Critical Limb Ischemia, Diabetes Mellitus, Lower Limb Amputation Knee, Peripheral Arterial Disease
Conditions
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.
Interventions
DRUGActive Arm N-acetyl cysteine (NAC)
N-acetyl cysteine (NAC) 1200mg twice a day for 6 days post-amputation
DRUGPlacebo Arm
Placebo 1/2 normal saline infusion twice a day for 6 days post-amputation
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 90 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Recruited from March 2017 to April 2020. We initially planned to enroll 15 subjects in each group but recruitment was suspended in May 2020 due to COVID-19. Study team leadership determined that unmasking of study randomization would facilitate analysis of primary/secondary endpoints and determine whether data supported overall study hypothesis. After pandemic disruptions were eased interim study analysis was completed and the study closed. No safety concerns led to early termination.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Active Arm N-acetyl cysteine (NAC): N-acetyl cysteine (NAC) 1200mg twice a day for 6 days post-amputation | 16 |
| 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.
Placebo Arm: Placebo 1/2 normal saline infusion twice a day for 6 days post-amputation | 17 |
| Total | 33 |
Baseline characteristics
| Characteristic | Active Arm N-acetyl Cysteine (NAC) | Placebo Arm | Total |
|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 12 | 62 years STANDARD_DEVIATION 11 | 65.5 years STANDARD_DEVIATION 11.5 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 17 |
| other Total, other adverse events | 6 / 16 | 5 / 17 |
| serious Total, serious adverse events | 0 / 16 | 0 / 17 |
Outcome results
Primary
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).
Time frame: Day 0, Day 3, Day 5
Population: Table represents fold change in amputation stump % perfusion defect between POD 0, 3, 5.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Arm N-acetyl Cysteine (NAC) | Change in Postoperative Laser-Assisted Fluorescent Angiography (LAFA) Perfusion. | POD 0 | 0.060 percentage of defect | Standard Deviation 0.056 |
| Active Arm N-acetyl Cysteine (NAC) | Change in Postoperative Laser-Assisted Fluorescent Angiography (LAFA) Perfusion. | POD 3 | 0.045 percentage of defect | Standard Deviation 0.047 |
| Active Arm N-acetyl Cysteine (NAC) | Change in Postoperative Laser-Assisted Fluorescent Angiography (LAFA) Perfusion. | POD 5 | 0.015 percentage of defect | Standard Deviation 0.026 |
| Placebo Arm | Change in Postoperative Laser-Assisted Fluorescent Angiography (LAFA) Perfusion. | POD 0 | 0.096 percentage of defect | Standard Deviation 0.117 |
| Placebo Arm | Change in Postoperative Laser-Assisted Fluorescent Angiography (LAFA) Perfusion. | POD 3 | 0.031 percentage of defect | Standard Deviation 0.055 |
| Placebo Arm | Change in Postoperative Laser-Assisted Fluorescent Angiography (LAFA) Perfusion. | POD 5 | 0.050 percentage of defect | Standard Deviation 0.058 |
Primary
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.
Time frame: 30 days
Population: Amputation Stump Incision Healing
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Active Arm N-acetyl Cysteine (NAC) | Stump Healing Assessment at Postoperative Day (POD) 30. | Overall Number of Participants Analyzed | 10 Participants |
| Active Arm N-acetyl Cysteine (NAC) | Stump Healing Assessment at Postoperative Day (POD) 30. | Perfusion Defects | 7 Participants |
| Active Arm N-acetyl Cysteine (NAC) | Stump Healing Assessment at Postoperative Day (POD) 30. | Adequate Perfusion | 3 Participants |
| Placebo Arm | Stump Healing Assessment at Postoperative Day (POD) 30. | Overall Number of Participants Analyzed | 16 Participants |
| Placebo Arm | Stump Healing Assessment at Postoperative Day (POD) 30. | Perfusion Defects | 13 Participants |
| Placebo Arm | Stump Healing Assessment at Postoperative Day (POD) 30. | Adequate Perfusion | 3 Participants |
Secondary
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.
Time frame: POD5
Population: Amputation stump perfusion at POD5.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Active Arm N-acetyl Cysteine (NAC) | Amputation Stump Perfusion in High Risk Patients | Perfusion Defects | 7 Participants |
| Active Arm N-acetyl Cysteine (NAC) | Amputation Stump Perfusion in High Risk Patients | Adequate Perfusion | 3 Participants |
| Placebo Arm | Amputation Stump Perfusion in High Risk Patients | Perfusion Defects | 13 Participants |
| Placebo Arm | Amputation Stump Perfusion in High Risk Patients | Adequate Perfusion | 3 Participants |