blood and urine to:  
a. Compare the change in metal internal dose (blood lead and urine 
cadmium) in TACT2 participants, from infusion 1 to infusion 40 (or 1 year) 
in the active versus placebo infusion arms. 
b. Evaluate whether higher screening metal internal dose (blood lead and 
urine cadmium) and the extent of depletion of those stores identify 
patients more likely to benefit from chelation.  
v. 
Collection of biospecimens for the constitution of a biorepository to support future 


TACT2 Protocol 
May 6, 2021 
7 
mechanistic work. Samples of blood (plasma and buffy coat) and urine will be 
stored at -80ºC in a secured biorepository to ensure their availability for the 
evaluation of future hypotheses that will be guided by the results of the trial. 
The above metal collections and biorepository will serve to support analyses to 
determine whether post-infusion urine metal measurements, alone and in comparison to 
the corresponding pre-infusion measurements, have clinical significance for predicting 
outcomes and clinical benefit of chelation; and whether the suite of additional metal 
levels measured in blood and urine by inductively coupled plasma mass multi-element 
analytic technique, some of which are not chelated by edetate disodium, have clinical 
(prognostic) significance in preliminary testing 
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
Chelation treatment was first reported to have clinical benefits in symptomatic CAD 
patients in 1956 and 1961.1-2 In the early 1960s, however, following a reappraisal by 
Kitchell,3 only alternative medicine practitioners continued to use chelation for 
prevention of complications of atherosclerosis based on their positive anecdotal 
experiences.4-6 Ultimately, academic authors published 3 small studies7-9 with an 
aggregate of <300 patients and concluded that there was no benefit from chelation for 
surrogate endpoints such as time to claudication or angina. Yet these studies were too 
small and of too short a duration to exclude a small or moderate effect on clinical 
endpoints.10 Despite recommendations against the practice of chelation by numerous 
professional medical associations,11 patients continued to seek, and some practitioners 
to administer, chelation therapy for a variety of medical conditions.5  
 
The National Institutes of Health (NIH) funded TACT in 2002. The design was a 2X2 
factorial, randomly allocating patients to intravenous edetate disodium-based chelation 
or placebo, and high-dose oral multivitamins and multiminerals or oral placebo. 
Standard chelation practice in the community also included the addition of oral 
supplements to the intravenous treatments; hence the factorial design.12 There were 
1708 post-MI patients enrolled in 134 sites and 55,222 infusions administered as part of 
TACT. 
 
In guideline-treated post-MI patients, chelation alone led to an 18% reduction in a 
combined cardiovascular endpoint (HR 0.82 (0.69, 0.99) P=0.035, 7-year NNT=18).13 
Patients with diabetes had dramatic benefit from IV chelation (HR 0.59, (0.44, 0.79), 
P=0.0002, 5-year NNT=6.5).14 An analysis of the factorial groups demonstrated that the 
strategy of intravenous chelation plus OMVM yielded a 26% reduction over double 
placebo (HR 0.74 (0.57, 0.95), P=0.016, 5-year NNT=12).15 The effect size and the 
potential for an impact on public health and health care financing were the primary 
reasons for the Investigators’ desire to move forward with TACT2, in this case focusing 
on the patients in whom the greatest benefit had been observed (Table 1). The 
investigators also felt that inclusion of an exploratory mechanistic component to the 
clinical trial would be desirable. TACT2, therefore, if positive, will be a confirmatory 


TACT2 Protocol 
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8 
second trial of edetate disodium-based chelation for patients with established coronary 
disease, and should provide the groundwork for mechanistic hypotheses – that 
ubiquitous pro-oxidant toxic metals, especially lead and cadmium, are associated with 
recurrent coronary events.16-20 
 
Table 1. Summary of Results from TACT 
* Post-MI, age ≥ 50 years, creatinine ≤ 2.0; ** time-to-event. Primary endpoint: time to death, MI, stroke, coronary revascularization, 
and hospitalization for angina; MVM: Multivitamins & Multiminerals; NNT: number needed to treat to prevent an event.  
 
The OMVM versus placebo comparison demonstrated an 11% relative reduction in risk 
that was not statistically significant.15 Yet, as can be seen above, there appears to be a 
numerical, but not statistically significant, signal of benefit from OMVM, reducing the 
hazard ratio by about 10% each time OMVM is added to the chelation infusion. The 
TACT vitamins included higher doses of the individual OMVM components than 
previously used in other trials, and the non-significant signal of potential benefit 
challenges current opinions on vitamin use for cardiovascular disease. Thus, the TACT2 
protocol replicates the 2x2 factorial design initially used in TACT.  
One of the two factors in the 2x2 factorial design – OMVM – is not incorporated in a 
primary or a secondary objective of the trial, and appears only in exploratory analyses. 
The reasons for this are as follows: 
1. A factorial design will allow us to discern whether there is replication of the effect 
of OMVM on clinical events. 
2. If there is an effect, the complex chelation strategy with 38 components will likely 
be linked, to the benefit of intravenous chelation, and new lines of research into 
the vascular effects of ultra-high dose oral anti-oxidant mixtures given new life. 
This will apply even if the effect is numerical and qualitative, and not necessarily 
statistically significant. Observing the same signal of benefit in 2 studies would be 
very important. 
3. The most likely result, given the weight of prior vitamin research, is that there will 
be no effect of OMVM. If this is true, then the 28 oral components can be 
unlinked from the chelation strategy. This will improve patient compliance and, 
for the cardiology community, reduce barriers to acceptance and implementation. 
4. There will be no statistical cost (assuming additive treatment effects) to the 
chelation vs placebo infusion comparison, which in TACT (diabetes) had a HR of 
0.59. The proposed sample size will provide 85% power to detect a HR of 0.70 
for the primary endpoint, and 95% power to detect a HR of 0.65, both 
conservative estimates based on TACT results. In summary, if vitamins are not 
an essential part of the effectiveness of the TACT regimen, being able to clarify 
Population*: 
Endpoint** 
Treatment comparison 
Event rate relative 
reduction 
p-value 
5-year NNT 
Overall 
Primary 
EDTA vs. placebo 
18% 
0.035 
18 
Overall 
Primary 
EDTA + OMVM vs. placebo 
+ placebo 
26% 
0.016 
12 
Diabetes 
Primary 
EDTA vs. placebo 
41% 
0.0002 
6.5 
Diabetes 
Death 
EDTA vs. placebo 
43% 
0.011 
12 
Diabetes 
Primary 
EDTA + OMVM vs placebo 
+ placebo 
51% 
<0.001 
5.5 


TACT2 Protocol 
May 6, 2021 
9 
this in TACT2 will allow FDA to consider the approval of chelation alone and will 
make the treatment significantly easier to administer clinically. At the same time, 
if the relationships in the factorial comparisons of TACT can be reproduced in 
TACT2 for both chelation and vitamins, we will have opened up two major new 
research areas rather than just one.  
2.2 
Study Rationale 
Coronary heart disease (CHD) is the leading cause of premature morbidity and mortality 
in the United States, including in patients with diabetes. In 2012 there were 29.1 million 
diabetic patients in the US, including 27% of people age 65 or older.21 Of these, 6.4 
million had coronary artery disease (CAD) and could potentially be eligible for the 
therapy to be tested in this application. Despite medical research advances that have 
identified effective medical therapy to reduce coronary events in diabetes, 68% of the 
223,000 diabetic patients who died in 2012 had heart disease as either the principal or 
contributing cause. Compared with non-Hispanic whites, the risk of diagnosed diabetes 
is 70% higher among African Americans and 80% higher among Hispanics.21 Although 
we do not fully understand the mechanism of chelation benefit and how it possibly 
relates to risk of diabetic patients, the chelation strategy diabetic patients had their risk 
of major adverse cardiovascular events reduced to the level of those patients who did 
not have diabetes. Chelation, in other words, appeared to lower the risk of diabetes for 
cardiovascular events to the non-diabetic post-MI patient level. This finding alone has 
potentially major public health implications. From an economic perspective, diabetes is 
a costly disease that consumes a large proportion of the national health care budget. In 
the US, 1 in 5 health care dollars is spent treating people with diabetes. The annual 
expenditure exceeds $245 billion (B), including $176B in direct costs and $69B in 
indirect costs (disability, work loss, premature mortality).22 TACT2, if positive, will likely 
have major public health and scientific impact. 
 
Possible Benefit of Chelation Therapy 
The epidemiologic evidence that many metals are toxic and promote cardiovascular 
disease is robust, particularly for lead and cadmium,16-20, 23-24 metals chelated by the 
edetates.25-26 One possible hypothesis, which is an exploratory analysis within the 
present trial, is that edetate disodium-based chelation depletes body stores of 
ubiquitous toxic metal pollutants, lead and cadmium in particular, acquired from the 
environment over many years and that depletion of toxicants leads to improved 
outcomes. 
 
EDTA Pharmacology 
The present trial requires intravenous administration of the test article, edetate 
disodium. This is supported by extensive literature demonstrating poor absorption from 
the gastrointestinal tract. Only 5-10% of an oral dose is absorbed in the body, 91% of an 
oral dose is recoverable from the feces, and 4% is recoverable from the urine.27 In 
blood, the drug is found in the plasma compartment. EDTA does not appear to 
penetrate cells; it is distributed primarily in the extracellular fluid with only about 5% of 
the plasma concentration found in the spinal fluid. The half- life of EDTA is 20 to 60 
minutes. EDTA is excreted primarily by the kidneys, with about 50% excreted in one 


TACT2 Protocol 
May 6, 2021 
10 
hour and over 95% within 24 hours.27 Calcium and other chelates are excreted in the 
urine bound to the EDTA. Almost none of the compound is metabolized.  
 
The biological effects of EDTA are due to the formation of chelates with divalent and 
trivalent metals. The stability of the metal-EDTA complex is directly related to its pH – 
the higher the pH, the more stable the chelate. Intravenous infusions of edetate 
disodium result in the chelation of ionized calcium.28 Transient but mild reduction of 
serum calcium can be observed following the slow intravenous infusion of EDTA, and 
was observed in TACT (below). 1gm of EDTA can effectively bind approximately 120 
mg of calcium. Among metals normally found as trace metals and metals present 
pathologically, EDTA has been demonstrated to bind and promote the excretion of 
cadmium, lead, zinc, copper, iron, manganese, and vanadium.29-30 Virtually all of the 
metals chelated by EDTA are excreted in the urine within 24 hours.26 In the case of 
calcium, 28% is excreted during the infusion, 60% in the 6 hours following the infusion, 
and the remainder between 6 and 12 hours after.31 Among the essential metals 
chelated by disodium EDTA are copper and iron. Both of these metals have an 
important role in oxidative state and generally exist in an intracellular compartment or 
protein-bound. However, there is an important, non-protein bound component that may 
be chelated by EDTA salts. EDTA salts may promote the excretion of up to 10 mg/day 
of iron and increase urinary copper by almost 140%.32 The oral supplement regimen in 
TACT2 repletes copper. Iron was not substantially diminished by EDTA in TACT, and 
will be measured during the TACT2 infusion regimen. 
 
Preliminary data on metal excretion following a TACT2 infusion 
A preliminary study measured metal excretion after one infusion of placebo, and one of 
active chelation. Twenty male participants (mean age 66, range 51 to 81) were recruited 
using the same criteria as in TACT (post-MI, age >50, creatinine ≤ 2.0 mg/dL). Urinary 
concentrations of 20 toxic metals (Al, Sb, As, Ba, Be, Bi, Cd, Cs, Gd, Hg, Pb, Ni, Pd, Pt, 
Te, Tl, Th, Sn, W, U) normalized to creatinine excretion were measured at baseline, for 
6 hours following a placebo infusion of 500 mL normal saline and 1.2% dextrose, and 
for 6 hours following a 3 gram edetate disodium-based infusion as used in TACT. 
 
