Perioperative Vitamin C Lung Transplant

Vitamin C: Assessing Safety After Lung Transplant

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.

Study Overview

• Status: Withdrawn
• Conditions: Lung Transplant; Complications; Primary Graft Dysfunction
• Intervention / Treatment: Drug: Vitamin C

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 Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: ascorbic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and Severity of Kidney Injury Post Operative Day (POD) 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).	Post Operative Day 1
Incidence and Severity of Kidney Injury POD 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).	Post Operative Day 2
Incidence and Severity of Kidney Injury POD 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).	Post Operative Day 3
Incidence and Severity of Kidney Injury POD 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).	Post Operative Day 4
Incidence and Severity of Kidney Injury POD 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).	Post Operative Day 7
Incidence of New Dialysis Initiation		up to Post Operative Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participant Vitamin C Levels		Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3
Participant Thiamine Levels		Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3
Incidence of Primary Graft Dysfunction (PGD)	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.	up to Post Operative Day 7
Incidence and Severity of PGD on POD 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.	Post Operative Day 3
Tacrolimus Levels		Post Operative Days 2, 3, 4, and 7
Tacrolimus Doses		Post Operative Days 4 and 7
Post-Operative Well Being: Mortality		at Post Operative Day 30 and Post Operative Day 90 via chart review
Post-Operative Well Being: Atrial Fibrillation		up to Post Operative Day 7
Post-Operative Well Being: ICU Length of Stay		up to Post Operative Day 30 (chart review)
Post-Operative Well Being: Hospital Length of Stay		up to Post Operative Day 90 (chart review)
Post-Operative Well Being: Nadir Cardiac Index		up to 72 hours post op
Post-Operative Well Being: Peak Pulmonary Artery Systolic Pressure		up to 72 hours post op
Post-Operative Well Being: Peak Pulmonary Artery Diastolic Pressure		up to 72 hours post op
Post-Operative Well Being: Duration of Inotrope Need		up to 72 hours post op
Post-Operative Well Being: Duration of Vasopressor		up to 72 hours post op
Post-Operative Well Being: Total Dose of Vasopressor		up to 72 hours post op
Post-Operative Well Being: Daily Crystalloid Volume	for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours	up to 72 hours post op
Post-Operative Well Being: Daily Blood Product Transfusion Volume	for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours	up to 72 hours post op
Post-Operative Well Being: Daily Chest Tube Output Volume	for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours	up to 72 hours post op
Post-Operative Well Being: Duration of Post-Operative Mechanical Ventilation		up to Post Operative Day 7
Post-Operative Well Being: PaO2 / FIO2 ratios	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 %).	Post Operative Day 1, Post Operative Day 2, Post Operative Day 3
Post-Operative Well Being: Time to Clearance of Lactate	"Clearance" is defined as a lactate <1 mmol/L.	up to Post Operative Day 3

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2023
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: August 5, 2020
• First Submitted That Met QC Criteria: August 5, 2020
• First Posted (Actual): August 10, 2020

Study Record Updates

• Last Update Posted (Actual): May 1, 2023
• Last Update Submitted That Met QC Criteria: April 27, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Vitamin C
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Reperfusion Injury; Primary Graft Dysfunction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• 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)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Time Frame: up to 7 years after the completion of the primary endpoint
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No