Clinical trial NCT03982693: Trial to Assess Chelation Therapy in Critical Limb Ischemia
Official title: Trial to Assess Chelation Therapy in Critical Limb Ischemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Critical Limb Ischemia
Diabetes
Keywords: Chelation
Critical Limb Ischemia
Diabetes
Lead sponsor: Mt. Sinai Medical Center, Miami
Sponsor class: OTHER
First posted: 2019-06-11
Enrollment: 50
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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:

* \<7 days following lower extremity (infra-popliteal), carotid, or coronary revascularization.
* 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 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
* 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
* eGFR \< 30 mL/min per 1.73 m2 or lower (CKD stages 1-3) calculated with MDRD
* Known or suspected acute kidney injury using prevalent KDIGO criteria45
* 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.

Primary outcomes:
measure: Prevention of major cardiovascular endpoints
timeFrame: 3 years (average follow-up 1.25 years)
Secondary outcomes:
measure: Amputations
timeFrame: 3 years (average follow-up 1.25 years)
measure: Heart failure
timeFrame: 3 years (average follow-up 1.25 years)
measure: Changes in Pain severity
timeFrame: 3 years (average follow-up 1.25 years)
measure: Urine Metals
timeFrame: 1 year
measure: Changes in Quality of Life
timeFrame: 3 years (average follow-up 1.25 years)
measure: Wound Severity
timeFrame: 3 years (average follow-up 1.25 years)
measure: Changes in skin perfusion pressure in the ankle
timeFrame: 3 years (average follow-up 1.25 years)
measure: Changes in skin perfusion pressure in the toe
timeFrame: 3 years (average follow-up 1.25 years)
measure: Changes in PAD Quality of Life
timeFrame: 3 years (average follow-up 1.25 years)
Other outcomes:
Locations:
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Gervasio Lamas, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Arenas IA, Navas-Acien A, Ergui I, Lamas GA. Enhanced vasculotoxic metal excretion in post-myocardial infarction patients following a single edetate disodium-based infusion. Environ Res. 2017 Oct;158:443-449. doi: 10.1016/j.envres.2017.06.039. Epub 2017 Jul 6.
citation: 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.
citation: Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y, Nahin RL, Ouyang P, Rozema T, Magaziner A, Nahas R, Lewis EF, Lindblad L, Lee KL. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes. 2014 Jan;7(1):15-24. doi: 10.1161/CIRCOUTCOMES.113.000663. Epub 2013 Nov 19.
citation: Ujueta F, Arenas IA, Diaz D, Yates T, Beasley R, Navas-Acien A, Lamas GA. Cadmium level and severity of peripheral artery disease in patients with coronary artery disease. Eur J Prev Cardiol. 2019 Sep;26(13):1456-1458. doi: 10.1177/2047487318796585. Epub 2018 Aug 28. No abstract available.
citation: Ujueta F, Arenas IA, Escolar E, Diaz D, Boineau R, Mark DB, Golden P, Lindblad L, Kim H, Lee KL, Lamas GA. The effect of EDTA-based chelation on patients with diabetes and peripheral artery disease in the Trial to Assess Chelation Therapy (TACT). J Diabetes Complications. 2019 Jul;33(7):490-494. doi: 10.1016/j.jdiacomp.2019.04.005. Epub 2019 Apr 14.