Following an edetate 
disodium-based TACT 
infusion, there was a striking 
increase in the urinary 
excretion of lead (mean 
3,926% increase, P<0.001; 
Figure A), cadmium (739% 
increase, P<0.001; Figure B), 
and nickel (131% increase, 
P<0.001). There was also a 
modest increase in the urinary 
excretion of tin and thallium 
(30-40%; P<0.05). These 
preliminary data25 show that 


TACT2 Protocol 
May 6, 2021 
11 
an edetate disodium-based infusion, identical to that used in TACT and proposed for 
TACT2, markedly increased excretion of lead and cadmium. Whether enhanced 
excretion of metals following repeated chelation infusions leads to a reduction in blood 
lead or pre-infusion urine cadmium (reflecting total body stores of each) is unknown, but 
will be identified by TACT2. 
 
FDA safety information and labeling on edetate disodium 
Edetate disodium is an old drug for which no clear modern indication exists. Its current 
approval, as listed on the FDA website,33 is for medical conditions for which more 
modern, better treatments exist: 
 
“Edetate disodium is approved by the FDA for use in selected patients with high 
blood calcium levels (hypercalcemia) as well as for use among patients with heart 
rhythm problems due to intoxication with the drug, digitalis.” 33  
 
Edetate disodium has a long safety record, which was reviewed by FDA in 2007. 
Between 1971 and 2007, a time period during which hundreds of thousands of doses of 
edetate disodium were likely used, there were 11 deaths reported to FDA associated 
with the use of edetate disodium. According to FDA, 7 of 11 deaths resulted from 
confusion of edetate disodium with another drug, and hence its misadministration, either 
with too high a dose or more commonly as an IV push rather than a slow infusion. Thus, 
in a period spanning 36 years, there were 4 deaths associated with edetate disodium, in 
which edetate disodium was not misused by being confused with a different drug. This 
is consistent with the safety data for TACT presented below. 
 
Safety of EDTA chelation as reported in TACT 
We amassed a substantial body of safety data in TACT. EDTA was associated with few 
side effects and there were no differences in serious adverse events compared with 
placebo.13,14,34 Some of the safety specifics are summarized below. 
 
 Calcium. Hypocalcemia, defined as a calcium level less than 8.5 mg/dL prior to 
an infusion, was reported in 52 chelation patients (6.2%) and 30 placebo patients 
(3.5%) (P=0.008). One patient, non-diabetic, had symptomatic hypocalcemia 
associated with muscle cramping that led to an emergency department visit. With 
regards to bone health, there were 2 fractures in the patients receiving the full 
chelation strategy and 2 fractures in those receiving double placebo (P=1.00). 
Although no safety signal pertaining to bone health was found in TACT, the effect 
of chelation on calcium makes it appropriate to measure calcium during the 
infusion period, as well as designate fractures as an event of interest and 
specifically query for it at regular intervals in the clinic visits and the telephone 
follow-up.  
 Kidney. An abnormal creatinine during the infusion phase was reported in fewer 
3/839 (0.4%) placebo patients than chelation 9/868 (1%) patients (P=0.093). 
Because EDTA is renally excreted, creatinine will be followed during the infusion 
period. Vitamin C in high doses has been associated with oxalate kidney stones, 
and this was a rare complication in TACT. 


TACT2 Protocol 
May 6, 2021 
12 
 Liver. There were no significant differences in liver enzyme abnormalities in the 
chelation compared with the placebo group. Liver function will therefore not be 
monitored after the screening study. 
 Hematology. There were no significant differences in abnormalities of 
hematologic parameters (white blood cells, hematocrit, and platelet count) in 
EDTA compared with placebo groups. Complete blood counts will be assessed 
at screening, infusion 20, and at the end of the infusion period or 1 year.  
 Hypoglycemia. There was 1 episode of hypoglycemia reported in TACT, not 
clearly caused by the infusion. Because diabetic patients in TACT2 may possibly 
have hypoglycemic events due to the treatment of their diabetes, we have 
retained this potential adverse event in the ICF. 
 Death. There were 2 deaths attributed by the blinded Medical Monitor as 
possibly or probably due to study therapy: 1 in the edetate disodium group and 1 
in the placebo group. This potential adverse effect has been retained in the ICF. 
 
Safety – chelation infusions in the population with diabetes: In the patients with 
diabetes, chelation was as safe as in the non-diabetic population. There were 95 
serious adverse events (non–endpoint events) in the population with diabetes mellitus 
(56 chelation placebo and 39 chelation active). 
 
Safety – Oral multivitamins and multiminerals: Serious adverse events occurred in 
124 (15%) vitamin recipients and 103 (12%) placebo recipients (difference, 3 
percentage points [95%CI=0.7 to 5.7 percentage points]). Adverse events included 12 
(1.4%) incident neoplasms in the vitamin group and 11 (1.3%) in the placebo group 
(difference, 0.1 percentage point [95%CI= 0.8 to 1.3 percentage points]). No evidence 
suggested harm from vitamin therapy in any category of adverse events.  
3. STUDY DESIGN 
TACT2, like TACT, is a 2X2 double-blind, placebo-controlled multicenter international 
(US and Canada) factorial trial testing 40-weekly edetate disodium-based chelation 
infusions and twice daily OMVM. On December 31, 2020, TACT2 completed enrollment. 
The study enrolled 1000 diabetic patients 50 years of age or older with a prior MI and a 
serum creatinine of 2.0 mg/dL or less. The factorial design was selected for TACT2 
because it replicates the TACT design and it provides the most information about the 
independent contributions of the chelation and OMVM factors. Patients will be randomly 
allocated (1:1:1:1) to 4 factorial groups: 
 
1. Active chelation + active OMVM 
2. Active chelation + placebo OMVM 
3. Placebo chelation + active OMVM 
4. Placebo chelation + placebo OMVM 
 
Patients will be followed for clinical events until the beginning of the analysis phase, 3 
months before the end of the 5-year trial. During the infusion period, patients will have 
frequent clinical and laboratory monitoring to determine whether a clinical endpoint has 


TACT2 Protocol 
May 6, 2021 
13 
been reached, to assess study safety, and to obtain biosamples for the exploratory 
analyses of metal excretion, and to establish the biorepository. Starting 6 months after 
randomization, patients will be followed by telephone from the DCRI Call Center. The 
combination of early clinic visits and samples, combined with later telephone follow-up 
will permit the ascertainment of clinical and laboratory goals in TACT2, as listed below 
and in greater detail in Section 6.1. 
 
The primary objective of TACT2 is to determine if the chelation-based strategy 
increases the time to the first occurrence of any of the components of the TACT2 
primary endpoint: all-cause mortality, myocardial infarction, stroke, coronary 
revascularization, or hospitalization for unstable angina compared to the placebo 
chelation strategy.  
 
The secondary objectives of TACT2 are to determine: 
  
1. if the chelation-based strategy reduces the overall rate of occurrence of the 
events which define the primary TACT2 endpoint: all-cause mortality, myocardial 
infarction, stroke, coronary revascularization, or hospitalization for unstable 
angina events compared to placebo chelation strategy.  
2. to determine if the chelation-based strategy increases the time to the first 
occurrence of a combined secondary endpoint: cardiovascular mortality, recurrent 
myocardial infarction, or stroke compared to placebo chelation strategy. 
3. to determine if the chelation-based strategy increases the time to all-cause 
mortality compared to placebo chelation strategy. 
 
Additional analyses, defined as those seeking to confirm a signal of benefit observed in 
TACT, or to develop mechanistic hypotheses for benefits of chelation expected in 
TACT2, include: 
i. 
Analysis of the primary endpoint in patients receiving OMVM compared with oral 
placebo to determine whether the signal of OMVM benefit is reproduced 
ii. 
Analysis of the primary endpoint in patients receiving active chelation + active 
OMVM, compared with placebo chelation + placebo OMVM to determine if 
combination therapy has a greater effect size, as observed in TACT 
iii. 
Analysis of markers of diabetes (fasting glucose, HbA1c, microalbuminuria) 
throughout the infusion regimen to determine whether changes in diabetes 
control or microvascular effects may be associated with the TACT2 results 
iv. 
Analysis of lead and cadmium levels collected at multiple times during the 
infusion regimen to assess whether toxic metal removal is associated with the 
TACT2 results 
v. 
Collection of a specimen biorepository to permit future analyses yet to be 
conceived 


TACT2 Protocol 
May 6, 2021 
14 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 
Inclusion and Exclusion Criteria 
All TACT2 participants must meet of the following inclusion criteria shown in Table 2. 
Potential TACT2 participants meeting any of the exclusion criteria in Table 2 will be 
excluded from study participation. 
 
Table 2: Inclusion and exclusion criteria 
INCLUSION CRITERIA (all must be present) 
EXCLUSION CRITERIA (none may be present) 
1. Age  50 years 
2. History of diabetes, defined as medical 
record evidence or patient report of 
currently using insulin or oral 
hypoglycemic agents, or with a history 
of fasting blood glucose measurement 
of 126 mg/dL or higher, or a history of 
HbA1c of 6.5% or higher.  
3. History of myocardial infarction based 
on the Universal Definition of MI.35  
a. When information about the MI 
hospitalization is available, all MI 
types except Type 2 qualify for 
study entry. 
b. When information about the MI 
hospitalization is not available, a 
wall motion abnormality on 
imaging or a perfusion defect on 
scan that corresponds to a 
coronary distribution, whether or 
not accompanied by pathological 
Q waves in the appropriate 
distribution, will qualify the patient 
for study entry. This criterion 
requires a call to the CCC for 
case review. 
 
1. Baseline serum creatinine >2.0 mg/dL. 
2. HbA1C >11%. 
3. Myocardial infarction within 6 weeks of 
randomization. 
4. History of allergic reactions to EDTA or any 
other components of the chelation solution, 
including heparin. Site personnel are to call 
the CCC to discuss heparin allergy. 
5. Coronary or peripheral arterial 
revascularization procedure performed within 
the last 6 months. 
6. Planned revascularization procedure in the 6 
months following enrollment. 
7. Heart failure hospitalization within 6 months 
prior to enrollment or in clinical heart failure 
at the time of proposed enrollment (such as 
NYHA Class 3 dyspnea + rales >basilar, and 
additional signs of fluid overload). Such 
patients may be treated with diuretics and 
enrolled when stable. 
8. Poor or no venous access in the upper 
extremities. 
9. a. Prior intravenous chelation therapy 
consisting of > 1 infusion within 5 years; if 
only 1 infusion took place, patient cannot be 
enrolled for at least 12 months after said 
infusion.  
b. Oral chelation therapy with an approved 
oral chelating agent within 2 years.  
10. Prior participation in TACT. 
11. Baseline platelet count <100,000. 
12. History of cigarette smoking within the last 3 
months. 
13. ALT or AST > 2.0 times the upper limit of 
normal. 
14. Wilson’s disease, hemochromatosis, or 
parathyroid disease. 
15. Any medical condition including a current 
diagnosis of cancer (except non-melanoma 
skin cancer) that will limit patient survival 
over the duration of the trial. 


