TACT3a: Trial to Assess Chelation Therapy in Critical Limb Ischemia

Sponsor

Mt. Sinai Medical Center, Miami (Other)

Overall Status

Recruiting

CT.gov ID

NCT03982693

Collaborator

(none)

Enrollment

Location

Arms

47.4

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

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

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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Mar 19, 2019

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

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

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 Names:

TACT EDTA infusion

Placebo Comparator: Placebo

Placebo infusion

Other: Placebo

Placebo infusions consist of 500 ml normal saline.

Outcome Measures

Primary Outcome Measures

Prevention of major cardiovascular endpoints [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

Amputations [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
Heart failure [3 years (average follow-up 1.25 years)]
• Heart failure hospitalizations or prolonged (>12 hours) ER stay for heart failure
Changes in Pain severity [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 Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference- Short Form 8a. The scale range is 1 to 5, with 1 being the best outcome (no pain interference) and 5 the worse (very much interference)
Urine Metals [1 year]
• Changes in urine metal levels measured at the Metals Core Lab and measured at baseline and infusion 40 (or final).
Changes in Quality of Life [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 the 36-Item Short Form Health Survey (SF-36 v2). The 36 questions assess eight health-related concepts: physical functioning, role limitations due to physical health problems (role physical), bodily pain, general health, energy levels/fatigue (vitality), social functioning, role limitations due to emotional problems (role emotional), and psychological distress (mental health). The scales vary depending on the question asked.The survey will be used to detect change (better or worse) in participants' health state over the course of the study.
Wound Severity [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
Changes in skin perfusion pressure in the ankle [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 index (mmHg)
Changes in skin perfusion pressure in the toe [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 toe-brachial index (mmHg).
Changes in PAD Quality of Life [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 Peripheral Artery Questionnaire (PAQ), which is a 20-item questionnaire measuring physical limitations, symptoms, symptom stability, treatment satisfaction, quality of life, and social function. The scales vary depending on the question asked. The survey will be used to detect change (better or worse) in participants responses over the course of the study.

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.