Trial to Assess Chelation Therapy (TACT)
Mount Sinai Medical Center

4300 Alton Road

Butler Building
Miami Beach, FL 33140
Tel: 305-674-2162 Fax: 305-674-3970
TACT @msmc.com /

The following modifications and clarifications were made to the TACT protocol dated May 30, 2003.

Page #;
Section #
(Version 5/30/03) / Description of Change
Throughout / Ensured all references to the TACT Principal Investigator were worded in this manner specifically.
Throughout / Removed Charles H. Hennekens, MD, DrPH as Co-Principal Investigator.
Throughout / Removed Danielle Hollar, PhD as Project Director.
Throughout / Deleted “PI” and replaced with “Principal Investigator” for all references to Principal Investigators.
Throughout / Corrected the title of the NHLBI Program Officer.
Throughout / Corrected the title of the NCCAM Program Officer.
Throughout / Changed title to “Project Director” from Danielle Hollar, PhD.
Throughout / Changed version date in all headers and ensure page numbers exist on all pages
Throughout / Deleted “Trial Co-Manager(s)” and replaced with “Clinical Manager.”
Throughout / Deleted “Senior” and replaced with “Site” for all references to Site Investigators.
Throughout / All references to clinical Site Investigators have been made consistent. The correct title used is “Site Investigator.”
Throughout / Project Co-Directors has been deleted because this trial role no longer exists.
Throughout / Appendix and page numbers were updated
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2.0 / Modifications were made to this section to clarify the following:
  • Low-dose supplements are provided during infusion period only.
  • Patients will take either high-dose supplements or high-dose supplement placebos.

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1.2.3 / Corrected the spelling of Knudtsen to “Knudtson”
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2.1 / “We will enroll 2372 patients 50 years of age or older with a prior myocardial infarction. Following baseline assessments, patients will be randomly assigned to receive 40 infusions of either the chelation or placebo solution, administered as 30 weekly infusions followed by 10 infusions administered 2-8 weeks apart. Following the infusions, patients will be followed an average of 2.5 yearsup to an additional 32 months. All patients will receive low-dose vitamin supplementation to replete chelation losses during the infusion period only. In this 2x2 factorial design, each of these groups also will be randomized to either high-dose supplements or high-dose supplement placeboslow-dose supplements as shown in diagram below. If both therapies are effective, This factorial design will permit the estimation of the contribution of high-dose supplementationto the overall effect. All patients will be followed for clinical events until the end of the trial. The results of TACT will provide either a significant positive result or an informative null or negative result upon which rational clinical decision-making and health policy can be based.”
The figure below this paragraph was modified to clarify treatment groups. In addition, the number of patients in each group was added
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3.2
(Figure 2) / Changed number of Clinical Units to “up to 150 Sites.”
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3.3 / Added “Clinical Manager” role to Figure 3 and deleted Danielle Hollar’s name.
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3.3 / The following statement was modified to explain that “Study Staff” includes consultants. In addition, names of study staff were deleted and only staff titles are included.
“A Project Director and Study Staff, including consultants, will assist Dr. Lamas in coordinating TACT.”
The following statement was modified because trial progress reports are submitted weekly in preparation for the weekly Operations Committee calls: “ Dr. Lamas will submit quarterly detailed recruitmentprogress reports to the NCCAM Project Officer and the NHLBI Project Officer. Trial progress reports will be given during TACT Operations meetings.”
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3.3 / Added clarification regarding the unblinding of individuals when necessary.
“In order to preserve the blinded nature of the trial, two physician Research Associates have been identified. These Research Associates will approve all prescriptions and deal with any items brought up by pharmacy that may require unblinding information. The Research Associates will not have any role in clinical patient management and recruitment at Mt. Sinai Medical Center or other clinical units. Prior to beginning this position in TACT, the Research Associates will undergo protocol training.”
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3.4 / The following clarification was made: “The Data Coordinating Center (DCC, Dr. Kerry Lee) is responsible for the treatment allocations of eligible patients, receipt and processingreview and monitoring of all data collected by the Clinical Sites and Central Units except economic data, quality control programs, and analysis of all study data except economic and quality of life data.”
Because the DCC does not visit sites prior to activation the following section was deleted.
“The DCC will also visit selected sites prior to site activation to ensure resources to carry out the trial are present. DCC will visit all sites in the trial.” “The DCC will visit all sites annually during the course of the trial.”
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3.6 / Because Accu-Care Services Pharmacy does not notify the DCC when safety labs are not received or have reached predefined alert values, the DCC was deleted from this section:
“suspend shipment and notify DCC and the CCC when safety labs are not received, or have reached predefined alert values”
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3.7 / A clarification about TACT Laboratory Services was added:
“providing the clinical sites with blood collection supplies and pre-printed ordering requisition forms”
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3.8 / “The clinical sites will play a major collaborative role with the CCC in the recruitment, retention, and drug administration efforts in TACT. We estimate that 120 up to 150 clinical sites will be sufficient to enroll 2372 eligible patients over 36 months.”
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3.7 / Added statement of clarification regarding processing of CardioCRP results:
“processing all labs within 48 hours of drawing (except high sensitivity C-reactive protein).”
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4.0 / A clarification was made about what will happen if the internet is unavailable “In the unlikely event that internet access is transiently unavailable at the clinical site (due to power failure, for example), the clinical site will be instructed to call the CCC, and data will be entered from the CCC into the internet-based system.
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5.1 / The TACT Project Director, TACT Clinical Manager, and Data Coordinating Center Project Leader were added as ex-officio non-voting members of the Steering Committee.
The following statement was modified because it may be necessary for Steering Committee members to participate in other activities over the course of the study.
“Each Steering Committee member will be expected to participate in all other Steering Committee activies, e.g., conference calls, special subcommittees, and others, as may be necessary.”
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5.2 / The TACT Project Director was added as a member of the Executive Committee.
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5.2 / The following statement was deleted from this section because weekly reports are provided during the weekly Operations Committee calls:
The TACT Principal Investigator, the Principal Investigator of the DCC, and the Principal Investigator of EQOL will update the recruitment progress of each center and of the whole trial bimonthly for the Executive Committee.
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5.4 / The Administrative Coordinator was removed from the Operations Committee. The Project Leader of the DCC was added to the Operations Committee.
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5.5 / The public information committee was deleted from the protocol because the functions of the committee are being met by other TACT committees and other activities carried out by the TACT management team. In addition, more effective methods of addressing the cardiology community have been planned, such as publishing a design paper.
The statement, “6 lay representatives with special interest in cardiac care and complementary medicine,” has been deleted from the section because these representatives do not participate on the Public Information Committee.
195.7 / The Databank and Ancillary Studies, Presentations, and Publications Committee members were modified. Two Consultants were replaced by at least one chelation consultant.
Additionally, the last sentence was modified to the following: “During the first meeting, The Committee will develop operational policies to be reviewed and approved by the Steering Committee.”
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5.7 / The TACT Principal Investigator will Chair the Databank and Ancillary Studies, Presentations, and Publications Committee.
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5.7 / The TACT Project Director was added as a member of the Databank and Ancillary Studies, Presentations, and Publications Committee.
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6.1.1 / The statement “(See Appendix 2A for a prototype HIPAA compliant informed consent form)” was added because it was missing from last few versions of the protocol.
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6.1.1.1 / The phrase, “(Hawaii, etc.),” was deleted because it was not needed.
The words, “the JNMA,” were deleted because the name was spelled out instead.
The bullet point stating, “ Develop a public interest section on the TACT web page including a Spanish-language information section,” was deleted because the budget does not allow for a special Spanish-language information section.
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6.1.3 / The following clarification was added about patients who are allergic to heparin. “Patients with known heparin allergy may be enrolled, as heparin will be omitted from the chelation solution.”
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6.1.3 / Inability to tolerate the weekly fluid load (500cc of normal salinefluids).
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6.1.5 / The following clarification was added to the statement, “Next, the Site Coordinator will log on toand complete the randomization screenin the Trial Master System.”
The following statement was deleted because the EDC system does not provide tracking of screened patients. Each site maintains a list of all patients screened. “The DCC will track the number of screen failures for each site.”
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6.2 / The following was added to the list of additives:
QS with sterile water to 500ml
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6.2 / The following editorial changes were made to the following statement:
“If there is any upward change in creatinine, but not enough to reach the threshold for withholding an infusion, the AccuCare Services Pharmacy will adjust downward the EDTA content of the infusion will be adjusted downward according to estimated creatinine clearance.”
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6.2.1 / The following editorial clarifications were made to the following statement: “EDTA (calcium disodium) is approved by the FDA for the treatment of lead poisoning and EDTA (disodium) is also used to treat hypercalcemia”
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6.2.1 / The following editorial changes were made, “In Appendix 4, we present the EDTA dosing regimen and renal adjustments for lead toxicity and hypercalcemia in TACT.”
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6.2.1.2.11
6.2.1.2.12 / The section numbers were modified to 6.2.1.211 for Pregnancy and 6.2.1.2.12 for Miscellaneous
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6.2.1.5 / The following editorial clarification was made to the following statement “The peer-reviewed literature includes case series and case reports of chelation therapy for CVD as well as for lead poisoning for which EDTA (calcium disodium) was approved by the FDA”
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6.2.3 / All patients will receive the low-dose vitamin and mineral regimen that repletes any chelation-related losses during the infusion period only.(information about high-dose regimen was moved to subsequent section) The low-dose regimen includes 1 pill containing the following ingredients in an olive oil base, to be taken once daily:
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6.2.3 / A clarification of treatment period for high-dose vitamins and placebos was added to the following statement: “Patients assigned to the high-dose regimen will receive the high-dose vitamin and mineral supplements listed below, or high-dose vitamin and mineral placebos. The high dose regimen consists of 3 pills containing the following ingredients, to be taken twice daily during the infusion and follow-up periods:”
The following was added to the chart “Total amount for 6 pills ” to clarify the amount of substances contained in the high dose regimen.
In the chart, the daily value of manganese was changed from 1000% to 400% because the incorrect value for the RDA (recommended daily allowance) of manganese was initially used in the calculation. Instead of the correct RDA value of 5 mg, the value that was used in the calculation was 2 mg.
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6.2.5 / “In this case, the 10 maintenance infusions will be administeredover 48 weeks,on an every 5 week schedule2-8 weeks apart. The DCC will provide an infusion schedule for each patient upon randomizationa vist scheduler to facilitate scheduling infusion visits.”
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6.2.7 / The table with TACT data collection points was modified. The row containing “Adverse Event and Endpoint Assessment” was modified to clarify Data Collection Points. The revised data collection points are “Adverse Event Assessment” and “Endpoint Assessment.” Additionally, The row titled Data Collection Points was modified because the visits may not exactly be bimonthly and the final infusion may not be at exactly 28th months. Also, in the row entitled “EQOL Questionnaire “*DCRI to collect” was added to clarify who was responsible to following up on EQOL questionnaire.
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6.2.9.1 / The name “Manual of Operations” was changed to “Study Manual” because that is what it is called in the trial.
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6.2.9.2 / “The treatment of hypoglycemia will be reviewed with the clinical sites at Investigators’ Meetings and during training sessions.”
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new section: 6.2.10 / Added new section 6.2.10; adjusted number of following two sections accordingly.
6.2.10 Recommended Safety Materials
Clinical Sites should ensure the following safety materials are available during administration of infusions:
  • Intravenous dextrose 50%
  • Intravenous calcium gluconate or chloride
  • Glucometer for measuring glucose levels in symptomatic diabetics (because diabetics on insulin have such devices, SIs and SCs should request their patients bring them to the infusion visits)
  • Snacks or juice for empiric treatment of symptoms of hypoglycemia

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6.4 / "If there is a fall in platelet count below 50% of the baseline platelet count, or to <100,000, infusions will stop for 2 weeks, and the Central Pharmacy will omit heparin from subsequent infusions for that patient. The site will be notified that the platelet count is low. Infusions without heparin will resume after the platelet count has risen to within 20% of the baseline platelet count."
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6.4 / The type of CRP test was clarified in the schedule of routine monitoring visits:
hs-CRP
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6.5 / The following clarification was added “The DCC will transmit monitoring reports regularly to the CCC.” The following statement was deleted “The DCC will transmit weekly status reports to the CCC.”
The following clarification was added “The DCC will continuously monitor the number of delinquent forms at each clinical site and provide update reports to the CCC regularly.” The following sentence was deleted “At the end of each month, the DCC will provide a monthly Delinquency Report.
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6.5.4 / The spelling of algorithm was corrected.
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6.5.4.1.1 / The spelling of fulfill was corrected.
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6.5.4.1.7 / The following statement was clarified “Unexpected” is when the specificity or severity of an AE is not consistent with the applicable product information (e.g. Investigator’s Brochure or risk information described in the investigational plan.) The new statement is “ ‘Unexpected’ is defined as an adverse drug experience, the specificity or severity of which is not consistent with the current investigator brochure or the risk information in the investigational plan.”
The following statement was clarified “ ‘Expected’ is when the specificity and severity of an AE is consistent with the applicable product information (e.g. Investigator’s Brochure or risk information described in the investigational plan).”
The new statement is “ ‘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.
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6.5.4.2 / The following clarification was made to the statement “SAE line listings, from the clinical database, will be provided to the DSMB chairman on a quarterly basis regularly for review.”
Language clarifications and clarifications of roles and responsibilities were made to this section. The following changes were made:
The protocol states, “All adverse events that occur from initiation of study drug through 30 days post final infusion that result in death or are serious and associated to drug (infusion) therapy are to be reported immediately (within 24 hours) to the DCRI Safety Surveillance Department, which for this trial, will function as an arm of the TACT Data Coordinating Center (DCC).”
The change is, “All serious adverse events that occur from initiation of study drug through 30 days post final infusion are to be reported immediately (within 24 hours) using the electronic data capture system. Adverse events that are serious and drug (infusion) therapy related or result in death will be followed by the DCRI Safety Surveillance Department, which for this trial, will function as an arm of the TACT Data Coordinating Center (DCC).”
The Protocol states, “This will include ensuring that serious criteria have been met and the SAE data received is reviewed, data based and coded using the MedDRA coding dictionary.”
The change is, “This will include, but will not be limited to ensuring that serious criteria have been met, the SAE data received is reviewed, data based and coded using the MedDRA coding dictionary.”
The Protocol states, “The DCRI Medical Monitor will review the data for medical clarity and regulatory reportability.”
The change is, “The DCRI Medical Monitor will review adverse events that are serious and drug (infusion) therapy related or result in death for medical clarity and regulatory reportability.”
The Protocol states, “DCRI Safety Surveillance will notify the NIH, Dr. Lamas, and the Data and Safety Monitoring Board (DSMB) chairman of all serious adverse events that result in death and adverse events that are both serious and drug (infusion) related in a blinded fashion within 1 business day of receipt of the initial notification of the SAE.”
The change is “DCRI Safety Surveillance will notify the NIH, Dr. Lamas, and the Data and Safety Monitoring Board (DSMB) chairman of all adverse events that are serious and drug (infusion) therapy related or result in death in a blinded fashion within 1 business day of receipt of the initial notification of the SAE.”