TACT2 Protocol 
May 6, 2021 
15 
 
4.2 
Study Enrollment Procedures  
TACT2 will enroll a population of stable, post-MI diabetic patients. The majority of 
patients, therefore, will be approached in the outpatient area, including: 
 
i. 
Cardiology practices of investigators, colleagues, or referral sources 
ii. 
Endocrinology practices of investigators, colleagues, or referral sources 
iii. 
Cardiac rehabilitation services (particularly in Canada) 
iv. 
Potential participants contacting clinical sites in response to IRB-approved 
advertisements 
v. 
Potential participants contacting clinical sites as a result of interviews, lectures, 
and social media 
 
Enrollment of Women and Racial and Ethnic Minorities 
The TACT2 investigators are committed to recruitment of a representative sample of 
women and minority subjects as required by NIH, and we understand that failure to do 
so will decrease the validity and generalizability of study results. TACT2 is well 
positioned to achieve its goals of enrolling subjects representative of the US population. 
We are selecting patients for study that are age 50 or older, which has the corollary 
benefit of achieving a more equivalent distribution of men and women for whom 
coronary artery disease (CAD) is the leading cause of death. Moreover, we anticipate 
randomizing patients who predominantly have Type 2 diabetes (T2D). Compared with 
non-Hispanic whites, the risk of diagnosed diabetes is 70% higher among African 
Americans and 80% higher among Hispanics, which also has the corollary effect of 
helping us to achieve a sample that is sufficiently representative of these minority 
populations. TACT2 will target enrollment of at least 40% women and 18% minority 
subjects, which is in line with the demographics of prevalent myocardial infarction (MI) 
in the US population and the realities of enrolling women and minorities, as shown by 
our review of the literature. 
 
Targeted Enrollment of Women 
We are committed to enrolling sufficient numbers of women so that the results of 
TACT2, if positive, will be plausibly applicable to women. The target proportion of 
women to be enrolled in TACT2 is lower than the overall proportion of women in 
estimates from the 2010 US Census (51%),36 but it is consistent with current estimates 
of the proportion of prevalent MI among women, especially those with diabetes. Based 
upon cardiovascular disease (CVD) surveillance from 1994-1997 in the NHLBI 
Atherosclerosis Risk in Communities (ARIC) Study, one of the largest NHLBI population 
cohort studies and CVD surveillance programs, 32% (n=4,253) of 13,068 
hospitalizations for MI occurred in women.37 More recent data from the 2014 Heart 
16. Any factor that suggests that the potential 
participant will not be able to adhere to the 
protocol. 
17. Women of child-bearing potential including 
those with plans for post-menopausal in vitro 
fertilization or other reproductive technology. 


TACT2 Protocol 
May 6, 2021 
16 
Disease and Stroke Statistics update from the American Heart Association (AHA) 
reported a similar proportion of prevalent MI in women (34%).38-39 Gore et al.,40 based 
on the National Registry of Myocardial Infarction (NRMI), reported that 44.8% of incident 
MIs in diabetics occurred in women, with an 8.4% in-hospital mortality that was slightly 
higher than that of men. Perhaps more to the point of the attainable, the FREEDOM 
Trial41 reported its results in 2012. This was an NIH study of revascularization strategies 
in diabetic patients with multivessel coronary disease. There were 1900 patients 
enrolled, and 29% were women (Similar to ARIC, above). The TACT2 leadership has 
carefully considered the population goal as reported by Gore, and the attainable goal 
from FREEDOM. While we believe we can improve on FREEDOM, we do not 
realistically believe we can enroll a population fully reflective of Gore et al. Thus, our 
goal of enrolling at least 40% women in the TACT2 trial is justified.37-41 
 
Targeted Enrollment of Minorities 
Our goal for enrollment of minorities is more reflective of the Gore data, which reported 
18.2% minorities in the NRMI diabetes dataset. This proportion included 9% black and 
3.4% Hispanics. Overall, the TACT2 enrollment target of 18% for minority patients is 
justified based on these data and is in accord with published data on the proportion of 
minority patients with prevalent MI used by the AHA, ACC-NCDR and VAMC.37-43  
 
Additional Strategies to Enroll and Retain Women and Minorities 
Current informal surveys of patients undergoing chelation have already led to 
suggestions for sites to consider infusions of multiple patients simultaneously in a 
socially compatible group setting, to consider gender-based infusion groups, particularly 
for women patients, and to consider extended hours or weekend infusions. 
 
Strategies will be added or modified throughout the study, as formal surveys of patients 
are performed, and sites apply or discard different approaches. These plans will form 
part of a living document external to this Protocol, entitled “Plans to Identify, Recruit, 
Enroll, and Retain Women & Minorities.”  
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
Chelation/placebo infusions: The active infusion contains up to 3 g of Na2EDTA 
adjusted based on eGFR, 2 g of magnesium chloride, 100 mg of procaine HCL, 2500 U 
of heparin, 7 g of ascorbate, 2 mEq KCl, 840 mg sodium bicarbonate, 250 mg 
pantothenic acid, 100 mg of thiamine, 100 mg of pyridoxine, and sterile water to 
complete 500 mL. Placebo infusions consist of 500 ml normal saline with 1.2% 
dextrose. Infusions are administered weekly for 40 weeks.12 More details can be found 
in the Manual of Procedures (MOP). 
The dose of edetate disodium in the infusion solution will be adjusted based onf 
estimated creatinine clearance and ideal body weight (IBW), but in no case will ever 
exceed 3 grams per infusion (3000mg): 
EDTA dose (mg) = [50mg x (IBW x 1.33) x min (100, creatinine clearance)] ÷100 


TACT2 Protocol 
May 6, 2021 
17 
 
The IBW is calculated based on the Devine formula:44 
 For men the weight is computed as 50 kg plus 2.3 kg for each inch of height 
over 5 feet (or 60 inches). 
 For women the weight is computed as 45.5 kg plus 2.3 kg for each inch of 
height over 5 feet (or 60 inches). 
 Actual body weight is used whenever it is less than computed ideal body 
weight. 
 
Correction for creatinine clearance should only be done if creatinine clearance is 
less than 100.  
 
Creatinine clearance will be computed by using a modified version of the Cockcroft-Gault 
equation:  
 
Creatinine Clearance (ml/min) =     (140 - age) x (IBW X 1.33)     
(72 x Cr) 
 
Creatinine Clearance = computed renal glomerular filtration rate in ml/min 
Age = patient’s age 
IBW = computed weight in Kg 
Cr = serum creatinine in mg/dL 
For women, multiply the above result by 0.85 
EDTA dose is automatically adjusted by the electronic data capture system based on 
the most recently calculated creatinine clearance value. If a prescription change for 
EDTA is required, the pharmacy is automatically notified by the electronic data capture 
system. The pharmacy will adjust the EDTA for the patient’s next scheduled infusion.  
 
Serum calcium is corrected by albumin level to generate a corrected calcium value that 
is an estimation of ionized calcium45 as follows: 
 
corrected calcium = serum calcium + (0.8 x [normal serum albumin - patient’s 
albumin]) 
 
calcium= mg/dL 
albumin= g/dL 
 
 When corrected calcium is greater than 8.5 mg/100mL, the infusion is 
administered over 3 hours. 
 When corrected calcium is between 8 and 8.5, the infusion is administered over 4 
hours.  
 When corrected calcium is less than 8, the next infusion is not administered and 
serum calcium is rechecked at least 1 week later. When corrected calcium is 
within acceptable range, infusions continue. This usually leads to a 2 week delay 
in infusions. 


TACT2 Protocol 
May 6, 2021 
18 
 
OMVM/placebo: The OMVM consists of 3 caplets, twice daily for a total intake of 
vitamin A 25000 IU, vitamin C 1200 mg, vitamin D3 100 IU, vitamin E 400 IU, vitamin 
K1 60 μg, thiamin 100 mg, niacin 200 mg, vitamin B6 50 mg, folate 800 μg, vitamin B12 
100 μg, biotin 300 μg, pantothenic acid 400 mg, calcium 500 mg, iodine 150 μg, 
magnesium 500 mg, zinc 20 mg, selenium 200 μg, copper 2 mg, manganese 20 mg, 
chromium 200 μg, molybdenum 150 μg, potassium 99 mg, choline 150 mg, inositol 50 
mg, para-aminobenzoic acid 50 mg, boron 2 mg, vanadium 35 μg, citrus bioflavonoids 
100 mg12. Placebo caplets consist of microcrystalline cellulose, stearic acid, 
croscarmellose sodium, silica and magnesium stearate. OPADRY® II complete film 
white coating, magnesium stearate and vanilla flavor are used to coat both active and 
placebo pills. These caplets are taken for the entire duration of the study. 
 
Low-dose vitamins: The low-dose supplements are taken by all patients to prevent 
any deficiency syndromes from chelation of essential minerals or vitamins. They 
consist of: vitamin B6, chromium, copper, manganese, and zinc. As was done in TACT, 
all patients will receive a low-dose regimen consisting of a single pill to be taken during 
the infusion regimen, stopping at 1 year at the latest. The low-dose regimen consists 
of: vitamin B6 25 mg, zinc 25 mg, copper 2 mg, manganese 15 mg, and chromium 50 
μg. 
5.2 
Handling of Study Interventions  
Infusion Encounter 
The clinical unit will administer infusions. Infusions will be received in a refrigerated 
individual overnight mailer that will contain an IV bag and 2 syringes, each labeled for 
the individual patient. Typically, the infusion kit is received the day before the infusion is 
scheduled, and is good for 72 hours if unmixed. Once mixed, the refrigerated infusion 
will be good for 24 hours only. The specifics will be covered in detail in the MOP. 
 
Each infusion encounter will be preceded by a brief interval history with specific 
emphasis on cardiac symptoms and clinical events, including hospitalizations. Vital 
signs will be measured before and after the infusion prior to discharge from the infusion 
site. A brief cardiopulmonary exam will be recorded at screening and at the end of each 
infusion. If there is weight gain of 3 lbs or more since the last infusion, or 5 lbs or more 
since the screening evaluation, the patient will be evaluated for heart failure. A trained 
study coordinator or infusion nurse may perform this examination. If there is heart 
failure, the infusion will be delayed until the patient is treated. Symptoms occurring 
during the infusions will be elicited and recorded on the eCRF. Patients will take their 
diabetes medications as scheduled unless a blood draw is scheduled. In that case, 
patients will arrive after an overnight fast and the diabetes medications will be held until 
the morning blood draw prior to the beginning of the infusion. Patients may consume 
food and drink during the infusion.  
 
Infusion Schedule 
Infusions will be administered on a weekly basis for 40 weeks through a peripheral 
intravenous line over at least 3 hours. Due to vacations, travels, weather, and illness, 


TACT2 Protocol 
May 6, 2021 
19 
the infusion regimen can be extended but is expected to be completed by 1 year. 
Clinical sites, however, will be instructed that if a patient has not completed the 
infusions by 1 year, they should continue trying to get the patient to clinic until the 40th 
infusion is complete. The total number of infusions is key, not the weekly schedule on 1-
year completion. The overall goal of the treatment schedule is to deliver all 40 
infusions; no matter how long it takes. The DCRI Call Center will follow patients for 
clinical events, but not for infusion scheduling or other site-centered events beginning 6 
and 12 months after randomization, and at 4 month intervals subsequently until the 
study ends.  
 
Distribution of Vitamins 
The TACT2 Central Pharmacy will be responsible for distributing the vitamins every four 
months to the individual patients. The study vitamins will be mailed directly to the 
subject’s home. In order to better preserve the blind and improve vitamin compliance, 
the study vitamins will be packaged in one month bottles and in individual dose packs. 
Vitamin compliance will be estimated by the site personnel and the DCRI Call Center at 
specific intervals and entered into the Electronic Data Capture (EDC) system. The 
details will be covered in the MOP. 
 
Managing Patient Safety During the Infusion Encounter 
Blood samples for safety will be collected during infusion visits as seen in the schedule 
below. 
 
Hypoglycemia – Among 839 chelation-treated patients in TACT receiving 27,382 
infusions, there was 1 episode of hypoglycemia. However, given that all patients in 
TACT2 have diabetes, all sites will be instructed in how to suspect, diagnose, and treat 
hypoglycemia. Patients with diabetes are more likely to have hypo and hyperglycemia 
based on the nature of their disease and its treatment. There is no expectation that 
patients with diabetes are prone to hypoglycemia from active or placebo treatment. 
 
Some patients using continuous glucose monitors (CGMs) may have incorrect readings 
due to the contents of the active/placebo infusion. This could result in either not giving 
insulin when it is needed or giving too much insulin. To avoid insulin-dosing errors due an 
incorrect CGM reading, patients will be directed do the following: 
 
 Do not depend on the results of CGMs for insulin dosing while receiving an infusion 
and for up to 12 hours post infusion; finger stick measurements are recommended in 
that timeframe. 
 
 Users of a closed loop insulin pump system should set the pump to manual mode for 
24 hours starting at the time of the infusion, and use finger stick measurements in 
that timeframe. 
 
Hypocalcemia – All sites will have training in how to recognize symptoms of 
hypocalcemia, and additionally have available calcium chloride or calcium gluconate for 
intravenous administration. Should hypocalcemia be suspected during an infusion, the 


TACT2 Protocol 
May 6, 2021 
20 
infusion will be stopped, and the patient will have blood drawn and be treated. The CCC 
should be called for a joint evaluation (with the site coordinator and site PI or designee) 
of the symptoms and result of the serum calcium drawn during the event before 
scheduling the next infusion. Symptomatic hypocalcemia requiring an ER visit was 
observed only once in TACT.  
 
Fluid overload – Patients are excluded from TACT2 if they are thought likely to be 
intolerant to 500 mL fluid infusions weekly or had a heart failure hospitalization within 
the past 6 months.  
 
When a patient gains more than 5 lbs from their screening weight or more than 3 lbs 
from their last visit, the site investigator or designee should evaluate the patient for heart 
failure. If, in the opinion of the site investigator or designee, the patient has heart failure, 
the infusion will not be started and the patient will be treated or referred for treatment. 
Heart failure throughout the trial will be considered an event of special interest and 
carefully tracked and compared between groups. 
 
Recommended Safety Materials  
Clinical Sites should ensure the following safety materials are available during 
administration of infusions: 
 
 Snacks or juice for empiric treatment of hypoglycemia 
 Intravenous dextrose 50% 
 Intravenous calcium gluconate or chloride 
 Glucometer for measuring glucose levels  
5.3 
Concomitant Interventions  
TACT2 will be conducted at a variety of clinical sites and there may be a range of 
medical therapies employed for secondary prevention. Specific medications for post-MI 
and diabetes will be recorded, as will injectable bisphosphonates for osteoporosis. 
TACT2 encourages the use of the latest, evidence-based care for diabetes and post-MI 
secondary prevention. To this end, the prevalent guidelines will be summarized in study 
material and made available to the sites. Patients will be encouraged to have an 
endocrinologist involved in their diabetes care. The Diabetes Science Consultant will 
evaluate summary data on HbA1c. The CCC will evaluate post-MI guideline compliance 
based on reports produced by the DCC. Sites will receive a quarterly report regarding 
the proportion of patients receiving guideline-based post-MI care, and HbA1c. Those 
placing in the lowest quartile will be notified by the CCC, and assisted in improving their 
compliance with evidence-based post-MI treatment and diabetes treatment.  
5.3.1 Optimal Concomitant Interventions 
All post-MI evidence-based medications, specifically anti-platelets, statins, beta-
blockers, ACE inhibitors or ARBs, and aldosterone blockers are encouraged, if indicated 
based on clinical need as assessed by the patient’s physician. All necessary 
cardiovascular procedures are allowed. All conventional diabetes management is 
permitted with a focus on optimal glucose control while avoiding episodes of 


TACT2 Protocol 
May 6, 2021 
21 
hypoglycemia. Recommended medical treatment for secondary cardiovascular 
prevention and diabetes management will form part of a living document outside the 
study protocol, that will be updated annually (Suggested Management of TACT2 
Patients) and circulated to sites. 
 
5.3.2 Prohibited Interventions Following randomization 
i. 
Effective, FDA-approved, oral chelation at any time during the course of the trial. 
ii. 
Intravenous chelation, outside of the TACT2 intervention, at any time during the 
course of the trial.  
iii. 
Over-the-counter vitamins having any of the same components as do the TACT2 
vitamins. In patients who are unwilling to discontinue outpatient vitamins, or 
whose participation in the infusion regimen is dependent on their continuing to 
take out of protocol oral vitamins, the CCC may grant a waiver based on 
discussion with site staff. 
iv. 
Injectable vitamins such as the Myers’ cocktail unless medically necessary (i.e. 
pernicious anemia). In patients whose participation in the infusion regimen is 
dependent upon their permission to receive a Myers’ cocktail no more than once 
monthly, the CCC may grant a waiver based on discussion with site staff. 
 
Exception: Vitamin D3 prescribed for bone health, along with calcium, may be taken and 
will be recorded in the eCRF. 
5.4 
Adherence Assessment  
Assessing infusion adherence: the site coordinators will enter in the eCRF if the infusion 
was completed. In cases where the infusion was started and not completed, the site 
coordinator will estimate whether more or less than ½ of the infusion was infused.  
 
Assessing OMVM adherence: During the study, OMVM will be delivered every 4 months 
in bottles.  Each dose pack will have 6 OMVM/placebo pills inside. Each bottle will have 
30 dose packs. At designated intervals during the study, the patient’s compliance will be 
assessed.  
 
Assessing low-dose vitamin adherence: The low-dose regimen is to be taken during the 
infusion phase only. The subjects should take one low-dose pill daily. When patients are 
non-compliant with this regimen they will be advised by site staff regarding its 
importance. 
 


TACT2 Protocol 
May 6, 2021 
22 
6. STUDY PROCEDURES  
6.1 Schedule of Evaluations 
SCHEDULE OF EVALUATIONS 
  
  
Clinic Visits 
DCRI Call Center Data 
Collection 
  
  
Infusion Phase 
Months 6, 12, 16, 20, 24, 28, 
32, 36, 40, 44, 48, 52, 56, 60 
 
Screening 
Every 
Inf 
Inf  
1 
Inf  
5 
Inf 
10 
Inf 
20 
Inf 
30 
Inf 
40 
Every 
Call 
Assess Inclusion / 
Exclusion Criteria 
X 
  
  
  
  
  
  
  
  
 
  
Obtain Informed Consent 
and Medical Records 
Release Form 
X 
  
  
  
  
  
  
  
  
  
   
Contact Information 
X 
  
  
  
  
  
  
  
 
Demographics 
X 
  
  
  
  
  
  
  
 
Medical History  
X 
  
  
 
 
 
 
 
  
Complications of Diabetes 
X 
 
 
 
 
X 
 
X 
X 
Laboratory Tests 
Creatinine 
X 
  
  
X 
X 
X 
X 
X 
 
Calcium 
X 
  
  
X 
X 
X 
X 
X 
 
Albumin 
X 
  
  
X 
X 
X 
X 
X 
 
Glucose 
X 
  
  
  
  
X 
  
X 
 
HbA1c 
X 
  
  
  
  
X 
  
X 
 
Microalbumin 
X 
  
  
  
  
X 
  
X 
 
CBC/plt 
X 
  
  
  
  
X 
  
  
 
Liver Function 
X 
  
  
  
  
  
  
  
 
Lipids 
X 
  
  
  
  
  
  
X 
 
Blood metals (pre/post infusions) 
Cadmium (urine)   
  
  
X 
X 
  
X 
  
X 
 
Lead (blood) 
  
  
X 
X 
  
X 
  
X 
 
Vital Signs 
Blood pressure 
X 
X 
  
  
  
  
  
  
 
Heart Rate 
X 
X 
  
  
  
  
  
  
 
Pulmonary check 
X 
X 
  
  
  
  
  
  
 
Height 
X 
  
  
 
 
 
 
 
 
Weight 
X 
X 
  
  
  
  
  
  
 
Medications 
Concomitant medications 
X 
  
  
X 
  
X 
  
X 
X 
Study Vitamins 
 
  
  
X 
 X 
X 
 X 
X 
X 
Endpoints 
Hospitalization 
  
X 
  
  
  
  
  
  
X 
All-cause Mortality 
  
X 
  
  
  
  
  
  
X 
Safety** 
  
X 
  
  
  
  
  
  
 
Economic Aims 
EQ-5D 
X 
  
  
X 
  
X 
  
X 
X 
Resource Utilization 
  
X 
  
  
  
  
  
  
X 
* EOS = end of study  
**Safety assessment = every visit and 30 days post final infusion 


TACT2 Protocol 
May 6, 2021 
23 
 
6.1.2 Laboratory Procedures 
The TACT2 laboratory procedures include safety monitoring, diabetes monitoring labs, 
and additional labs (metals and biorepository). Abnormalities in the safety lab results 
collected will be compiled and reported to the DSMB. Biosample processing, analysis, 
storage, and data management details are covered in the separate MOP for each 
laboratory. 
 
In brief, there are 2 types of blood and urine specimens that will be sent for analysis: 
 
1. Safety labs will be sent to study central laboratory. 
2. Blood and urine for metals analyses and for preparation and storage will be 
sent to the TACT2 Biorepository. The Biorepository will be responsible for 
processing and storage of samples during the study and intermittent batch 
transfer of urine and blood samples to the analysis laboratory.  
 
Safety Laboratory collection at the Clinical Site 
Blood and urine samples will be collected at screening, infusion 5, 10, 20, 30 and 40. 
See Schedule of Evaluations in Section 6.1 for specific laboratory tests. The study 
central laboratory will provide the supplies for collection and packaging for pick-up. This 
is explained in greater detail in the MOP. 
 
Biorepository blood and urine sample collection at the Clinical Site 
Blood and urine samples will be collected at infusion 1, 5, 20 and 40 to measure metal 
levels and for long term storage. The biorepository will ship the collection kits to the 
clinical sites. This is explained in greater detail in the MOP. 
6.2 
Description of Evaluations  
6.2.1 Screening Evaluation 
Consenting Procedure 
Patients agreeing to participate will be asked to provide informed consent, medical 
record release form, and the pharmacy agent designation form which permits the 
pharmacy to ship the study infusion to sites rather than to the patient. Patients will also 
agree to follow-up by the DCRI Call Center beginning six months after randomization. If 
a site closes prior to study end, the randomized subjects will be asked to re-consent 
using an addendum for DCRI Call Center continuation of follow-up calls. Study 
personnel obtaining consent are specifically trained to explain the study, answer 
questions and ascertain that the patient understands the key elements of the research.  
 
The original informed consent, pharmacy agent designation and medical release forms 
will be maintained as a hardcopy at the site in the study file. Copies of the signed forms 
will be given to the patient, and a scanned copy of the informed consent and medical 
release form will be emailed or faxed to the DCRI Call Center. The pharmacy agent 
designation form will be emailed to the central pharmacy. The site will document the 
version and date of the signed consent in the eCRF. 


TACT2 Protocol 
May 6, 2021 
24 
Screening assessment, enrollment, and randomization 
Screening Visit 
After providing informed consent, the site will enter the patient in the EDC system where 
a unique identifier will be assigned. The patient will have the medical history reviewed 
by study staff, and blood and urine samples will be drawn. Eligibility will be based on the 
following: 
 All inclusion criteria are met 
 No exclusion criterion is present  
Data collected will include relevant cardiac history, particularly of the qualifying MI 
(anterior or non-anterior), whether patients have Type 1 or Type 2 diabetes, 
complications of diabetes, and treatment of diabetes. Sites are encouraged to discuss 
any questions about qualifying criteria with the CCC. Medication data will include post-
MI evidence-based medications and treatments for diabetes. Laboratory test results will 
be entered to characterize the patient population, in particular with regards to diabetes 
control, renal function, and safety parameters to be followed during follow-up.  
Randomization and scheduling first infusion 
A simple randomization scheme reflecting an equal allocation ratio to the four different 
treatment groups (1 active chelation / active OMVM: 1 active chelation / placebo 
OMVM: 1 placebo chelation / active OMVM: 1 placebo chelation / placebo OMVM) will 
maximize the power for detecting treatment differences at the time of the interim and 
final analyses. 
 
Patients who are confirmed eligible to participate in TACT2 will be notified by the site 
study personnel. The patient will be randomly assigned to a blinded treatment group by 
the EDC system (this is the randomization date), and the first infusion visit will be 
scheduled. The allowable range of time during which all screening activity (defined by 
date of consent) must be completed is 30 days. After 30 days, if randomization has not 
taken place, screening labs must be re-drawn. The first infusion, should occur within 2 
weeks of randomization.  
6.2.2 First infusion visit 
This visit will involve collection of urine and blood for metals and biorepository. The 
biorepository will provide specific labels identifying patient number, infusion number, 
sample type, including kits with metal-free urine and metal-free blood collection 
containers. More detail about blood and urine collection and shipping will be found in 
the MOP. 
6.2.3 Subsequent Infusion Visits (2-40) 
The detailed schedule and activities of the follow-up visits are covered in Section 6.1 
(Table 2). Within the infusion period in Year 1, most visits are associated with an 
infusion number, and do not have a traditional time-window for performance.  
 
 
 


TACT2 Protocol 
May 6, 2021 
25 
During the infusion year, the only time-dependent visit landmarks in TACT2 are: 
 
1. The first infusion, which should occur within 2 weeks of randomization. 
2. In non-adherent patients who have stopped receiving infusions, safety labs will 
not be checked. However, the study site will make all possible efforts to bring 
these patients in for blood and urine metal collection as well as scheduled fasting 
glucose, HbA1c, and microalbumin. During these specimen visits, patients will 
also complete a clinical visit including history, and a brief exam. Subjects no 
longer receiving infusions are expected to return at week 5, 20, and 40 post-
randomization for these visits. For patients who have stopped receiving infusions, 
a urine / blood sample within 4 months of the last infusion is informative 
regarding their metal levels at the time the patient stopped infusions. The CCC 
should be consulted for all non-adherent patients. The management of the non-
adherent patient will be covered in detail in the MOP. 
 
The data collected in each call is covered in the Table in Section 6.1. 
 
6.2.4 Blinding 
Blinding 
The shipped and refrigerated infusion package will contain an ascorbic acid syringe (or 
ascorbic acid placebo if the patient is assigned to the placebo arm), one syringe with 
EDTA (or EDTA placebo if the patient is assigned to the placebo arm), and a bag for 
intravenous infusion with all the other components mixed (or a bag containing only 
normal saline if the patient is assigned to the placebo arm). EDTA in solution is clear 
and of a viscosity indistinguishable by clinical staff from that of water. Thus, the 
placebo-EDTA syringe will contain normal saline. The ascorbic acid solution is generally 
a pale yellow color, which, upon mixing (14 ml of ascorbic acid solution in 500 ml) 
becomes indistinguishable from the clear saline placebo solution. In addition, ascorbic 
acid, in the concentration provided by the manufacturer, is viscous and provides 
resistance to transfer into the infusion bag through a 21-gauge needle. A colored but 
translucent syringe will mask the color of the active ascorbate syringe. Regarding 
blinding procedures for the vitamin and mineral supplements, placebo and active 
treatment groups will take identical-appearing pills and capsules. The above blinding 
was proven successful in TACT. 
Procedure for Unmasking 
Unblinding is rarely justified or necessary. If the clinical site wishes to unmask for an 
adverse event, however, the clinical site will contact the CCC PI to discuss the clinical 
details of the case. Following these discussions, if the participant’s physician still 
desires unmasking, the CCC PI will contact the DCC Co-PI to request unmasking. The 
treatment assignment will be made available to the treating physician. The CCC PI will 
remain blinded, and a request will be made to the treating physician to maintain the 
patient blind. These requests will be submitted and handled on a case-by-case basis, 
but will be entered into the eCRF. 
  


TACT2 Protocol 
May 6, 2021 
26 
Resource Utilization Assessments 
Health care resource use will be collected on the clinical trial eCRF covering the period 
from the first infusion through end of follow-up. For all hospitalizations, length of stay by 
intensity of care (e.g., number of step down, intensive care nights) will be recorded 
along with major procedures. Discharge disposition for each acute care stay (e.g., 
home, skilled nursing, rehabilitation, nursing home, death) will be documented. In 
addition, dates of care at non-acute care facilities (e.g., skilled nursing, rehabilitation, 
long-term care) will also be collected to the end of the study follow-up. The dates of 
significant outpatient diagnostic and therapeutic procedures will be recorded.  
 
6.2.5 Completion/Final Evaluation 
All of these assessments will be discussed in detail in site training and will be an 
important part of the MOP. 
7. SAFETY ASSESSMENTS  
Institutional Review Boards (IRBs) 
All TACT2 sites will submit the study protocol, informed consent form, and other study 
documents to their corresponding IRB for approval. Any amendments to the protocol, 
other than minor administrative changes, must be approved by the TACT2 DSMB and 
each IRB before they are implemented.  
7.1 
Specification of Safety Parameters 
TACT amassed a substantial body of safety data. Edetate disodium was associated 
with few side effects and there were no differences in serious adverse events compared 
with placebo.13,14,34 The safety specifics are summarized below. 
 
 Calcium. Hypocalcemia, defined as a calcium level less than 8.5 mg/dL prior to 
an infusion, was reported in 52 chelation patients (6.2%) and 30 placebo patients 
(3.5%) (P=0.008). One patient, non-diabetic, had symptomatic hypocalcemia 
associated with muscle cramping that led to an emergency department visit. With 
regards to bone health, there were 2 fractures in the patients receiving the full 
chelation strategy and 2 fractures in those receiving double placebo (P=1.00). 
Although no safety signal pertaining to bone health was found in TACT, the effect 
of chelation on calcium makes it appropriate to measure calcium during the 
infusion period, as well as designate fractures as an event of interest and 
specifically query for it at regular intervals in the clinic visits and the telephone 
follow-up in TACT2.  
 Kidney. An abnormal creatinine during the infusion phase was reported in 3/839 
(0.4%) chelation patients and 9/868 (1%) placebo patients (P=0.093). Because 
EDTA is renally excreted, creatinine will be followed during the infusion period. 
 Liver. There were no differences in liver enzyme abnormalities in the chelation 
compared with the placebo group. Liver function will therefore not be monitored 
after the screening study. 


TACT2 Protocol 
May 6, 2021 
27 
 Hematology. There were no significant differences in abnormalities of 
hematologic parameters (white blood cells, hematocrit, and platelet count) in 
EDTA compared with placebo groups. Complete blood counts will be assessed 
at screening, infusion 20, and at infusion 40 or 1 year, whichever is earlier.  
 
Safety in the projected TACT2 population of post-MI diabetic patients: In the 
patients with diabetes, chelation was as safe as in the non-diabetic population. There 
were 95 serious adverse events (non–endpoint events) in the population with diabetes 
mellitus (56 chelation placebo and 39 chelation active). 
 
Safety – Oral multivitamins and multiminerals: Serious adverse events occurred in 
124 (15%) vitamin recipients and 103 (12%) placebo recipients (difference, 3 
percentage points [95%CI=0.7 to 5.7 percentage points]). Adverse events included 12 
(1.4%) incident neoplasms in the vitamin group and 11 (1.3%) in the placebo group 
(difference, 0.1 percentage point [95%CI=0.8 to 1.3 percentage points]). No evidence 
suggested harm from vitamin therapy in any category of adverse events.  
 
Routine safety labs: Study staff will review all laboratory values, including safety labs 
and diabetes monitoring labs. Patients and their physicians will be informed when 
laboratory values are abnormal if, in the judgment of the research team, a change in 
medical therapy is warranted, or the abnormal laboratory value has diagnostic value of 
clinical importance. These procedures are covered in detail in the MOP. 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
Safety Labs and the TACT2 infusion regimen. 
The timing of safety labs is covered in section 6.1 (Schedule of Evaluations) 
 
Renal function. Edetate disodium is excreted by the kidneys, and the dose of edetate 
disodium administered is adjusted based on estimated creatinine clearance.46 There 
was no difference in renal function between groups at the end of 30 infusions in TACT. 
In TACT2, each assessment of serum creatinine will potentially lead to a change in total 
edetate disodium dose for the next series of infusions, with the following 2 “trigger 
points.” 
 
1. If estimated creatinine clearance is reduced by 25% or more compared with 
baseline, there will be a “lab delay” transmitted to the site and to the CCC and 
DCC. The site will be contacted and asked to review whether there have been 
medication or over-the-counter supplement changes as well as changes in 
clinical status that might account for a reduction in renal function, and the lab will 
be repeated. The dose of edetate disodium will be recalculated before re-
administration. This will be entered in the EDC system. 
2. If creatinine doubles or exceeds 2.5 mg/dL, whichever is lower, the site will be 
contacted and asked to review whether there have been medication or over-the-
counter supplement changes as well as changes in clinical status that might 
account for a reduction in renal function, and the lab will be repeated. Infusions 


TACT2 Protocol 
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28 
will be resumed when creatinine is <2.0 mg/dL and the edetate disodium dose 
recalculated at that time. This will be entered in the EDC system. 
 
Calcium levels. Edetate disodium chelates ionized calcium and can lead to 
hypocalcemia. In TACT, however, there was only one episode of symptomatic 
hypocalcemia leading to an Emergency Room visit. Calcium levels will be monitored, 
and if corrected calcium is between 8.0 mg/dL and 8.5 mg/dL, infusions will be 
administered over 4 hours, instead of 3 hours. If corrected calcium is below 8.0 mg/dL, 
there will be a lab delay, and infusions will be held until calcium is 8.0 mg/dL or higher, 
based on bi-weekly blood draws. This information will be entered in the EDC system. 
 
Metals labs 
The handling of the trace metals analyses and biorepository will be available in the 
MOP for each of these study units. If the lead or cadmium levels measured by the Trace 
Metals Laboratory are outside the upper boundaries for American Conference of 
Governmental Industrial Hygienists (ACGIH)47 (after a repeated measurement at the 
Trace Metals Laboratory) the clinical site and the CCC will be notified. In most cases, 
this will require repeating the levels in a commercial lab. If levels are still high, the 
participant will be recommended to contact their local public health department who will 
follow standard procedures for the evaluation of metal exposures. Because removal 
from exposure is the primary treatment, this should not interrupt the TACT2 infusions. 
The study sample is unlikely to have any such values. 
 
Clinical Assessments 
In TACT, the principal concern that emerged related to the weekly infusions of 500 ml of 
fluid and the potential precipitation of heart failure (HF). Patients are not eligible for 
TACT2 if they have had a hospitalization for heart failure in the 6 months preceding 
initial eligibility assessment. Nonetheless, like in TACT, in order to reduce ongoing 
patient risk, weight will be monitored at each infusion. If there is weight gain of 3 lbs or 
more since the last infusion, or 5 lbs or more since the screening evaluation, the patient 
will be evaluated for heart failure. A trained study coordinator or infusion nurse may 
perform this examination. If there is HF present, this will be entered into the EDC, the 
infusion delayed for 1 week, and a suitable treatment regimen developed with the 
patient’s clinical physician. 
 
