Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Active Arm N-acetyl cysteine (NAC) | Drug | N-acetyl cysteine (NAC) 1200mg twice a day for 6 days post-amputation |
|
| 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 |
| 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 |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Mohamed Zayed, MD | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35129469 | Derived | 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. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Mar 26, 2020 |
Not provided
Not provided
Not provided
Not provided
Not provided
| Placebo Arm | Drug | Placebo 1/2 normal saline infusion twice a day for 6 days post-amputation |
|
|
| 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 |
| COMPLETED |
|
| NOT COMPLETED |
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | 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 |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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). | Table represents fold change in amputation stump % perfusion defect between POD 0, 3, 5. | Posted | Mean | Standard Deviation | percentage of defect | Day 0, Day 3, Day 5 |
|
|
| ||||||||||||||||||||||||||||
| 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. | Amputation Stump Incision Healing | Posted | Count of Participants | Participants | 30 days |
| |||||||||||||||||||||||||||||||
| 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. | Amputation stump perfusion at POD5. | Posted | Count of Participants | Participants | POD5 |
|
|
Postoperative Day 30 (POD30)
There were no study-related adverse events observed throughout the duration of this clinical trial.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 | 0 | 16 | 0 | 16 | 6 | 16 |
| EG001 | PLACEBO | 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 | 0 | 17 | 0 | 17 | 5 | 17 |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Non-healing amputation site | Vascular disorders | Non-systematic Assessment | Non-healing amputation site |
| |
| Conversion from BKA to AKA | Surgical and medical procedures | Non-systematic Assessment | Conversion from below knee amputation (BKA) to above knee amputation (AKA) |
| |
| Erosive esophagitis | General disorders | Non-systematic Assessment | Erosive esophagitis |
| |
| Stump pain | Vascular disorders | Non-systematic Assessment | Stump pain |
| |
| Constipation resulting in hospitalization | Gastrointestinal disorders | Non-systematic Assessment | Constipation resulting in hospitalization |
| |
| Fecal impaction | Gastrointestinal disorders | Non-systematic Assessment | Fecal impaction |
| |
| Wound necrosis | Infections and infestations | Non-systematic Assessment | Wound necrosis |
| |
| Hypovolemia | Blood and lymphatic system disorders | Non-systematic Assessment | Hypovolemia |
| |
| Diabetic ketoacidosis (DKA) | Endocrine disorders | Non-systematic Assessment | Diabetic ketoacidosis (DKA) |
| |
| Amputation stump revision due to a fall | General disorders | Non-systematic Assessment | Amputation stump revision due to a fall |
| |
| Death | Infections and infestations | Non-systematic Assessment | Complications associated with diabetic ketoacidosis (DKA) |
|
Not provided
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mohamed A Zayed | Washington University School of Medicine | 314-362-5648 | zayedm@wustl.edu |
| Jun 20, 2022 |
| Prot_SAP_ICF_000.pdf |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D000089802 | Chronic Limb-Threatening Ischemia |
| D058729 | Peripheral Arterial Disease |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D050197 | Atherosclerosis |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D016491 | Peripheral Vascular Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007511 | Ischemia |
Not provided
Not provided
| ID | Term |
|---|---|
| D000111 | Acetylcysteine |
| ID | Term |
|---|---|
| D003545 | Cysteine |
| D000603 | Amino Acids, Sulfur |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
Not provided
Not provided
|
|
| POD 3 |
|
|
| POD 5 |
|
|
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
|
|
|
|