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

NCT03253328 | Completed Early Phase 1 Results DMC FDA Drug

• 1 other identifier: 201611065
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Diabetes Mellitus; Critical Limb Ischemia; Lower Limb Amputation Knee; Peripheral Arterial Disease

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• Amputation Stump Perfusion in High Risk Patients

  POD5

Study Arms (2)

Active Arm N-acetyl cysteine (NAC)

ACTIVE COMPARATOR

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)

Placebo Arm

PLACEBO COMPARATOR

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

Interventions

Active Arm N-acetyl cysteine (NAC) DRUG

N-acetyl cysteine (NAC) 1200mg twice a day for 6 days post-amputation

Also known as: N-acetyl cysteine (NAC)

Active Arm N-acetyl cysteine (NAC)

Placebo Arm DRUG

Placebo 1/2 normal saline infusion twice a day for 6 days post-amputation

Also known as: Placebo 1/2 normal saline infusion

Placebo Arm

Eligibility Criteria

• Age: 30 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• 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.

  PMID: 35129469 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus; Chronic Limb-Threatening Ischemia; Peripheral Arterial Disease

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Peripheral Vascular Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Ischemia

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Mohamed A Zayed
• Organization: Washington University School of Medicine

zayedm@wustl.edu

314-362-5648

Study Officials

• Mohamed Zayed, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 17, 2017
• First Posted: August 17, 2017
• Study Start: March 1, 2017
• Primary Completion: August 31, 2021
• Study Completion: June 27, 2022
• Last Updated: August 16, 2024
• Results First Posted: August 16, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)