Perioperative Vitamin C Lung Transplant

• ClinicalTrials.gov Identifier: NCT04505878
• Recruitment Status: Recruiting
• First Posted: August 10, 2020
• Last Update Posted: May 10, 2022
• Sponsor: University of Wisconsin, Madison
• Information provided by (Responsible Party): University of Wisconsin, Madison

Study Description

Brief Summary:

This study is being done to determine if parenterally administered ascorbic acid (Vitamin C) given at the time of lung transplant is safe. Vitamin C may be an effective intervention towards primary graft dysfunction (PGD). The study will enroll 69 participants who consent to the intervention. Participants who do not consent to the intervention will be treated according to standard-of-care, but may choose to be consented to have their data retrospectively reviewed. Based on our consent rate, this group may include 40-70 participants. Participants will be on study for up to 12 months.

Condition or disease	Intervention/treatment	Phase
Primary Graft Dysfunction; Lung Transplant; Complications	Drug: Vitamin C	Phase 2

Detailed Description:

PGD is a frequent and severe outcome that impacts both short- and long-term outcomes after lung transplantation. Major pathophysiologic contributors include ischemia and reperfusion injury, mitochondrial dysfunction and endothelial failure. No directed therapy exists. Vitamin C is a first-line antioxidant that also acts at the endothelium and mitochondria to decrease permeability and leak, inhibit mitochondrial dysfunction and improve ischemia and reperfusion. When combined with steroids, part of standard care for lung transplant recipients, these effects may be enhanced and synergistically inhibit instigators of patient injury. A pilot trial will ensure safety of this potential intervention and guide future research into this important outcome measure. It will be readily received in the literature.

For the present study, vitamin C will be administered parenterally at a dose of 1,500 mg every 6 hours, a dose that is widely accepted and used in other clinical contexts where the drug is studied, such as sepsis. This will predictably reconstitute levels and achieve supratherapeutic benefit towards oxidant scavenging, while avoiding the potential pro-oxidant effects seen at exceedingly high doses. To this end, the investigators will exclude patients where the standard dosing of vitamin C will exceed 100 mg/kg/day (excluding patients <60 kg). Dosing will continue through post-operative day (POD) 3 to effectively assess for the impact of vitamin C on PGD.

Primary Objectives

• To assess whether parenterally administered ascorbic acid (vitamin C) is safe in the lung transplant population
• To estimate adherence to ascorbic acid administration protocol in this study population and to identify obstacles to feasibility of future trials using this protocol

Secondary Objectives

• To assess whether parenterally administered ascorbic acid (vitamin C) may decrease the rate and severity of PGD after lung transplant
• To establish the incidence of vitamin C and vitamin B1 (thiamine) deficiencies in the lung transplant population, and the responsiveness of vitamin C levels to our selected parenteral therapy
• To identify interventions that will optimize the post-operative wellbeing of patients receiving lung transplants by decreasing primary graft dysfunction (short and intermediate-to-long term

Stop Criteria

• Anuria x 3-hours
• Moderate, Grade 2 AKI (doubling of baseline creatinine)
• An acute, unexplained hemoglobin drop of >2 mg/dL

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 110 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: This is a pilot single-arm unblinded trial to assess whether parenterally administered ascorbic acid (vitamin C) is safe in the lung transplant population.The investigators will not randomize or control; a retrospective cohort of participants not treated with vitamin C will be reviewed from 2015-2020. Those participants who decline the intervention will have the choice to consent to having their data be considered as part of the (non-retrospective) controls and be considered in our statistical analysis for outcomes, including analysis between this group and the historical controls. All participants who consent will be administered the therapy and participants will be evaluated via an intention-to-treat analysis.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Vitamin C: Assessing Safety After Lung Transplant
• Estimated Study Start Date: June 2022
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Vitamin C Arm; Ascorbic Acid will be administered at a dose of 1500 mg in 100 mL of saline over 30 minutes intravenously once every 6 hours for a total of 72 hours	Drug: Vitamin C; Vitamin C is a first-line antioxidant that directly scavenges free radicals, inhibits reactive oxygen species (ROS) producing enzymes and recovers other cellular antioxidants; Other Name: ascorbic acid

Outcome Measures

Primary Outcome Measures :

1. Incidence and Severity of Kidney Injury Post Operative Day (POD) 1 [ Time Frame: Post Operative Day 1 ]
   The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis).
2. Incidence and Severity of Kidney Injury POD 2 [ Time Frame: Post Operative Day 2 ]
   The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis).
3. Incidence and Severity of Kidney Injury POD 3 [ Time Frame: Post Operative Day 3 ]
   The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis).
4. Incidence and Severity of Kidney Injury POD 4 [ Time Frame: Post Operative Day 4 ]
   The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis).
5. Incidence and Severity of Kidney Injury POD 7 [ Time Frame: Post Operative Day 7 ]
   The primary endpoint is the safety of the vitamin C intervention. This will be measured by the incidence and severity of kidney injuries on POD 1, POD 2, POD 3, POD 4, and POD 7. Acute kidney injury (AKI) is defined as any creatinine (Cr) that is 1.5-times the participant's baseline / immediate preoperative creatinine. Severity escalates with increasing ratios: Mild, stage 1 AKI (Cr 1.5-1.99x baseline); Moderate, stage 2 AKI (Cr 2-2.9x baseline); and Severe, stage 3 AKI (Cr >3x baseline or any initiation of dialysis).
6. Incidence of New Dialysis Initiation [ Time Frame: up to Post Operative Day 7 ]

