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Perioperative Vitamin C Lung Transplant

Primary Purpose

Primary Graft Dysfunction, Lung Transplant; Complications

Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Vitamin C
Sponsored by
University of Wisconsin, Madison
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Graft Dysfunction focused on measuring Vitamin C

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Vitamin C Arm

    Arm Description

    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

    Outcomes

    Primary Outcome Measures

    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).
    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).
    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).
    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).
    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).
    Incidence of New Dialysis Initiation

    Secondary Outcome Measures

    Participant Vitamin C Levels
    Participant Thiamine Levels
    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.
    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.
    Tacrolimus Levels
    Tacrolimus Doses
    Post-Operative Well Being: Mortality
    Post-Operative Well Being: Atrial Fibrillation
    Post-Operative Well Being: ICU Length of Stay
    Post-Operative Well Being: Hospital Length of Stay
    Post-Operative Well Being: Nadir Cardiac Index
    Post-Operative Well Being: Peak Pulmonary Artery Systolic Pressure
    Post-Operative Well Being: Peak Pulmonary Artery Diastolic Pressure
    Post-Operative Well Being: Duration of Inotrope Need
    Post-Operative Well Being: Duration of Vasopressor
    Post-Operative Well Being: Total Dose of Vasopressor
    Post-Operative Well Being: Daily Crystalloid Volume
    for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours
    Post-Operative Well Being: Daily Blood Product Transfusion Volume
    for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours
    Post-Operative Well Being: Daily Chest Tube Output Volume
    for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours
    Post-Operative Well Being: Duration of Post-Operative Mechanical Ventilation
    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 Well Being: Time to Clearance of Lactate
    "Clearance" is defined as a lactate <1 mmol/L.

    Full Information

    First Posted
    August 5, 2020
    Last Updated
    April 27, 2023
    Sponsor
    University of Wisconsin, Madison
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04505878
    Brief Title
    Perioperative Vitamin C Lung Transplant
    Official Title
    Vitamin C: Assessing Safety After Lung Transplant
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    April 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Decided not to proceed with study
    Study Start Date
    April 2023 (Anticipated)
    Primary Completion Date
    December 2023 (Anticipated)
    Study Completion Date
    December 2023 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    University of Wisconsin, Madison

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. 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.
    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

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Primary Graft Dysfunction, Lung Transplant; Complications
    Keywords
    Vitamin C

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    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)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Vitamin C Arm
    Arm Type
    Experimental
    Arm Description
    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
    Intervention Type
    Drug
    Intervention Name(s)
    Vitamin C
    Other Intervention Name(s)
    ascorbic acid
    Intervention Description
    Vitamin C is a first-line antioxidant that directly scavenges free radicals, inhibits reactive oxygen species (ROS) producing enzymes and recovers other cellular antioxidants
    Primary Outcome Measure Information:
    Title
    Incidence and Severity of Kidney Injury Post Operative Day (POD) 1
    Description
    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).
    Time Frame
    Post Operative Day 1
    Title
    Incidence and Severity of Kidney Injury POD 2
    Description
    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).
    Time Frame
    Post Operative Day 2
    Title
    Incidence and Severity of Kidney Injury POD 3
    Description
    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).
    Time Frame
    Post Operative Day 3
    Title
    Incidence and Severity of Kidney Injury POD 4
    Description
    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).
    Time Frame
    Post Operative Day 4
    Title
    Incidence and Severity of Kidney Injury POD 7
    Description
    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).
    Time Frame
    Post Operative Day 7
    Title
    Incidence of New Dialysis Initiation
    Time Frame
    up to Post Operative Day 7
    Secondary Outcome Measure Information:
    Title
    Participant Vitamin C Levels
    Time Frame
    Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3
    Title
    Participant Thiamine Levels
    Time Frame
    Baseline, Post Operative Day 1, Post Operative Day 2, Post Operative Day 3
    Title
    Incidence of Primary Graft Dysfunction (PGD)
    Description
    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.
    Time Frame
    up to Post Operative Day 7
    Title
    Incidence and Severity of PGD on POD 3
    Description
    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.
    Time Frame
    Post Operative Day 3
    Title
    Tacrolimus Levels
    Time Frame
    Post Operative Days 2, 3, 4, and 7
    Title
    Tacrolimus Doses
    Time Frame
    Post Operative Days 4 and 7
    Title
    Post-Operative Well Being: Mortality
    Time Frame
    at Post Operative Day 30 and Post Operative Day 90 via chart review
    Title
    Post-Operative Well Being: Atrial Fibrillation
    Time Frame
    up to Post Operative Day 7
    Title
    Post-Operative Well Being: ICU Length of Stay
    Time Frame
    up to Post Operative Day 30 (chart review)
    Title
    Post-Operative Well Being: Hospital Length of Stay
    Time Frame
    up to Post Operative Day 90 (chart review)
    Title
    Post-Operative Well Being: Nadir Cardiac Index
    Time Frame
    up to 72 hours post op
    Title
    Post-Operative Well Being: Peak Pulmonary Artery Systolic Pressure
    Time Frame
    up to 72 hours post op
    Title
    Post-Operative Well Being: Peak Pulmonary Artery Diastolic Pressure
    Time Frame
    up to 72 hours post op
    Title
    Post-Operative Well Being: Duration of Inotrope Need
    Time Frame
    up to 72 hours post op
    Title
    Post-Operative Well Being: Duration of Vasopressor
    Time Frame
    up to 72 hours post op
    Title
    Post-Operative Well Being: Total Dose of Vasopressor
    Time Frame
    up to 72 hours post op
    Title
    Post-Operative Well Being: Daily Crystalloid Volume
    Description
    for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours
    Time Frame
    up to 72 hours post op
    Title
    Post-Operative Well Being: Daily Blood Product Transfusion Volume
    Description
    for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours
    Time Frame
    up to 72 hours post op
    Title
    Post-Operative Well Being: Daily Chest Tube Output Volume
    Description
    for 0-24h, 24-48h and 48-72h; total volume balance at 72-hours
    Time Frame
    up to 72 hours post op
    Title
    Post-Operative Well Being: Duration of Post-Operative Mechanical Ventilation
    Time Frame
    up to Post Operative Day 7
    Title
    Post-Operative Well Being: PaO2 / FIO2 ratios
    Description
    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 %).
    Time Frame
    Post Operative Day 1, Post Operative Day 2, Post Operative Day 3
    Title
    Post-Operative Well Being: Time to Clearance of Lactate
    Description
    "Clearance" is defined as a lactate <1 mmol/L.
    Time Frame
    up to Post Operative Day 3

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    80 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    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.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Micah Long, MD
    Organizational Affiliation
    UW School of Medicine and Public Health
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing 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

    Learn more about this trial

    Perioperative Vitamin C Lung Transplant

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