Clinical trial NCT04505878: Perioperative Vitamin C Lung Transplant
Official title: Vitamin C: Assessing Safety After Lung Transplant
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Primary Graft Dysfunction
Lung Transplant; Complications
Keywords: Vitamin C
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
First posted: 2020-08-10
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
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.
Primary purpose: TREATMENT

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.

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

Eligibility 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.

Primary outcomes:
measure: Incidence and Severity of Kidney Injury Post Operative Day (POD) 1
timeFrame: Post Operative Day 1
measure: Incidence and Severity of Kidney Injury POD 2
timeFrame: Post Operative Day 2
measure: Incidence and Severity of Kidney Injury POD 3
timeFrame: Post Operative Day 3
measure: Incidence and Severity of Kidney Injury POD 4
timeFrame: Post Operative Day 4
measure: Incidence and Severity of Kidney Injury POD 7
timeFrame: Post Operative Day 7
measure: Incidence of New Dialysis Initiation
timeFrame: up to Post Operative Day 7
Secondary outcomes:
measure: Participant Vitamin C Levels
timeFrame: Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3
measure: Participant Thiamine Levels
timeFrame: Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3
measure: Incidence of Primary Graft Dysfunction (PGD)
timeFrame: up to Post Operative Day 7
measure: Incidence and Severity of PGD on POD 3
timeFrame: Post Operative Day 3
measure: Tacrolimus Levels
timeFrame: Post Operative Days 2, 3, 4, and 7
measure: Tacrolimus Doses
timeFrame: Post Operative Days 4 and 7
measure: Post-Operative Well Being: Mortality
timeFrame: at Post Operative Day 30 and Post Operative Day 90 via chart review
measure: Post-Operative Well Being: Atrial Fibrillation
timeFrame: up to Post Operative Day 7
measure: Post-Operative Well Being: ICU Length of Stay
timeFrame: up to Post Operative Day 30 (chart review)
measure: Post-Operative Well Being: Hospital Length of Stay
timeFrame: up to Post Operative Day 90 (chart review)
measure: Post-Operative Well Being: Nadir Cardiac Index
timeFrame: up to 72 hours post op
measure: Post-Operative Well Being: Peak Pulmonary Artery Systolic Pressure
timeFrame: up to 72 hours post op
measure: Post-Operative Well Being: Peak Pulmonary Artery Diastolic Pressure
timeFrame: up to 72 hours post op
measure: Post-Operative Well Being: Duration of Inotrope Need
timeFrame: up to 72 hours post op
measure: Post-Operative Well Being: Duration of Vasopressor
timeFrame: up to 72 hours post op
measure: Post-Operative Well Being: Total Dose of Vasopressor
timeFrame: up to 72 hours post op
measure: Post-Operative Well Being: Daily Crystalloid Volume
timeFrame: up to 72 hours post op
measure: Post-Operative Well Being: Daily Blood Product Transfusion Volume
timeFrame: up to 72 hours post op
measure: Post-Operative Well Being: Daily Chest Tube Output Volume
timeFrame: up to 72 hours post op
measure: Post-Operative Well Being: Duration of Post-Operative Mechanical Ventilation
timeFrame: up to Post Operative Day 7
measure: Post-Operative Well Being: PaO2 / FIO2 ratios
timeFrame: Post Operative Day 1, Post Operative Day 2, Post Operative Day 3
measure: Post-Operative Well Being: Time to Clearance of Lactate
timeFrame: up to Post Operative Day 3
Other outcomes:
Locations:
Study officials:
affiliation: UW School of Medicine and Public Health
name: Micah Long, MD
role: PRINCIPAL_INVESTIGATOR
References: