Alcoholic Hepatitis, Sepsis
Conditions
Brief summary
The purpose of this research study is to test the safety, tolerability, and effectiveness of Vitamin C (ascorbic acid) intravenous infusion when used to treat alcoholic hepatitis (inflammation of the liver from heavy alcohol use) and sepsis (life-threatening complication of an infection).
Detailed description
Alcoholic hepatitis is inflammation of the liver due to alcohol consumption. It can cause one or more of the following symptoms such as jaundice (yellow discoloration of the eyes and skin), pain on the right side of the abdomen, and is accompanied by an enlarged liver. Sepsis is a life-threatening complication of an infection. As the body tries to fight an infection it sends chemicals into the bloodstream. These chemicals that are trying to fight the infection can cause inflammation. This inflammation can cause damage to many body systems and make them fail. Patients with alcoholic hepatitis and sepsis have low levels of Vitamin C in the bloodstream. Vitamin C has been shown to reduce inflammation and organ dysfunction in patients with severe infections. The investigators do not yet know if Vitamin C will be effective in alcoholic hepatitis. Taking Vitamin C by mouth is not effective as a treatment in people with this condition so participants will receive the Vitamin C intravenously (IV). Participants will be randomly assigned to receive either Vitamin C or a placebo given through an IV every six hours for four days.
Interventions
DRUGVitamin C
200mg/kg/24hours
50mL intravenously every 6 hours
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Study drug will be double-blind with matching placebo. Vitamin C 200mg/kg/24hours or placebo (Dextrose 5% in water) will be given intravenously every 6 hours for up to 96 hours of treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Alcoholic Hepatitis diagnosed by one of the following methods: 1. liver biopsy 2. clinical diagnosis based on history of alcohol use, presence of jaundice (yellowing of skin), blood tests indicating liver injury, and absence of other causes of liver injury (autoimmune disease, viral hepatitis, drug toxicity) 2. Suspected or proven infection 3. Presence of systemic inflammatory response to infection (fever, hypothermia (low temperature), tachycardia (fast heart rate), leukocytosis (high white blood cell count), leukopenia (low white blood cell count), high respiratory (breathing) rate, or need for mechanical ventilation (a machine to assist in breathing). 4. Presence of organ failure due to the body's response to infection indicated by any of the following: 1. Hypotension (low blood pressure) or need for medications to raise blood pressure 2. Arterial hypoxemia (low blood oxygen) or need for high flow of oxygen 3. High lactate level (blood test indicating active response to infection) 4. Low urine output despite administration of intravenous fluids 5. Low platelet count (blood test) 6. Coagulopathy (decreased blood clotting ability based on a blood test) 7. High bilirubin (blood test) 8. Mental status changes (confusion or delirium) 5. Absence of drugs present on urine or blood tests that indicate the possibility of liver damage or mental status changes from other causes
Exclusion criteria
1. Allergy to Vitamin C 2. Unable to provide consent 3. Age less than 18 years 4. No intravenous access (IV line) in a patient needing glucose (blood sugar) checks more than twice daily 5. Presence of diabetic ketoacidosis (a serious complication of diabetes) 6. Inability of patient, legally authorized representative and/or physician to commit to full medical support 7. Pregnancy or breast feeding 8. Life expectancy less than 24 hours 9. Active or history of kidney stone 10. History of chronic kidney disease 11. History of glucose-6-phosphate deficiency (a low blood protein that can cause red blood cells to break down) 12. Active cancer (except non-melanoma skin cancer) 13. Uncontrolled gastrointestinal bleeding 14. Other causes of liver injury such as viruses, autoimmune disease, drug toxicity 15. History of severe liver cirrhosis complications including variceal bleeding within the last 3 months, large ascites (fluid accumulation in the abdomen) or hepatocellular carcinoma (liver cancer) 16. History of organ transplantation 17. Initial AST or ALT (blood test indicating a liver problem) 18. Presence of acetaminophen or other drugs on urine or blood toxicology test 19. Non-English speaking 20. Prisoner or other ward of the state
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Model for End Stage Liver Disease (MELD) Score | Baseline and 96 hours | Change in MELD score from Day 0 to Day 4. MELD score ranges from 6 (least sick) to 40 (most sick) based on blood tests which ranks the degree of sickness from liver disease. The lab tests used to determine the MELD score are creatinine, bilirubin, and international normalized ratio (INR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Aspartate Aminotransferase (AST) Level | Baseline and 96 hours | Standard blood test used to determine the severity and nature of liver problems. |
| Change in Alanine Aminotransferase (ALT) Level | Baseline and 96 hours | Standard blood test used to determine the severity and nature of liver problems. |
| Change in Total Bilirubin | Baseline and 96 hours | Standard blood test used to determine the severity and nature of liver problems. |
| Change in Alkaline Phosphatase | Baseline and 96 hours | Standard blood test used to determine the severity and nature of liver problems. |
| Change in Albumin | Baseline and 96 hours | Standard blood test used to determine the severity and nature of liver problems. |
| Number of Treatment-related Adverse Events as Assessed by CTCAE v5.0 | up to 96 hours | Observation about the need to change the dose of study medication and symptoms such as headache, dizziness, dry mouth, nausea, vomiting, flushing, rash, or hypotension (low blood pressure) |
| Change in Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) Score | Baseline and 96 hours | A number that ranges from 0 (least sick) to 24 (most sick) and ranks the degree of sickness from liver failure and several other organ systems in a critically ill person. The score is determined by evaluating a person's liver function, kidney function, nervous system (brain), coagulation (blood clotting), circulation (blood pressure), and respiratory status (breathing) |
| Changes to Urine pH | Baseline and 96 hours | Urine samples are collected to determine changes in pH (acidity) that could indicate a risk for kidney stones. The pH scale ranges from 0 to 14, with smaller numbers meaning more acidic and higher numbers meaning more basic. A pH of 7 is considered to be neutral. Normal levels of urine pH range from 4.6 - 8 on the pH scale. |
| Changes to Urine Microscopy | Baseline and 96 hours | Urine samples are collected to check for the presence of crystalluria (microscopic crystals) that could indicate a risk for kidney stones. |
| Changes to Level of Medical Care | up to 168 hours | Documentation of the need for more intensive medical care such as ventilator (breathing machine) or vasopressors (intravenous medications use increase blood pressure) when not needed at baseline |
| ICU-free Days | Day 28 | The number of days not spent in an intensive care unit (ICU) |
| Number of Deaths Due to Any Cause | Day 28 | Any cause of death that is anticipated or unanticipated |
| Hospital-free Days | Day 90 | The number of days spent outside of the hospital |
| Changes to Corrected QT Interval (QTc) | Baseline and 96 hours | An electrocardiogram (ECG or test of the electrical activity of the heart) is performed to determine if there are changes to the heart rhythm. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vitamin C Infusion (Ascorbic Acid) Vitamin C 200mg/kg/24hours administered in four doses per day (given every 6 hours)
Vitamin C: 200mg/kg/24hours
Dextrose 5% in water: 50mL intravenously every 6 hours | 10 |
| Placebo Dextrose 5% in water 50 milliliters (mL) administered intravenously every 6 hours
Dextrose 5% in water: 50mL intravenously every 6 hours | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Discharge from hospital | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Vitamin C Infusion (Ascorbic Acid) | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 40.1 years STANDARD_DEVIATION 9.5 | 46.9 years STANDARD_DEVIATION 12.5 | 48.4 years STANDARD_DEVIATION 14.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 19 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 17 Participants | 9 Participants |
| Region of Enrollment United States | 10 participants | 20 participants | 10 participants |
| Sex: Female, Male Female | 7 Participants | 14 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 10 | 4 / 10 |
| other Total, other adverse events | 7 / 10 | 5 / 10 |
| serious Total, serious adverse events | 2 / 10 | 0 / 10 |
Outcome results
Primary
Change in Model for End Stage Liver Disease (MELD) Score
Change in MELD score from Day 0 to Day 4. MELD score ranges from 6 (least sick) to 40 (most sick) based on blood tests which ranks the degree of sickness from liver disease. The lab tests used to determine the MELD score are creatinine, bilirubin, and international normalized ratio (INR).
Time frame: Baseline and 96 hours
Population: Labs were not collected from 4 participants on day 4 so change in MELD score could not be calculated for those participants and they are omitted from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Change in Model for End Stage Liver Disease (MELD) Score | All patients | -0.13 score on a scale | Standard Deviation 7 |
| Vitamin C Infusion (Ascorbic Acid) | Change in Model for End Stage Liver Disease (MELD) Score | Patients alive at 4 weeks | -2.3 score on a scale | Standard Deviation 5.2 |
| Placebo | Change in Model for End Stage Liver Disease (MELD) Score | All patients | -2.9 score on a scale | Standard Deviation 3.3 |
| Placebo | Change in Model for End Stage Liver Disease (MELD) Score | Patients alive at 4 weeks | -2.4 score on a scale | Standard Deviation 1.3 |
Secondary
Change in Alanine Aminotransferase (ALT) Level
Standard blood test used to determine the severity and nature of liver problems.
Time frame: Baseline and 96 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Change in Alanine Aminotransferase (ALT) Level | 62.71 IU/L | Standard Deviation 155.26 |
| Placebo | Change in Alanine Aminotransferase (ALT) Level | 1.00 IU/L | Standard Deviation 14.65 |
Secondary
Change in Albumin
Standard blood test used to determine the severity and nature of liver problems.
Time frame: Baseline and 96 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Change in Albumin | -0.10 g/dL | Standard Deviation 0.71 |
| Placebo | Change in Albumin | 0.06 g/dL | Standard Deviation 0.99 |
Secondary
Change in Alkaline Phosphatase
Standard blood test used to determine the severity and nature of liver problems.
Time frame: Baseline and 96 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Change in Alkaline Phosphatase | -5.71 U/L | Standard Deviation 67.9 |
| Placebo | Change in Alkaline Phosphatase | -7.50 U/L | Standard Deviation 52.86 |
Secondary
Change in Aspartate Aminotransferase (AST) Level
Standard blood test used to determine the severity and nature of liver problems.
Time frame: Baseline and 96 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Change in Aspartate Aminotransferase (AST) Level | 176.0 IU/L | Standard Deviation 466.28 |
| Placebo | Change in Aspartate Aminotransferase (AST) Level | -16.5 IU/L | Standard Deviation 53.07 |
Secondary
Change in Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) Score
A number that ranges from 0 (least sick) to 24 (most sick) and ranks the degree of sickness from liver failure and several other organ systems in a critically ill person. The score is determined by evaluating a person's liver function, kidney function, nervous system (brain), coagulation (blood clotting), circulation (blood pressure), and respiratory status (breathing)
Time frame: Baseline and 96 hours
Population: Data not recorded for all participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Change in Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) Score | Baseline | 14 score on a scale | — |
| Placebo | Change in Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) Score | Baseline | 15.33 score on a scale | Standard Deviation 0.577 |
| Placebo | Change in Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) Score | Day 4 | 12.75 score on a scale | Standard Deviation 1.708 |
Secondary
Change in Total Bilirubin
Standard blood test used to determine the severity and nature of liver problems.
Time frame: Baseline and 96 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Change in Total Bilirubin | -0.30 mg/dL | Standard Deviation 5.69 |
| Placebo | Change in Total Bilirubin | 0.45 mg/dL | Standard Deviation 5.79 |
Secondary
Changes to Corrected QT Interval (QTc)
An electrocardiogram (ECG or test of the electrical activity of the heart) is performed to determine if there are changes to the heart rhythm.
Time frame: Baseline and 96 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Changes to Corrected QT Interval (QTc) | -10.00 milliseconds | Standard Deviation 29.47 |
| Placebo | Changes to Corrected QT Interval (QTc) | -58.17 milliseconds | Standard Deviation 88.56 |
Secondary
Changes to Level of Medical Care
Documentation of the need for more intensive medical care such as ventilator (breathing machine) or vasopressors (intravenous medications use increase blood pressure) when not needed at baseline
Time frame: up to 168 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Changes to Level of Medical Care | 2 Participants |
| Placebo | Changes to Level of Medical Care | 1 Participants |
Secondary
Changes to Urine Microscopy
Urine samples are collected to check for the presence of crystalluria (microscopic crystals) that could indicate a risk for kidney stones.
Time frame: Baseline and 96 hours
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Changes to Urine Microscopy | Number of participants with crystalluria at baseline | 0 Participants |
| Vitamin C Infusion (Ascorbic Acid) | Changes to Urine Microscopy | Number of patients with crystalluria at Day 4 | 0 Participants |
| Placebo | Changes to Urine Microscopy | Number of participants with crystalluria at baseline | 0 Participants |
| Placebo | Changes to Urine Microscopy | Number of patients with crystalluria at Day 4 | 0 Participants |
Secondary
Changes to Urine pH
Urine samples are collected to determine changes in pH (acidity) that could indicate a risk for kidney stones. The pH scale ranges from 0 to 14, with smaller numbers meaning more acidic and higher numbers meaning more basic. A pH of 7 is considered to be neutral. Normal levels of urine pH range from 4.6 - 8 on the pH scale.
Time frame: Baseline and 96 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Changes to Urine pH | 5.31 units on a scale | Standard Deviation 2.01 |
| Placebo | Changes to Urine pH | 5.17 units on a scale | Standard Deviation 0.41 |
Secondary
Hospital-free Days
The number of days spent outside of the hospital
Time frame: Day 90
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Hospital-free Days | 58.40 days | Standard Deviation 32.91 |
| Placebo | Hospital-free Days | 48.88 days | Standard Deviation 33.04 |
Secondary
ICU-free Days
The number of days not spent in an intensive care unit (ICU)
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | ICU-free Days | 16.40 days | Standard Deviation 14.17 |
| Placebo | ICU-free Days | 13.20 days | Standard Deviation 13.06 |
Secondary
Number of Deaths Due to Any Cause
Any cause of death that is anticipated or unanticipated
Time frame: Day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Number of Deaths Due to Any Cause | 4 Deaths |
| Placebo | Number of Deaths Due to Any Cause | 3 Deaths |
Secondary
Number of Deaths Due to Any Cause
Any cause of death that is anticipated or unanticipated
Time frame: Day 90
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Number of Deaths Due to Any Cause | 5 Deaths |
| Placebo | Number of Deaths Due to Any Cause | 4 Deaths |
Secondary
Number of Treatment-related Adverse Events as Assessed by CTCAE v5.0
Observation about the need to change the dose of study medication and symptoms such as headache, dizziness, dry mouth, nausea, vomiting, flushing, rash, or hypotension (low blood pressure)
Time frame: up to 96 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin C Infusion (Ascorbic Acid) | Number of Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 12 Adverse Events |
| Placebo | Number of Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 11 Adverse Events |