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: Completed
• 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 (Actual): 33
• Phase: Early Phase 1

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

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 Assignment
• 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
Change in Postoperative Laser-Assisted Fluorescent Angiography (LAFA) Perfusion.	Images were collected from the SPY Elite LAFA apparatus. Regions of interest were drawn in a standardized fashion around either the incision or the whole amputation stump. NIH image J software was used to evaluate peak perfusion signal intensity in all regions of interest. Change in LAFA was assessed at postoperative day (POD) 0, 3, and 5. Fold change in % perfusion in the ROI's between POD 0/3/5 was determined and compared between study groups. The primary outcomes were change in postoperative Laser-Assisted Fluorescent Angiography (LAFA) perfusion at POD3 and POD5 and stump healing at postoperative day 30 (POD30).	Day 0, Day 3, Day 5
Stump Healing Assessment at Postoperative Day (POD) 30.	Amputation stump photographs were serially obtained for all study patients immediately before LAFA assessments on POD 0, 3, and 5. A blinded observer evaluated amputation stump incision healing using a modified Bates-Jensen Score (mBJS) wound assessment tool. As previously described, the amputation stumps were evaluated on the following criteria: amputation stump skin color, epithelialization, amount of exudate, and the presence and volume of eschar. Each wound healing characteristic was given a score of 1 to 5, with higher scores indicating worse healing. Eschar volume was determined using ImageJ software. Aggregate mBJS scores were derived for both the whole stump and along the suture line. Clinical amputation stump healing was determined by the surgeon at follow-up clinical evaluations up until POD30. De Silva GS, Saffaf K, Sanchez LA, et al. Amputation stump perfusion is predictive of post-operative necrotic eschar formation. Am J Surg. 2018;216:540-546.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amputation Stump Perfusion in High Risk Patients	POD0 LAFA was evaluated for all patients and patients that demonstrated amputation stump peak perfusion defects were considered high risk. Within these patients we then evaluated amputation stump perfusion at POD5. Change in perfusion over this time was compared between the study groups.	POD5

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): March 1, 2017
• Primary Completion (Actual): August 31, 2021
• Study Completion (Actual): June 27, 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): August 16, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Disease Attributes; Atherosclerosis; Chronic Disease; Diabetes Mellitus; Peripheral Arterial Disease; Peripheral Vascular Diseases; Chronic Limb-Threatening Ischemia; 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 drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes