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

Early Phase 1

Completed

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

• Registration Number: NCT03253328
• Lead Sponsor: Washington University School of Medicine

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.

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 Timeline

• Study Start: 2017-03-01
• Study First Submitted: 2017-03-17
• Study First Submitted QC: 2017-08-14
• Study First Posted: 2017-08-17
• Primary Completion: 2021-08-31
• Results First Submitted: 2022-06-21
• Study Completion: 2022-06-27
• Status Verified: 2024-03
• Results First Submitted QC: 2024-03-13
• Last Update Submitted: 2024-03-13
• Results First Posted: 2024-08-16
• Last Update Posted: 2024-08-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 33

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

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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).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active Arm N-acetyl cysteine (NAC)	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.
Placebo Arm	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.

Primary Outcome Measures

Name	Time	Method
Change in Postoperative Laser-Assisted Fluorescent Angiography (LAFA) Perfusion.	Day 0, Day 3, Day 5	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).
Stump Healing Assessment at Postoperative Day (POD) 30.	30 days	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.

Secondary Outcome Measures

Name	Time	Method
Amputation Stump Perfusion in High Risk Patients	POD5	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.

Trial Locations

Locations (1)

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States