Secondary Outcome Measures :

1. Participant Vitamin C Levels [ Time Frame: Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3 ]
2. Participant Thiamine Levels [ Time Frame: Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3 ]
3. Incidence of Primary Graft Dysfunction (PGD) [ Time Frame: up to Post Operative Day 7 ]
   Primary Graft Dysfunction is defined as chest x-ray (CXR)-infiltrates with or without depressed oxygenation function, assessed by the "PF-Ratio," which is the PaO2 / FiO2.
4. Incidence and Severity of PGD on POD 3 [ Time Frame: Post Operative Day 3 ]
   Primary Graft Dysfunction is defined as chest x-ray (CXR)-infiltrates with or without depressed oxygenation function, assessed by the "PF-Ratio," which is the PaO2 / FiO2. Severity is defined as: PGD Grade 1 = CXR findings and any PF Ratio > 300; PGD Grade 2 = CXR findings and PF Ratio 200-300; and PGD Grade 3 = CXR findings and PF Ratio <200.
5. Tacrolimus Levels [ Time Frame: Post Operative Days 2, 3, 4, and 7 ]
6. Tacrolimus Doses [ Time Frame: Post Operative Days 4 and 7 ]
7. Post-Operative Well Being: Mortality [ Time Frame: at Post Operative Day 30 and Post Operative Day 90 via chart review ]
8. Post-Operative Well Being: Atrial Fibrillation [ Time Frame: up to Post Operative Day 7 ]
9. Post-Operative Well Being: ICU Length of Stay [ Time Frame: up to Post Operative Day 30 (chart review) ]
10. Post-Operative Well Being: Hospital Length of Stay [ Time Frame: up to Post Operative Day 90 (chart review) ]
11. Post-Operative Well Being: Nadir Cardiac Index [ Time Frame: up to 72 hours post op ]
12. Post-Operative Well Being: Peak Pulmonary Artery Systolic Pressure [ Time Frame: up to 72 hours post op ]
13. Post-Operative Well Being: Peak Pulmonary Artery Diastolic Pressure [ Time Frame: up to 72 hours post op ]
14. Post-Operative Well Being: Duration of Inotrope Need [ Time Frame: up to 72 hours post op ]
15. Post-Operative Well Being: Duration of Vasopressor [ Time Frame: up to 72 hours post op ]
16. Post-Operative Well Being: Total Dose of Vasopressor [ Time Frame: up to 72 hours post op ]
17. Post-Operative Well Being: Daily Crystalloid Volume [ Time Frame: up to 72 hours post op ]
    for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours
18. Post-Operative Well Being: Daily Blood Product Transfusion Volume [ Time Frame: up to 72 hours post op ]
    for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours
19. Post-Operative Well Being: Daily Chest Tube Output Volume [ Time Frame: up to 72 hours post op ]
    for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours
20. Post-Operative Well Being: Duration of Post-Operative Mechanical Ventilation [ Time Frame: up to Post Operative Day 7 ]
21. Post-Operative Well Being: PaO2 / FIO2 ratios [ Time Frame: Post Operative Day 1, Post Operative Day 2, Post Operative Day 3 ]
    The PF Ratio assesses the lungs' ability to oxygenate the blood. It is defined as the ratio of the partial pressure of oxygen in the arteries (PaO2 in mmHg) to the fractional inspired oxygen content from the ventilator (FiO2 in %).
22. Post-Operative Well Being: Time to Clearance of Lactate [ Time Frame: up to Post Operative Day 3 ]
    "Clearance" is defined as a lactate <1 mmol/L.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Participant is scheduled for lung transplantation

Exclusion Criteria:

• Non-English speaking
• Subject is known or believed to be pregnant
• Subject is a prisoner.
• Subject has impaired decision-making capacity.
• Subject has known allergy to vitamin C.
• Subject has history of nephrolithiasis, oxalosis or hyperoxaluria. (Cystic Fibrosis patients are at risk of occult oxalosis / hyperoxaluria, therefore they will also be excluded from the study.)
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Sickle cell anemia
• Heredity hemochromatosis
• Baseline creatinine >2 mg/dL or any current kidney injury
• Weight <60 kg
• Vitamin C supplement use or administration (including HAT therapy) within the last month prior to transplantation
• Current enrolment in another research study
• Not suitable for study participation due to other reasons at the discretion of the investigators.

Contacts and Locations

Contacts

Contact: Helen F Akere; (608) 265-3243; akere@wisc.edu

Locations

United States, Wisconsin

University of Wisconsin Hospital and Clinics; Recruiting

Madison, Wisconsin, United States, 53792

Contact: Helen Akere 608-265-3243 akere@wisc.edu

Sponsors and Collaborators

University of Wisconsin, Madison

Investigators

• Principal Investigator: Micah Long, MD; UW School of Medicine and Public Health

More Information

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT04505878
• Other Study ID Numbers: 2020-0503; A530900 ( Other Identifier: UW Madison ); SMPH/ANESTHESIOLOGY ( Other Identifier: UW Madison ); Protocol Version 0.05 ( Other Identifier: UW Madison )
• First Posted: August 10, 2020
• Last Update Posted: May 10, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data from this study may be requested from other researchers up to 7 years after the completion of the primary endpoint by contacting Dr. Micah Long, the Principal Investigator of this study.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: up to 7 years after the completion of the primary endpoint

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Wisconsin, Madison:

Vitamin C

Additional relevant MeSH terms:

Primary Graft Dysfunction; Reperfusion Injury; Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Ascorbic Acid; Vitamins; Micronutrients; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents