N-Acetyl-Cysteine (NAC) for Healing of Amputation Stumps in the Setting of Diabetes

N-Acetyl-Cysteine for Healing of Amputation Stumps in the Setting of Diabetes

In this pilot clinical study the investigators propose to conduct a prospective, randomized, double-blinded, placebo-controlled clinical trial for 30 days for participants with critical limb ischemia (CLI) who undergo a major (above-knee or below-knee) lower extremity amputation. By exploring the primary endpoints we aim to determine whether NAC can affect amputation stump perfusion and healing. Based on preclinical data, the investigators hypothesize that NAC will augment both amputation stump perfusion as well as healing. The investigators will utilize the data from this trial to determine the true effect size that is necessary for a larger clinical trial to determine the clinical efficacy of NAC is healing surgical sites such as major lower extremity amputation stumps.

Study Overview

• Status: Suspended
• Conditions: Diabetes Mellitus; Peripheral Arterial Disease; Critical Limb Ischemia; Lower Limb Amputation Knee
• Intervention / Treatment: Drug: Active Arm N-acetyl cysteine (NAC); Drug: Placebo Arm

Detailed Description

In this pilot clinical study the investigators propose to conduct a prospective, randomized, double-blinded, placebo-controlled clinical trial, in 50 participants with CLI who have undergone a major (above-knee or below-knee) lower extremity amputation. 25 participants will receive NAC 1200mg intravenously twice a day for 6 consecutive days following amputation. 25 participants will receive placebo saline intravenous infusion twice a day for 6 days following amputation. Post-amputation participants will be monitored for specific anthropometric parameters and stump perfusion assessments (using laser-assisted fluorescent angiography and transcutaneous oxygen pressure measurement). The primary study endpoints are to determine if lower extremity stump healing and perfusion are affected by perioperative NAC administration. A secondary endpoint will be to determine the effect size that would be necessary to power a larger clinical trial to determine whether NAC treatment can affect tissue perfusion and healing at major lower extremity amputation stumps in participants with CLI.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject undergoing elective major (above-knee or below-knee) lower extremity amputation for CLI
• Both male and female patients
• All ethnic groups
• Between of the ages of 30-90 years old
• Adequate nutritional status - defined as BMI > 19

Exclusion Criteria:

• Pregnant women, and women who are breastfeeding
• Known history of end-stage liver disease
• Severe asthma
• Heavy alcohol consumption (male > 2 drinks per day and women > 1 drink per day)
• Individuals actively receiving chemotherapy.
• Anticipated enrollment in another study that investigates another drug agent within 30 days from enrollment in this study.
• Patients receiving carbamazepine.
• Severe anemia (HCT < 22).
• Allergy to either NAC or Indocyanine Green (ICG).
• Patients with open wound(s) from a prior amputation on the ipsilateral limb (excluding patients who had prior partial foot amputation, who are now requiring a below-knee or above-knee amputation).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Active Arm N-acetyl cysteine (NAC); Upon study enrollment, patients will be randomized 1:1 by Investigational Pharmacy to a standard adult intravenous dose of NAC (1200mg twice a day) for 6 days post-amputation.	Drug: Active Arm N-acetyl cysteine (NAC); N-acetyl cysteine (NAC) 1200mg twice a day for 6 days post-amputation; Other Names: N-acetyl cysteine (NAC)
PLACEBO_COMPARATOR: Placebo Arm; Upon study enrollment, patients will be randomized 1:1 by Investigational Pharmacy to placebo ½ normal saline infusion (twice a day) for 6 days post-amputation.	Drug: Placebo Arm; Placebo 1/2 normal saline infusion twice a day for 6 days post-amputation; Other Names: Placebo 1/2 normal saline infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stump Healing using the Bates-Jensen Wound Assessment Tool	A validated scoring algorithm used to determine the degree to which a wound has successfully healed. We will use a modified version of this tool and score the following parameters: amputation stump skin color, epithelialization, amount and type of exudate, and the size and type of necrotic eschar tissue. Each feature was evaluated on a 1 through 5 scoring system, with lower scores indicating best healing, and higher scores indicating poor healing. Participants are given an overall aggregate score, with higher scores indicating poor healing. These measurements are taken at the participant's first clinical follow up appointment.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine effect size to power a larger trial	Statistical measurement of effect size to power a larger trial.	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perfusion	The Primary Study Endpoints will measure if patients who receive peri-operative NAC administrative have lower Bates-Jensen Wound Healing Scores than their non-NAC counterparts.	30 days
Stump Healing	The Primary Study Endpoints will measure if patients who receive peri-operative NAC administrative have lower Bates-Jensen Wound Healing Scores than their non-NAC counterparts.	5 days

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Mohamed Zayed, MD, Washington University School of Medicine

Publications and helpful links

General Publications

• Lee JV, Engel C, Tay S, DeSilva G, Desai K, Cashin J, Semenkovich CF, Zayed MA. Impact of N-Acetyl-Cysteine on Ischemic Stumps Following Major Lower Extremity Amputation: A Pilot Randomized Clinical Trial. Ann Surg. 2022 Nov 1;276(5):e302-e310. doi: 10.1097/SLA.0000000000005389. Epub 2022 Jan 24.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 15, 2016
• Primary Completion (ACTUAL): August 31, 2021
• Study Completion (ANTICIPATED): August 31, 2022

Study Registration Dates

• First Submitted: March 17, 2017
• First Submitted That Met QC Criteria: August 14, 2017
• First Posted (ACTUAL): August 17, 2017

Study Record Updates

• Last Update Posted (ACTUAL): April 12, 2022
• Last Update Submitted That Met QC Criteria: April 11, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Atherosclerosis; Diabetes Mellitus; Ischemia; Peripheral Arterial Disease; Peripheral Vascular Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: 201611065

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No