7.3 
Adverse Events and Serious Adverse Events  
Adverse Event (AE) 
An adverse event is any undesired, noxious or pathological change in a patient as 
indicated by signs, symptoms, or laboratory changes that occur in association with the 
use of trial intervention/medication, whether or not considered drug or biologic related. 
This definition includes intercurrent illness or injuries, exacerbation of existing 
conditions, psychological events, psychosocial events, associated temporally 
associated with the use of a pharmaceutical product or study intervention. Pre-existing 
conditions, which worsen during a study, are considered adverse events and can 
become serious if they fulfil one of the seriousness criteria described below.  


TACT2 Protocol 
May 6, 2021 
29 
 
Note: Diseases, signs, symptoms, and/or laboratory abnormalities already existing at 
study admission are not considered adverse events when observed during the trial 
unless they represent an exacerbation in intensity or frequency. (Definition modified 
from ICH-E2B)  
 
Assessment of Adverse Event Intensity 
The intensity of an adverse event is an estimate of the relative severity of the 
experience made by the investigator based on his or her total clinical experience and 
familiarity with the literature. The maximal intensity reported during the evaluation period 
should be recorded. The intensity of adverse events will be characterized as mild, 
moderate or severe as follows: 
 
Mild 
Events are usually transient, require no special treatment, and do 
not interfere with the patient’s daily activities. 
Moderate 
Events usually introduce a low level of inconvenience or concern to 
the patient and may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures. 
Severe 
Events interrupt a patient’s usual daily activity and generally require 
systemic drug therapy or other treatment. 
 
Assessment of Causal Relationship 
A medically-qualified investigator must assess the relationship of any AE to the use of 
study drug, based on available information, using the following guidelines: 
 
1. Related – There is a reasonable possibility that the adverse event may have 
been caused by the study intervention 
2. Not Related – There is not a reasonable possibility that the adverse event may 
have been caused by the study intervention 
 
Adverse event collection and recording procedures must be designed to meet DSMB 
review and regulatory submission requirements, and ensure drug safety. 
 
Expectedness  
The expectedness of an adverse event or suspected adverse reaction shall be 
determined according to the most current investigator’s brochure or product label. 
“Expected” is defined as an adverse drug experience, the specificity and severity of 
which is consistent with the current investigator brochure or the risk information in the 
investigational plan. This term relates only to the drug, not the patient’s underlying 
condition. Any AE that is not identified in nature, severity, or specificity in the current 
study drug reference document(s) (e.g., investigator’s brochure) is considered 
unexpected. Events that are mentioned in the investigator's brochure as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug, but 
not specifically mentioned as occurring with the particular drug under investigation are 
considered unexpected. For example: Hepatic necrosis would be unexpected if the 


TACT2 Protocol 
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30 
investigational brochure or plan only referred to elevated hepatic enzymes or hepatitis. 
(Adapted from 21 CFR Part 312. 32) 
 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if it results in any 
of the following outcomes: 
 
1. Death 
2. Life-threatening 
3. Persistent or significant disability/incapacity, 
4. Requires or prolongs hospitalization 
5. Congenital anomaly/birth defect  
6. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious adverse events when, 
based upon appropriate medical judgment, they may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (Source CFR: 21 CFR 312.32) 
 
Laboratory Test Abnormalities  
For laboratory test abnormalities that meet the definition of an SAE, that required the 
subject to have the investigational product discontinued or interrupted or required the 
subject to receive specific corrective therapy, the clinical diagnosis rather than the 
laboratory term will be used by the reporting investigator (e.g., anemia versus low 
hemoglobin value). 
 
Life-Threatening 
Life-threatening refers to any adverse event that places the patient at immediate risk of 
death from the reaction as it occurred. It does not include a reaction that, had it 
occurred in a more severe form, might have caused death. (Source CFR: 21 CFR 
312.32) 
 
Requires or Prolongs Hospitalization 
A patient must be admitted to the hospital for a period greater than 24 hours, for the 
hospitalization to be considered a serious adverse event. Elective hospital admissions, 
scheduled prior to the study, are not considered serious adverse events unless the 
hospitalization is prolonged. Planned admissions (as part of a study), hospitalizations 
for less than 24 hours, hospitalization for an elective procedure, and Emergency 
Room/Department visits are not considered serious adverse events. Exception: Any 
disposition of the patient to the hospital or emergency room within 24 hours following 
study drug (infusion) therapy. 
7.4 
Reporting Procedures 
The SAE reporting flow chart will be included in the MOP. 
 


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31 
Protocol Specific Exceptions to SAE Reporting 
Specified outcome events in the study will be recorded in their respective appropriate 
modules of the eCRF. These events and specific corresponding symptoms will NOT 
require reporting as serious adverse events on the SAE eCRF. Specifically, the events 
covered in this exception are as follows: 
 
1. Myocardial infarction 
2. Stroke 
3. Coronary revascularization 
4. Hospitalization for unstable angina 
 
Serious Adverse Event Reporting  
The site investigator is responsible for monitoring the safety of participants enrolled into 
the study. All SAEs must be reported from the time of randomization through 30 days 
post final infusion, using the electronic data capture system. Non-serious adverse 
events will not be collected on the eCRF. All SAEs whether or not deemed drug-related 
or expected must be reported by the investigator or qualified designee within 24 hours 
of first becoming aware of the event. The investigator or qualified designee will enter the 
required information regarding the SAE into the appropriate module of the eCRF. If the 
eCRF system is temporarily unavailable, the event, including the investigator-
determined causality to study drug will be reported via the back-up paper SAE form to 
DCRI Safety Surveillance at 1-866-668-7138. Upon return of the availability of EDC 
system, the SAE information must be entered into the eCRF. 
 
Adverse events that are serious and drug (infusion) therapy related or result in death 
will be reviewed by the DCRI Safety Surveillance Department Medical Monitor to assess 
medical clarity and unexpectedness. DCRI Safety Surveillance will review all SAE data 
including all deaths, within 1-2 business days to: 
 
1. Ascertain seriousness  
2. Ascertain drug (infusion) therapy causal relationship 
3. Verify that all data are complete 
4. Follow-up with the site for incomplete data and/or data clarification. 
 
This will include, but will not be limited to, ensuring that serious criteria have been met 
and the SAE data received are reviewed, entered and coded using the MedDRA coding 
dictionary.  
 
DCRI Safety Surveillance will notify the study sponsors (NIH and TACT2 Principal 
Investigators from Mount Sinai and Duke Clinical Research Institute), and Data Safety 
Monitoring Board Chairman (DSMB)) in a blinded fashion, within 1 business day of 
receipt of the initial notification of the SAE, of: 
 All serious adverse events that are drug (infusion) therapy related – defined as 
taking place within 24 hours of an infusion, and attributed to the infusion by the 
site PI or by DCRI Medical Monitor, and/or  
 All SAEs resulting in death  


TACT2 Protocol 
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32 
 
The DCRI Safety Surveillance will provide the DCRI Regulatory Services with the event 
specific forms necessary to report the expedited adverse event according to country 
specific regulatory guidelines. This will include all deaths assessed by the DCRI Medical 
Monitor as warranting expedited reporting to the regulatory authorities and all adverse 
events that are serious, unexpected and drug (infusion) therapy related (as assessed by 
the site investigator, DCRI Medical Monitor and TACT2 study leadership).  
 
Procedures for Enhanced Reporting of Specific Adverse Events 
DCRI Safety Surveillance will also report specific adverse and/or serious adverse 
events, not otherwise eligible for expedited SAE reporting as in Section 7.2, within 2 
business days to the DSMB or its designee, and the NIH Program Officers. The adverse 
events for enhanced scrutiny include: 
 
1. 
Heart failure hospitalization during the entire infusion phase of the patient’s 
participation in the study, not otherwise subjected to expedited SAE reporting. 
2. 
Any disposition of the patient to the hospital or emergency room within 24 
hours following study drug (infusion) therapy, not otherwise subject to 
expedited SAE reporting.  
 
These events would not be eligible for expedited SAE reporting if the causality criterion 
were not met. Notification of these events will be made electronically. 
7.5 
Follow-up for Serious Adverse Events 
All reported SAEs will be followed until resolution, stabilization or until 60 days after the 
last patient enrolled in the trial completes the study drug (infusion) therapy. At the time 
of database lock, unresolved SAEs may be closed (final outcome assigned as 
“unresolved”) per the discretion of the DCRI Medical Monitor and/or the DCC PI. The 
site investigator will be responsible for reporting adverse events and unanticipated 
problems involving risks to subjects to their local IRBs/IECs in accordance with local 
regulations. 
7.6 
Safety Monitoring  
Data and Safety Monitoring Board 
TACT2 will have an independent DSMB appointed by and reporting to NIH. The DSMB 
will be expected to meet with the study leadership at least 2 times per year to review 
study progress and overall safety. For ethical reasons, an interim examination of key 
safety and endpoint data will be performed during the course of the trial. A separate 
DSMB charter outlining the operating guidelines for the committee and the protocol for 
evaluation of data will be created prior to study enrollment and agreed upon during the 
initial meeting of the DSMB.  
 
 


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33 
8. INTERVENTION INTERRUPTION  
Reasons for Withdrawal/ Interruption 
There may be reasons for subject withdrawal and/or interruption of the study infusions 
and/or OMVM. 
 
Some possible reasons are: 
 
 Died 
 Lost to follow-up  
 Informed consent withdrawal  
 
Subject adherence and retention strategies will be included in the site personnel 
training. Site personnel will be encouraged to have weekly communications with 
enrolled subjects as a means of continued participation. The site investigator should 
make every attempt to accommodate the subject to continue the therapy where feasible 
and encourage subject to allow follow-up by the DCRI Call Center.  
  
Withdrawal Procedures 
Site study personnel must immediately communicate, with the CCC PI, all information 
from subjects that express desire to stop study treatment (either infusions or OMVM), 
follow-up or withdrawing informed consent. When all attempts by the site study 
personnel to accommodate the subject are unsuccessful, the final disposition of a 
subject withdrawal from study treatment and/or follow-up will require approval by the 
CCC PI. See the MOP for details. 
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
Analysis of the TACT2 2x2 factorial trial will be based on intention to treat (ITT). That is, 
participants will be analyzed (and endpoints attributed) according to the treatment 
strategy to which participants are randomized, regardless of subsequent additional post-
randomization treatment and medical care. Statistical comparisons will be performed 
using two-sided significance tests. Treatment dropouts and consent withdrawals will be 
tracked by verifiable means within the eCRF at each follow-up interval. Baseline 
demographic and clinical variables will be summarized for each randomized arm of the 
study. Descriptive summaries of the distribution of continuous variables will be 
presented in terms of percentiles (e.g., median, 25th and 75th percentiles) along with 
means and standard deviations. Categorical variables will be summarized in terms of 
frequencies and percentages. 
9.2 
Sample Size and Randomization 
Participants will be randomized in a 1:1:1:1 allocation ratio using simple randomization. 
The study was originally designed to enroll a total of 1200 participants with a minimum 
follow-up of 12 months. The DSMB conducted a blinded review of enrollment aggregate 
event rates, and projected event rates in July 2019. Following this blinded review, the 


TACT2 Protocol 
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34 
DSMB recommended a reduction in the target sample size to 1100 participants and an 
increase in the minimum follow-up from 1 year to approximately 2.5 years. Due to 
slowed enrollment related to the COVID-19 pandemic, in the fall of 2020, the DSMB and 
the NIH leadership agreed to a proposal to complete enrollment by 12/31/2020 with an 
allowance to follow the study participants until there are enough primary endpoint 
events to maintain 85+% power. 
 
Several design factors and research objectives have been considered in developing an 
appropriate sample size for the TACT2 study. First, patient enrollment and follow-up has 
been determined so there would be a sufficient number of endpoints to provide a high 
degree of confidence for testing the primary hypothesis. Second, the statistical power 
for secondary endpoints has been considered. Finally, the sample size has been 
determined to provide a reasonable level of confidence for detecting clinically important 
differences in outcome between treatment strategies even if current projections of event 
rates and hypothesized differences in clinical outcomes between the treatment groups 
prove to be optimistic. 
 
Table 3 shows the required number of endpoint events to have 80% to 90% power with 
hazard ratios varying from 0.50 to 0.75. The two factors (EDTA chelation and OMVM) 
are assumed to be additive for the sample size calculations. Based on TACT we 
anticipate a hazard ratio of 0.70 (active chelation vs. placebo chelation) to determine the 
sample size requirements. This hazard ratio assumption is very conservative compared 
to the observed effect in TACT. Assuming a two-sided 0.05 type I error rate and 
approximately 5% consent withdrawal or loss-to-follow-up per year, the final sample 
size of 1000 participants will provide approximately 85% power to detect a hazard ratio 
of 0.70 for the primary endpoint of time to all-cause mortality, myocardial infarction, 
stroke, coronary revascularization, or hospitalization for unstable angina comparing 
active chelation vs. placebo chelation. 
 
Table 3. Required number of events 
 
HR=0.50 
HR=0.55 
HR=0.60 
HR=0.65 
HR=0.70 
HR=0.75 
80% 
power 
65 
88 
120 
169 
247 
379 
85% 
power 
75 
100 
138 
194 
282 
434 
90% 
power 
87 
118 
161 
226 
330 
508 
Calculations performed using nQuery 7.0 and assume a 0.05 type I error rate (two-sided) with 1:1 
randomization. 
 
For other exploratory endpoints, we outline a general power justification for 
comparisons to be made among the four arms of the 2x2 factorial design. We anticipate 
that roughly 1000 participants will have blood and urine samples available from baseline 
and one or more follow-up time points. A sample size of 250 participants per group will 
provide 80% or greater power for any between group differences greater than ¼ of a 
standard deviation. These calculations are based on a two-sample t-test and assume a 
two-sided type I error rate of 0.05. 


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35 
9.3  
Definition of ITT Population 
The ITT population will correspond to all randomized participants. The primary and 
secondary analyses will follow the ITT principle.  
9.4 
Interim Analyses and Stopping Rules 
For ethical reasons, interim examinations of key safety and process data will be 
performed at regular intervals during the course of the trial. It is anticipated that the 
DSMB will meet at 6-month intervals to review the accumulating data. Prior to 
performing interim analyses, aggregate event rates will be assessed to compare 
predicted vs. actual event rates. The DCC will create regular reports to track patient 
enrollment reports, rates of adherence with the assigned treatment strategy, and 
frequency of protocol violations. Prior to each meeting, the data coordinating center will 
conduct any requested statistical analyses and prepare a summary report along with the 
following information: patient enrollment reports, rates of adherence with the assigned 
treatment, and description of SAEs (statistical comparisons of the randomized arms with 
respect to these SAEs will use chi-square or other appropriate 2-sample or >2-sample 
methods). Safety data will be reported by all 4 treatment groups as well as active 
chelation vs. placebo chelation and active OMVM vs. placebo OMVM. The DSMB will 
review data partially masked by study group (such as X vs. Y and not active chelation 
vs. placebo chelation).  
 
Safety reports will be prepared for the DSMB approximately once every 3 months. 
Futility and efficacy monitoring will focus solely on the active chelation vs. placebo 
chelation comparison. The DSMB will review the active OMVM vs. placebo OMVM data 
for safety purposes only. 
 
For futility monitoring, TACT2 will employ a modification of the inefficacy monitoring 
guideline of Freidlin, Korn, and Gray48 to stop the trial if the chelation strategy is not 
beneficial. We plan to use a conservative boundary, denoted as LIB0, along with a harm 
look at 25% of expected information. This approach will include 4 interim looks 
scheduled at roughly 25%, 40%, 60%, and 80% of expected information. With the 
proposed design, a total of roughly 280 primary endpoint events are expected and the 
first interim review for futility and efficacy will be scheduled after approximately 70 
primary endpoint events have been observed. The harm look at 25% of expected 
information would suggest stopping the trial if the data suggests harm for the chelation 
strategy vs. the placebo chelation with p-values <0.05 for both the primary outcome and 
the all-cause mortality endpoint. For the interim reviews at 40%, 60%, and 80%, the 
inefficacy guideline suggests stopping the trial if the chelation infusion strategy has a 
hazard ratio > 1.0 compared to placebo for both the primary outcome and the all-cause 
mortality endpoint. This inefficacy monitoring approach will result in a trivial loss of 
power and requires no sample size adjustment.  
 
The method of Haybittle and Peto49,50 will be proposed as the primary guide for 
interpreting interim efficacy analyses. The timing of the interim efficacy analyses will 
correspond to the futility monitoring reviews (i.e. at roughly 25%, 40%, 60%, and 80% of 
expected information). The proposed efficacy monitoring guideline requires large critical 


TACT2 Protocol 
May 6, 2021 
36 
values (Z=3, p≤0.001) for every assessment until the planned final analysis. The TACT2 
investigators suggest that both the primary outcome and the all-cause mortality 
outcome are evaluated at the interim reviews with a focus on the comparison of active 
chelation vs. placebo.  
 
The CCC PI, DCC PIs, CCC staff, clinical study Co-PIs, site investigators, NIH Program 
Staff and study participants will remain blinded until database lock. Limited staff will be 
unblinded to handle randomization codes, deliver the interventions to sites, and prepare 
DSMB reports. The statistical staff responsible for preparing DSMB reports will not 
directly interact with the clinical team that delivers care to the study participants or the 
CEC that determines clinical events. 
 
9.5 Outcomes  
9.5.1 Primary Outcome  
The primary outcome is the time to the first occurrence of all-cause mortality, 
myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable 
angina. 
9.5.2 Secondary Outcomes  
The three secondary outcomes of TACT2 are: 
  
 the overall rate of events due to all-cause mortality, myocardial infarction, stroke, 
coronary revascularization, or hospitalization for unstable angina events 
  
 the time to the first occurrence of cardiovascular mortality, recurrent myocardial 
infarction, or stroke 
 
 the time to all-cause mortality 
 
The TACT2 CEC will review all primary and secondary endpoints.  
9.6 
Data Analyses  
Primary Endpoint Analysis 
The primary objective of TACT2 is to determine if the chelation-based strategy 
increases the time to composite of all-cause mortality, myocardial infarction, stroke, 
coronary revascularization, or hospitalization for unstable angina compared to the 
placebo chelation strategy. The statistical comparison will be based on the time from 
randomization to the first occurrence of all-cause mortality, myocardial infarction, stroke, 
coronary revascularization, or hospitalization for unstable angina. The Cox proportional 
hazards regression model will be used to assess outcome differences between the 
treatments. An initial Cox model will include indicator variables for the active chelation 
and active OMVM groups, an interaction term for the active chelation and active OMVM, 
age, sex, and use of insulin. If the interaction term for the active chelation and active 
OMVM is not statistically significant at the two-sided 0.05 level, the primary analysis will 
be based on a Cox model which includes indicator variables for the active chelation and 


TACT2 Protocol 
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37 
active OMVM groups, age, sex, and use of insulin. The chelation treatment effect will be 
summarized using hazard ratios and associated 95% confidence intervals. In addition to 
the statistical hypothesis testing, Kaplan-Meier51 survival estimates will be constructed 
based on the time from randomization to the first primary event occurrence. 
 
The OMVM treatment effect from the Cox model will be estimated using the Cox model 
described above. Given the results of TACT and the focus on chelation therapy, the 
interpretation of the OMVM treatment effect will be considered exploratory. 
Assessment of the proportional hazards assumption will be evaluated using visual 
analysis (of the survival and log {-log (survival)} functions), as well as tools within the 
“proportionality test” statement of Proc Phreg in SAS. 
 
Secondary Endpoint Analysis 
The analyses for the time-to-event secondary endpoints will be similar to those outlined 
for the primary endpoint using the time from randomization through the first occurrence 
of any component of a specific secondary endpoint (or censoring) as the response 
variable, and assessing group differences using the Cox proportional hazards model. 
The effect of the chelation treatment strategy vs. placebo chelation on these time-to-
event secondary endpoints will be summarized using hazard ratios (with associated 
confidence intervals) computed from the Cox model. Kaplan-Meier curves will be 
constructed to display the cumulative event rates of the treatment groups.  
To test the individual treatment strategies against the placebo chelation – placebo 
OMVM group, we will add three indicator variables to the Cox proportional hazards 
model described above. 
 
Recurrent event analyses encompassing the overall event rate of endpoints for 
each patient.  
The components of this endpoint will include all-cause mortality, myocardial infarction, 
stroke, coronary revascularization, or hospitalization for unstable angina events. We 
plan to analyze this endpoint using two statistical techniques. The two approaches are: 
  
a) A generalization of the Cox model to handle recurrent events, developed by 
Anderson & Gill, with robust standard errors to account for heterogeneity.52,53 
b) A marginal modeling approach developed by Wie, Lin, and Weissfeld.54 
 
The Anderson-Gill approach will be considered the primary analysis for the total number 
of all-cause mortality, myocardial infarction, stroke, coronary revascularization, or 
hospitalization for unstable angina events endpoint. 
 
Exploratory Endpoints 
The comparison of costs will test mean direct medical costs incurred during the study 
(index infusion through end of follow-up). To account for staggered entry and 
incomplete follow-up, costs will be adjusted using the approach of Bang and Tsiatis.55 
Statistical comparisons will be made using a normal approximation with standard errors 


TACT2 Protocol 
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38 
estimated using the bootstrap approach. The probability of differences in cost greater 
than thresholds of policy interest (such as $1000, $2000, or $5000) will be calculated. 
Differences in cost by treatment group will be interpreted in the context of the trial 
clinical results, looking for both consistency and plausibility. Follow-up costs will be 
presented both overall and by category (e.g., inpatient readmission, outpatient 
procedures, concomitant medications, non-acute institutional care). Cumulative costs 
over the study period between treatment groups will be compared. Descriptive 
comparisons of cost according to clinical variables defining subgroups of interest will 
also be performed. 
 
The analyses for toxic metals in blood and urine in the TACT2 population will proceed in 
three phases. First, we will evaluate if the chelation regimen has the effect on metal 
internal dose that we have postulated. To do this, we will compare body metal levels 
(lead in blood, pre-chelation urine lead and cadmium, and post-chelation urine lead and 
cadmium, in separate analyses) between active and placebo chelation groups at 
baseline and over the treatment phase of TACT2. Second, we will relate those levels to 
changes in the primary clinical endpoint (a composite of death from any cause, 
recurrent MI, stroke, coronary revascularization, or hospitalization for unstable angina) 
caused by chelation therapy relative to placebo. Finally, we will perform the exploratory 
analyses described below.  
 
Over the 1-year period, we hypothesize there will be no change in metal levels in the 
placebo chelation group and significant reductions in the active chelation group. We 
also postulate these patterns of change in metal levels will explain, in a statistical sense, 
the clinical benefits we expect to see in TACT2 (the way LDL-cholesterol level lowering 
“explains” the benefits of statin therapy) using three complementary analytic 
approaches: 1] prespecified subgroup analyses (patients in the highest tertile of blood 
lead, urine cadmium, and post-chelation urine lead and cadmium at infusion 1, will show 
significantly larger treatment benefits (chelation vs. placebo) than patients with lower 
baseline levels), 2] landmark analyses (patients in the chelation arm with lower metal 
levels after 40 infusions/1 year of chelation will show significantly larger clinical benefits 
than patients with higher levels), and 3] we will apply causal inference modeling to 
evaluate whether the pattern of metal changes (lead in blood and cadmium in urine) in 
the chelation arm over the treatment period of TACT2 statistically “explains” the 
variation in clinical outcomes responsible for the hypothesized superiority of the 
chelation strategy.  
 
We will also do exploratory analyses to examine the clinical implications of different 
patterns of metal removal over time on the benefits of chelation therapy (can metal 
levels be used as a biomarker to guide the number of chelation sessions needed to 
maximize clinical benefit from this therapy?) and to examine the effects of the oral 
multivitamin/mineral treatment regimen versus placebo vitamins on metal levels and on 
the effectiveness of chelation in reducing those levels (does the TACT2 vitamin regimen 
augment the ability of the chelation regimen to remove metals, or might there be a 
different mechanism of action altogether?). The latter case could be inferred if there 
were clinical benefits of OMVM, but no changes in lead and cadmium levels. 


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39 
 
Subgroup Analyses 
To examine the heterogeneity of the treatment effect, subgroup analyses for the primary 
and secondary endpoints will be performed in order to explore whether the treatment 
effect is consistent across subgroups. Subgroup analyses to evaluate variation in the 
effect of treatments will be performed using interaction terms within the Cox proportional 
hazards model. For binary variables, we will include the subgroup factor as a 
stratification variable within the Cox regression model. This model structure will 
decrease the reliance on the proportional hazards assumption. Additionally, treatment 
effects within each categorical subgroup will be examined separately using Cox 
proportional hazards models. Event rates by treatment and HRs with 95% confidence 
intervals will be reported for each subgroup. Forest plots will be generated displaying 
the estimated hazard ratios and 95% confidence intervals for each subgroup. For 
subgroups defined using continuous variables, the analysis based on the continuous 
form will be considered primary but for display purposes these variables can also be 
categorized.  
 
We have pre-specified sex, minorities, age greater than 70, myocardial infarction 
location (anterior MI or not), type of diabetes (1 or 2), insulin treatment of diabetes, use 
of statin therapy at baseline (for the OMVM analyses only), known peripheral artery 
disease at baseline as key subgroups of interest. There are also pre-specified analyses 
by tertiles of lead and cadmium as indicated above. The examination of these pre-
specified subgroups will include formal tests of interaction within the Cox regression 
model. 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
A validated Electronic Data Capture (EDC) system will be used for this study. The 
majority of the study data will be transcribed by study personnel from the source 
documents onto an eCRF and transmitted in a secure manner to the DCC. All data 
relating to the study must be recorded in eCRFs developed by DCRI and approved by 
the study sponsor. Data must be entered into eCRFs in English. The investigator’s 
electronic signature, a compliant platform (21 CFR Part 11) is recorded in the database 
as verification that all data are complete and accurate.  
10.2 Data Management  
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
 
Computerized data will be accessible only by password, and a centralized monitoring 
system will record and report all access to data. The DCRI computer network is 
protected by a firewall. Electronic CRFs (eCRFs) will be identified by study number only, 
to ensure participant anonymity. No participant identifiers will be used in the 
presentation of data. Except when required by law, participants will not be identified by 
name, personal identification number (e.g., social security number in US and Canada, 


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40 
address, telephone number) or any other direct personal identifier in study records. This 
information will be retained by each individual center and will not be disclosed to the 
Clinical or Data Coordinating Center except as needed for centralized clinical, quality of 
life and economic follow-up of the participants. Participants will be informed that the 
study physician and his/her study team will report the results of study-related tests to 
the Clinical and Data Coordinating Center and to the NIH. Participants will be informed 
that their records may be reviewed in order to meet federal, state or regional/local 
regulations. Reviewers may include the CCC/DCC monitors, IRBs/ECs, the NIH, other 
government regulators as dictated by local law, or their delegates. 
 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study 
product, regulatory documents, and other sponsor correspondence pertaining to the 
study must be kept in the appropriate study files at the site. Source documents include 
all recordings and observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study. These 
records will be retained in a secure file for the period required by the institution or site 
policy. Prior to transfer or destruction of these records, the DCC must be notified in 
writing and be given the opportunity to further store such records. 
 
10.3 
Quality Assurance  
Greater detail will be found in the MOP for the TACT2 and the individual Manuals for the 
Metals Lab and Biorepository. Steps to be taken to ensure the accuracy and reliability of 
data include: 
 
 
 the selection of qualified investigators and appropriate study centers. 
 
 review of protocol procedures with the investigator and associated personnel 
before the study. 
 
 periodic monitoring visits to clinical sites, central pharmacy, metals lab, and 
biorepository.  
 
 written instructions will be provided for collection, preparation, and shipment of 
blood and plasma samples. 
 
 electronic CRF completion guidelines will be provided and reviewed with study 
personnel before the start of the study. 
 
 The DCRI CRA will review eCRFs for accuracy and completeness during site 
monitoring; any discrepancies will be resolved with the investigator or designee, 
as appropriate. 
 
At regular intervals, all data will be transferred from the EDC database to SAS for 
statistical summarization, data description, and data analysis. Further cross-checking of 


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41 
the data will be performed in SAS, and discrepant observations flagged and 
appropriately resolved through a data query system.  
 
10.3.1 Training 
Training procedures will be described in the MOP. Site training, in particular, will be 
provided via in-person study meetings as well as online training. 
 
10.3.2 Quality Control  
The Data Coordinating Center will perform internal database quality-control checks, and 
data audits throughout the course of the trial, as well as coordinate blinded repeat 
metals analyses in a statistically valid proportion of samples. 
 
10.3.3 Metrics 
The Clinical Events Committee at the Brigham and Women’s Hospital will adjudicate all 
components of the primary endpoint except for coronary revascularization. Coronary 
revascularization will be clinically confirmed by the Clinical Events Committee.  
 
10.3.4 Protocol Deviations 
Documentation and management of protocol deviations will be the responsibility of the 
DCRI Site Management team. Incidences identified will be discussed with the site 
investigator and study team for corrective action and follow-up with their IRB.  
 
10.3.5 Monitoring 
The DCRI Site Management team will be responsible for: 
 
 verifying that the appropriate assurances and certification of training in the 
protection of human subjects are in place prior to the initiation of any protocol. 
 
 providing education to all site staff regarding the conduct of clinical studies 
according to good clinical practices. 
 
 assisting sites in the development of informed consent templates to make sure 
that they contain appropriate elements. 
 
 ensuring that the CRA monitors each site according to the approved 
comprehensive monitoring plan. 
 
 assuring during the site initiation visit that the site has adequate facilities/staff 
integral to the successful operation of the study. The site initiation visit may also 
be utilized to conduct training regarding regulatory compliance or individual 
protocol procedures. 
 


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42 
 tracking recruitment of patients entered updating relevant trial information on the 
trial web site. 
10.4 Medical Information Coding 
For medical information, the following thesauri will be used: 
 
 Latest version of MedDRA for adverse events, and 
 World Health Organization Drug Dictionary for concomitant medications. 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
All TACT2 sites will submit the study protocol, informed consent form, and other study 
documents to their corresponding IRB for approval. Any amendments to the protocol, 
other than minor administrative changes, must be approved by each IRB before they 
are implemented.  
 
11.2 Informed Consent Forms 
TACT2 sites will obtain informed consent from each study participant prior to 
randomization. Trained personnel as listed in the Delegation of Authority log will obtain 
consent. In all cases in which the patient does not have an understanding of English, 
sites will obtain an IRB approved translation of the study consent to present to the 
patient. Patients will have ample opportunity to review the consent form, ask questions, 
and make an informed decision on risks and benefits. 
11.3 Participant Confidentiality  
Overall policy: Any data, specimens, forms, reports, video recordings, and other records 
that leave the site will be identified only by a participant identification number 
(Participant ID, PID) to maintain confidentiality. All records will be kept in a locked file 
cabinet. All computer entry and networking programs will be done using PIDs only. 
Information will not be released without written permission of the participant, except as 
necessary for monitoring by IRB, the FDA, the NCCIH, and the OHRP. 
 
Exceptions to the policy: 
1. The Study Pharmacy, following standard regulatory procedures, will deliver a -
specific prescription for each study infusion. As such, they will know PHI for each 
patient. The PHI for each patient will be kept in a secured pharmacy computer, 
behind a firewall, and will be known to a minimum number of pharmacy 
personnel. 
2. The DCRI Call Center will make the initial patient follow-up by phone. As such, 
they will need to know PHI including patient name, next-of-kin, etc. Again, this 
information will be kept secured in the DCRI Call Center. 


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43 
11.4 Study Discontinuation  
Procedures for study discontinuation will be detailed in the TACT2 MOP.  
12. COMMITTEES 
 
The Steering Committee 
The main governing body and decision-making committee for the trial and assumes 
overall responsibility for the design, quality control, and conduct of the study. All major 
scientific decisions will be discussed with the Steering Committee. The Steering 
Committee will review the baseline characteristics and pooled event rate after 70 
primary endpoint events have occurred. The Steering Committee will determine whether 
the patient population or sample size needs to be modified. 
 
Executive Committee 
The Executive Committee is advisory to the Steering Committee and is responsible for 
objective evaluation for the course of the trial, design and conduct. Recommendations 
for all scientific decisions will be made to the Steering Committee.  
 
Biorepository Committee 
This committee will coordinate communication between Columbia University, the CDC 
and DCRI on aspects related to sample collection, shipments and laboratory analysis 
(for metals); keep track of shipments (both specimen collection kits and samples) and 
samples collected, received, processed, stored and analyzed (for metals); troubleshoot 
any problems as they arise and report to the TACT2 operations committee. 
 
Operations Committee  
This subcommittee of the Steering Committee will provide oversight for the day-to-day 
progress of the study. 
 
Publications, Presentations and Ancillary Studies (PPAS) Committee 
The objectives of this committee will be to facilitate timely dissemination of study 
findings, maintain high scientific standards for published material, prioritize the order of 
publication and presentations, and ensure equitable investigator participation and 
attribution of authorship. The committee will ensure publications are well-aligned with 
the trial’s research agenda and are not redundant. The PPAS committee will review all 
proposals for data analysis, as well as research abstracts, presentations, and 
manuscripts before submission. The committee will also review proposals for ancillary 
studies. The committee will also ensure that each publication that meets NIH Open 
Access criteria is deposited in PubMed Central. 
 
Committee for the Recruitment of Women and Minority Subjects 
Recruitment of women and minority subjects is a critically important part of developing a 
clinical trial whose results can be generalized to the overall US population. The TACT2 
leadership has therefore constituted a committee of experts to assist in enhancing 
recruitment of women and minority subjects. They will report to the Steering Committee 


TACT2 Protocol 
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44 
with suggestions as to how to increase the enrollment of women and minorities. Some 
of these activities are covered earlier in this document. 
 
Data-Driven Trial Management Committee 
The objectives of this committee will be to:  
 review the established mapped key risk indicators and triggers (thresholds) 
 modify the risk levels where indicated 
 document actions taken and results 
 provide summary report of findings by subject, site, and study levels to study 
leadership. 
13. PUBLICATION OF RESEARCH FINDINGS  
Publication of the results of this trial will be governed by the policies and procedures 
developed by the Steering Committee, and the PPAS Committee. Both Committees will 
have NIH scientists as members. Any abstract, manuscript or major presentation will be 
made available for review by NIH, in accordance with NIH policies, prior to submission. 
Per NIH policies, a public data set that is not identifiable will become available when the 
study has been completed. 
 
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