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Trial to Assess Chelation Therapy in Critical Limb Ischemia (TACT3a)

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ClinicalTrials.gov Identifier: NCT03982693
Recruitment Status : Recruiting
First Posted : June 11, 2019
Last Update Posted : June 11, 2019
Sponsor:
Information provided by (Responsible Party):
Gervasio Lamas, MD, Mt. Sinai Medical Center, Miami

Brief Summary:
TACT3a is a double blind, placebo-controlled, randomized trial to test a novel therapy, edetate disodium-based chelation of environmentally acquired toxic metals, to reduce cardiovascular events including amputation in high-risk diabetic patients.

Condition or disease Intervention/treatment Phase
Critical Limb Ischemia Diabetes Drug: Edetate Disodium Other: Placebo Phase 3

Detailed Description:

TACT3a is a double blind, placebo-controlled, randomized trial to test a novel therapy, edetate disodium-based chelation of environmentally acquired toxic metals, to reduce cardiovascular events including amputation in high-risk diabetic patients.

The study plans to enroll 50 patients with diabetes and critical limb ischemia (CLI) to prevent the major cardiovascular endpoints of major amputation, coronary revascularization, stroke, Myocardial Infarction (MI), or death (all-cause) during an average 1.25 years of follow-up. Patients will be randomly assigned to chelation or placebo with a 3:2 (30 active, 20 placebo) allocation ratio. Treatment will consist of 40 active or placebo infusions over 30 weeks. Active therapy will be the same edetate disodium-based infusion used safely and successfully in a previous published study, Trial to Assess Chelation Therapy (TACT). Baseline and post infusion urine metals will be collected. Following the final infusion, patients will be contacted quarterly until the end of the study.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: double-blind
Primary Purpose: Treatment
Official Title: Trial to Assess Chelation Therapy in Critical Limb Ischemia
Actual Study Start Date : March 19, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : March 2022


Arm Intervention/treatment
Active Comparator: Active
edetate disodium (EDTA)dff active infusion
Drug: Edetate Disodium
The solution contains up to 3 g of edetate disodium adjusted based on creatinine clearance, 2 g of magnesium chloride, 100 mg of procaine hydrochloride, 2500 U of heparin, 7 g of ascorbate, 2 milliequivalent (mEq) potassium chloride (KCl), 840 mg sodium bicarbonate, 250 mg pantothenic acid, 100 mg of thiamine, 100 mg of pyridoxine, and sterile water to complete 500 mL.
Other Name: TACT EDTA infusion

Placebo Comparator: Placebo
Placebo infusion
Other: Placebo
Placebo infusions consist of 500 ml normal saline.




Primary Outcome Measures :
  1. Prevention of major cardiovascular endpoints [ Time Frame: 3 years (average follow-up 1.25 years) ]
    Major cardiovascular endpoints include: coronary revascularization, stroke, MI, death (all-cause), or major amputation


Secondary Outcome Measures :
  1. Amputations [ Time Frame: 3 years (average follow-up 1.25 years) ]
    • Major amputations due to vascular disease. Major amputations are defined as any procedure that results in amputation at the level above the ankle. 49, 50
    • Total amputations due to vascular disease

  2. Heart failure [ Time Frame: 3 years (average follow-up 1.25 years) ]
    • Heart failure hospitalizations or prolonged (>12 hours) ER stay for heart failure

  3. Changes in Pain severity [ Time Frame: 3 years (average follow-up 1.25 years) ]
    • Any changes in pain will be recorded at baseline, infusions 10, 20, 40 (or final), and end of study recorded using the NIH Toolbox Questionnaire

  4. Urine Metals [ Time Frame: 1 year ]
    • Changes in urine metal levels measured at the Metals Core Lab and measured at baseline and infusion 40 (or final).

  5. Changes in Quality of Life [ Time Frame: 3 years (average follow-up 1.25 years) ]
    • Health-related quality of life (QOL) changes recorded at baseline, 10, 20, 40 (or final), and end of study using SF-36

  6. Wound Severity [ Time Frame: 3 years (average follow-up 1.25 years) ]
    Wound severity (quantified and imaged with HIPAA-compliant photography) photographed at baseline 10, 20, 40 (or final), and end of study

  7. Changes in skin perfusion pressure [ Time Frame: 3 years (average follow-up 1.25 years) ]
    • Changes in skin perfusion pressure will be measured at 10, 20, 40 (or final), and end of study, using the ankle-brachial and toe-brachial indices.

  8. Changes in PAD Quality of Life [ Time Frame: 3 years (average follow-up 1.25 years) ]
    • PAD related quality of life (QOL) changes recorded at baseline, 10, 20, 40 (or final), and end of study using the PAD Questionnaire



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 50 years
  • 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.
  • Significant stenosis (≥ 75%) of two or more infra-popliteal arteries in the affected limb as verified by at least one imaging technique (angiography, magnetic resonance angiogram, coronary computed tomography angiogram, or doppler examination) within 6 months prior to enrollment;
  • History of CLI defined as moderate or high-risk infra-popliteal chronic critical limb ischemia (Rutherford Clinical Severity Score 4 or 5) defined as:

    • The presence of rest pain or non-healing ulceration or gangrene for at least 2 weeks plus documentation of severely compromised tissue perfusion:
    • If there is tissue loss, a resting ankle systolic pressure of ≤ 60 mmHg in the affected limb; or a resting toe systolic pressure of ≤ 40 mmHg or a tissue perfusion pressure (TPP) <40 mmHg.
    • If there is no tissue loss, a resting ankle pressure of ≤ 50 mmHg or resting toe systolic pressure of ≤ 30 mmHg or a tissue perfusion pressure (TPP) < 30 mmHg.
  • Not a candidate or a failed candidate for surgical or transcatheter revascularization;
  • Able to give informed consent.

Exclusion Criteria:

  • Arterial insufficiency in the lower extremity as the result of a non-atherosclerotic disorder.
  • Subjects with evidence of active infection (e.g., cellulitis, osteomyelitis) or deep ulceration exposing bone or tendon or extensive heel ulceration
  • Subjects with extensive gangrene extending above the Metatarsophalangeal (MT) joint
  • Subjects in whom there is severe pain at rest uncontrollable with pain medications
  • 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.
  • Oral chelation with an FDA-approved chelating agent within 2 years
  • Allergy to any components of the study drug
  • Coronary or carotid revascularization within 3 months
  • Planned leg revascularization within 1 month of enrollment
  • Symptomatic or clinically evident acute heart failure
  • Heart failure hospitalization within 3 months
  • Blood pressure >160/100
  • No venous access
  • Estimated glomerular filtration ratee (GFR) < 30 mL/min per 1.73 m2 or lower (CKD stages 1-3) calculated with the Modification of Diet in Renal Disease Study (MDRD) equation
  • Known or suspected acute kidney injury using prevalent Kidney Disease: Improving Global Outcomes (KDIGO) criteria
  • Platelet count <100,000/mm3
  • Cigarette smoking within the last 3 months
  • Liver disease or Alanine aminotransferase (ALT), aspartate aminotransferase (AST) > 2.0 times the upper limit of normal (this will require clearance by the Study PI)
  • Diseases of copper, iron, or calcium metabolism (other than osteopenia or osteoporosis, or simple iron deficiency). These require evaluation by the Study PI
  • Inability to tolerate the study-required fluid load
  • Other medical condition likely to affect patient survival within 3 years
  • Women of child-bearing potential
  • Any factor that suggests that the potential participant will not be able to adhere to the protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03982693


Contacts
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Contact: Francisco Ujueta, MD 305-674-2162 Francisco.Ujueta@msmc.com
Contact: Beatriz Acevedo 305-674-2162 Beatriz.Acevedo@msmc.com

Locations
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United States, Florida
Mount Sinai Medical Center Recruiting
Miami Beach, Florida, United States, 33140
Contact: Francisco Ujueta, MD    305-674-2162    Francisco.Ujueta@msmc.com   
Contact: Beatriz Acevedo    305-674-2162    Beatriz.Acevedo@msmc.com   
Sponsors and Collaborators
Mt. Sinai Medical Center, Miami
Investigators
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Principal Investigator: Gervasio Lamas, MD Icahn School of Medicine at Mount Sinai

Publications:

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Responsible Party: Gervasio Lamas, MD, Principal Investigator, Mt. Sinai Medical Center, Miami
ClinicalTrials.gov Identifier: NCT03982693     History of Changes
Other Study ID Numbers: 19-05-H-01
First Posted: June 11, 2019    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Gervasio Lamas, MD, Mt. Sinai Medical Center, Miami:
Chelation
Critical Limb Ischemia
Diabetes

Additional relevant MeSH terms:
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Ischemia
Pathologic Processes
Edetic Acid
Pentetic Acid
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Antidotes
Protective Agents
Physiological Effects of Drugs
Iron Chelating Agents