NCT03253328

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

Completed EARLY_PHASE1 Results posted Last updated 16 August 2024

What this trial tests

EARLY_PHASE1 trial testing Active Arm N-acetyl cysteine (NAC) in Diabetes Mellitus in 33 participants. Completed in 27 June 2022.

Timeline

1 March 2017

Primary endpoint
31 August 2021

27 June 2022

Quick facts

Lead sponsor	Washington University School of Medicine
Phase	EARLY_PHASE1
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	33
Start date	1 March 2017
Primary completion	31 August 2021
Estimated completion	27 June 2022
Sites	1 location across United States

Drugs / interventions tested

• Active Arm N-acetyl cysteine (NAC) — full drug profile →
• Placebo Arm

Conditions studied

• Diabetes Mellitus — all drugs for Diabetes Mellitus →
• Critical Limb Ischemia — all drugs for Critical Limb Ischemia →
• Lower Limb Amputation Knee — all drugs for Lower Limb Amputation Knee →
• Peripheral Arterial Disease — all drugs for Peripheral Arterial Disease →

Sponsor

Washington University School of Medicine

Who can join

Adults 30 to 90, any sex, with Diabetes Mellitus or Critical Limb Ischemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change in Postoperative Laser-Assisted Fluorescent Angiography (LAFA) Perfusion. Primary · 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 postop

POD 0

Group	Value	95% CI
Active Arm N-acetyl Cysteine (NAC)	0.060	± 0.056
Placebo Arm	0.096	± 0.117

POD 3

Group	Value	95% CI
Active Arm N-acetyl Cysteine (NAC)	0.045	± 0.047
Placebo Arm	0.031	± 0.055

POD 5

Group	Value	95% CI
Active Arm N-acetyl Cysteine (NAC)	0.015	± 0.026
Placebo Arm	0.050	± 0.058

Stump Healing Assessment at Postoperative Day (POD) 30. Primary · 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 Im

Overall Number of Participants Analyzed

Group	Value	95% CI
Active Arm N-acetyl Cysteine (NAC)	10
Placebo Arm	16

Perfusion Defects

Group	Value	95% CI
Active Arm N-acetyl Cysteine (NAC)	7
Placebo Arm	13

Adequate Perfusion

Group	Value	95% CI
Active Arm N-acetyl Cysteine (NAC)	3
Placebo Arm	3

Amputation Stump Perfusion in High Risk Patients Secondary · 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.

Group	Value	95% CI
Active Arm N-acetyl Cysteine (NAC)	7
Placebo Arm	13
Active Arm N-acetyl Cysteine (NAC)	3
Placebo Arm	3

Adverse events — posted to ClinicalTrials.gov

Time frame: Postoperative Day 30 (POD30). Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Active Arm N-acetyl Cysteine (NAC)

Serious: 0/16 (0%)

Deaths: 0/16

PLACEBO

Serious: 0/17 (0%)

Deaths: 0/17

Other adverse events (11 terms — click to expand)

Reaction	System	Active Arm N-acetyl Cystei…	PLACEBO
Non-healing amputation site	Vascular disorders	—	—
Conversion from BKA to AKA	Surgical and medical procedures	—	—
Erosive esophagitis	General disorders	—	—
Stump pain	Vascular disorders	—	—
Constipation resulting in hospitalization	Gastrointestinal disorders	—	—
Fecal impaction	Gastrointestinal disorders	—	—
Wound necrosis	Infections and infestations	—	—
Hypovolemia	Blood and lymphatic system disorders	—	—
Diabetic ketoacidosis (DKA)	Endocrine disorders	—	—
Amputation stump revision due to a fall	General disorders	—	—
Death	Infections and infestations	—	—

Data from ClinicalTrials.gov NCT03253328 adverse events section.

Sponsor's own description

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.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Impact of N-Acetyl-Cysteine on Ischemic Stumps Following Major Lower Extremity Amputation: A Pilot Randomized Clinical Trial.
   Lee JV, Engel C, Tay S, DeSilva G, et al · · 2022 · cited 4× · PMID 35129469 · DOI 10.1097/sla.0000000000005389