Parenteral Ascorbic Acid Repletion in TransplantatIon (PARTI)

Parenteral Ascorbic Acid Repletion in TransplantatIon (PARTI): A Randomized, Double-Blinded, Placebo-Controlled Trial

A single-center, randomized, double-blinded placebo-controlled trial is proposed to investigate administration of supraphysiologic doses of ascorbic acid (vitamin C, AA) to patients undergoing liver transplantation. Participants randomized to the intervention group will receive intravenous (IV) AA 1500 mg every 6 hours for 48 hours. Participants randomized to the control group will receive a saline placebo. The primary study outcome will be a change in the Sequential Organ Failure Assessment (SOFA) score from baseline to three days after the first dose of drug (dSOFA3). Secondary outcomes will include total vasopressor dose in norepinephrine equivalents, 30-day and 1-year mortality, and serum AA levels.

Study Overview

• Status: Recruiting
• Conditions: Liver Transplant Failure and Rejection
• Intervention / Treatment: Other: Placebo; Drug: Ascorbic acid

Detailed Description

HYPOTHESIS: Administration of supraphysiologic doses of parenteral AA in the perioperative period for patients undergoing liver transplantation will improve Sequential Organ Failure Assessment (SOFA) scores, vasopressor usage and biochemical, cellular and clinical end-organ damage.

Specific Aim: Determine the clinical response to parenteral AA supplementation in patients undergoing liver transplantation by a randomized, double-blinded, placebo-controlled clinical trial.

Study Design: This study is a prospective, single-center, randomized trial in which 90 participants will be enrolled at the University of Wisconsin Hospitals and Clinics (UWHC). Participants must meet study eligibility criteria and be scheduled to undergo primary deceased donor solitary liver transplantation. Participants will be randomized to receive 8 doses of 1500 mg AA IV or volume-equivalent placebo every 6 hours for 48 hours, in addition to standard medical management.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Helen Akere; Phone Number: (608) 265-3243; Email: akere@wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Recruiting
      • University of Wisconsin Hospital and Clinics
      • Contact: Brian Payne; Phone Number: 608-890-0156; Email: bepayne@wisc.edu
      • Principal Investigator: Molly Groose, MD, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• The subject is scheduled to undergo primary deceased donor solidary liver transplantation

Exclusion Criteria:

• Non-English speaking
• Known or believed to be pregnant
• Subject is a prisoner
• Impaired decision-making capacity (i.e., current encephalopathy)
• Known allergy to AA
• Concurrent organ transplantation (i.e., simultaneous liver-kidney transplantation)
• Planned veno-venous bypass use in the operating room
• Prior parenteral or oral AA repletion
• History of nephrolithiasis or oxaluria
• Vitamin C supplement use or administration (including HAT therapy) within the last month prior to transplantation
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Sickle cell anemia
• Hereditary hemochromatosis
• Preoperative anuria or creatinine >2.5mg/dL in patient not on renal replacement therapy
• Current enrollment in another research study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ascorbic Acid (AA); The first intravenous dosage of 1500mg of AA in 100mL of normal saline (NS) will be administered after induction of general anesthesia and invasive line placement prior to surgical incision. An identical dosage will be delivered approximately every 6 hours for the first 48 hours, for a total of 8 doses	Drug: Ascorbic acid; Intravenous vitamin C; Other Names: vitamin C; ASCOR
Placebo Comparator: Placebo; The first intravenous dosage of placebo (100 mL of NS) will be administered after induction of general anesthesia and invasive line placement prior to surgical incision. An identical dosage will be delivered approximately every 6 hours for the first 48 hours, for a total of 8 doses	Other: Placebo; Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Sequential Organ Failure Assessment (SOFA) Score	SOFA scores are a widely used composite measure of multiorgan dysfunction, validated as an accurate predictor of short- and long-term mortality in the general ICU and liver transplant populations. Change in SOFA from baseline (delta SOFA or dSOFA) has been shown to be more predictive of mortality than other derivatives such as absolute interval SOFA scores and has been recommended as the preferred endpoint in critical care settings The total possible range of scores is 0-24, higher scores are indicative of a higher degree of dysfunction.	baseline to 3 days after first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum AA Levels		Pre-treatment (baseline) and Post-treatment (up to 1 week)
Total Vasopressor Dose in Norepinephrine Equivalents per Kilogram		from start of anesthesia (day 1) to end of ICU stay (up to 1 week)
Incidence of Early Graft Dysfunction	As defined per Olthoff as: total bilirubin ≥10 or INR≥1.6 on day 7, or transaminase >2000 within first 7 days	postoperative (up to 7 days or until discharge, whichever came first)
Postoperative Day 7 SOFA Score	Total range of scores 0-24 where higher scores indicate higher dysfunction.	postoperative (up to 3 days)
Days on Ventilator		postoperative (up to ~ 7 days)
Incidence of Infection	Surgical site, bloodstream & intra-abdominal infection rates	postoperative (up to ~ 7 days)
Length of ICU stay		postoperative (up to ~ 7 days)
Length of Hospital stay		postoperative (up to ~ 30 days)
30 day Mortality		up to 30 days post-op
1-year Mortality		up to 1-year post-op

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Investigators: Principal Investigator: Molly Groose, MD, MS, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: February 11, 2021
• First Submitted That Met QC Criteria: February 15, 2021
• First Posted (Actual): February 16, 2021

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: 2020-1153 (M D Anderson Cancer Center); A530900 (Other Identifier: UW Madison); SMPH/ANESTHESIOLOGY (Other Identifier: UW Madison); Protocol Version 10/20/2020 (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. Molly Groose, the Principal Investigator of this study
• IPD Sharing Time Frame: up to 7 years after primary completion
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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