Back to resultsThe Effect of Acetaminophen on Non-alcoholic Fatty Liver Disease Patients
Primary Purpose
Non-alcoholic Fatty Liver Disease (NAFLD)
Status
Withdrawn
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Acetaminophen
Sponsored by
About this trial
This is an interventional other trial for Non-alcoholic Fatty Liver Disease (NAFLD) focused on measuring Acetaminophen, Non-alcoholic Fatty Liver Disease (NAFLD)
Eligibility Criteria
NAFLD patients:
Inclusion criteria:
- "Presence of NAFLD": This will be defined by the presence of at least two of the following criteria: (a) suggestion of liver fat by an imaging study (ultrasound, CT scan, MRI or MR spectroscopy) performed in the 6 months prior to enrollment; (b) elevated aminotransferase levels (ALT > 31 U/L for men or > 19 U/L for women, or AST > 30 U/L) on at least two occasions in the 6 months preceding enrollment; and (c) presence of the metabolic syndrome, defined according to the modified AHA/NCEP criteria. Biopsies are not required; however, previous biopsy done within the 6 months prior to the initiation of the study will be considered diagnostic if typical findings of NAFLD are described and other causes of liver disease are ruled out;
- Individuals who are 18-70 years old;
- Written informed consent.
Exclusion criteria:
- Serum ALT > 3 times ULN at baseline.
- Evidence of another form of liver disease including viral hepatitis, autoimmune hepatitis, cholestatic liver disease, Wilson's disease, Alpha-1-antitrypsin deficiency, hemochromatosis or DILI.
- History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol intake averaging greater than 10 gm/day (1 drink per day: 7 drinks per week) in the previous one year.
- Evidence of liver cirrhosis on labs or imaging.
- History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis in the previous 6 months.
- Significant systemic or major illnesses other than liver disease.
- Positive test for anti-HIV.
- Active substance abuse.
- Pregnancy or inability to practice adequate contraception in women of childbearing potential
- Evidence of hepatocellular carcinoma.
- Any other condition which, in the opinion of the investigators, would impede competence or compliance.
- Serum creatinine >1.5 mg/dl.
- Starting medications that have been shown to cause drug induced liver injury (eg, augmentin, statins.) within one month prior to enrollment. Medications that have been known to cause DILI but have taken for more than one month prior to enrollment (such as statins) should not be an exclusion.
Healthy Controls:
Inclusion criteria:
- Individuals who are 18-70 years old
- Normal Liver enzymes
- Negative hepatitis B surface antigen, and hepatitis C antibody
- BMI (18.5 - 24.9) kg/m2
- Written informed consent.
Exclusion criteria:
- Presence of the metabolic syndrome, defined according to the modified AHA/NCEP criteria
- Taking concomitant medications
Sites / Locations
- USC
- USC HCC II (Fatty Liver Clinic)
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
NAFLD patients
Healthy controls
Arm Description
Twenty patients with NAFLD will take 3g of APAP daily for 14 days. Serum liver chemistries and trough acetaminophen (APAP) concentrations will be measured on treatment days 0, 2, 4, 7, 9, 11, 14 and on follow up day 17
Twenty healthy controls will take 3g of APAP daily for 14 days. Serum liver chemistries and trough acetaminophen (APAP) concentrations will be measured on treatment days 0, 2, 4, 7, 9, 11, 14 and on follow up day 17
Outcomes
Primary Outcome Measures
This pilot study will seek to answer the question of whether or not NAFLD patients are more prone to APAP toxicity and whether or not lower doses should be recommended.
Liver injury in controls will be defined as an increase in the alanine aminotransferase (ALT) level and/or Aspartae aminotransferase (AST) ≥ three times the upper limit of normal (ULN). Liver Injury in NAFLD patients will be defined as rise of ALT and/or AST ≥3 times baseline levels (which are likely to be elevated) and reaching 5 times ULN. Acetaminophen will be immediately discontinued once the ALT and/or AST reache the defined liver injury level and patients will continue to be monitored. Comparison between the two groups will assess whether or not NAFLD patients are more prone to liver injury than controls.
Secondary Outcome Measures
Exploring possible mechanism of acetaminophen liver injury in NAFLD patients
We plan to measure the serum and urine levels of APAP metabolites including serum levels of acetaminophen-glucuronide (APAP-G) and acetaminophen-sulfate (APAP-S) and the urine levels of cysteine and mercapturic acid conjugates (APAP-C and APAP-M). We also plan to measure APAP protein adducts which are biomarkers of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite NAPQI. We will measure the serum glutathione level and serum markers of mitochondrial injury, including glutamate dehydrogenase (GLDH) and acylcarnitine, as well as markers of necrosis such as miR-122, high-mobility group box-1 protein (HMGB1), full-length keratin 18 and apoptosis marker keratin 18 fragments. The activity of UGT will be estimated by the plasma ratio of APAP-G to APAP at 4 hours (when the first sample is drawn). Expression of CYP2E1 in the peripheral lymphocytes will be assessed using reverse transcription polymerase chain reaction (RT-PCR).
Full Information
NCT ID
NCT02194894
First Posted
June 7, 2014
Last Updated
March 28, 2017
Sponsor
University of Southern California
1. Study Identification
Unique Protocol Identification Number
NCT02194894
Brief Title
The Effect of Acetaminophen on Non-alcoholic Fatty Liver Disease Patients
Official Title
The Effect of Daily Acetaminophen on Patients With Non-alcoholic Fatty Liver Disease (NAFLD) Compared to Healthy Controls
Study Type
Interventional
2. Study Status
Record Verification Date
June 2014
Overall Recruitment Status
Withdrawn
Why Stopped
No patients enrolled
Study Start Date
June 2014 (undefined)
Primary Completion Date
March 19, 2015 (Actual)
Study Completion Date
March 19, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Southern California
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
In this first pilot study, we will examine the effects of acetaminophen dosing in adult patients with NAFLD in comparison to the effects in a healthy control group. Both groups will receive 3 grams (g) of acetaminophen, the maximum recommended daily dose, daily for 14 days. We hypothesize that NAFLD patients are more prone to APAP toxicity than normal controls.Treatment will be stopped after two weeks or in the following conditions:
Treatment with APAP will be stopped in healthy volunteers if ALT and/or AST reached three times the ULN. In patients with NAFLD, treatment will be stopped if: ALT or AST reach ≥ three times the upper limit of entry value or ≥ 5 times the ULN; or if there is ALT or AST >3 times ULN and TBili >2xULN or INR >1.5; or if there is ALT or AST >3 times ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). We follow a conservative approach derived from the FDA guidelines for stopping medications expected to cause drug induced liver injury (DILI). Indeed, the FDA allows continuation of the medication until ALT or AST are >8x ULN in the absence of elevated Tbili or INR. Patients who have hepatotoxicity will have close monitoring of their liver enzymes until they normalize. Taking acetaminophen up to 3g daily has been shown to be safe and acceptable. We have followed very strict criteria for monitoring and stopping rules however in the usually cases of toxicity the patient will be admitted for monitoring.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-alcoholic Fatty Liver Disease (NAFLD)
Keywords
Acetaminophen, Non-alcoholic Fatty Liver Disease (NAFLD)
7. Study Design
Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
NAFLD patients
Arm Type
Active Comparator
Arm Description
Twenty patients with NAFLD will take 3g of APAP daily for 14 days. Serum liver chemistries and trough acetaminophen (APAP) concentrations will be measured on treatment days 0, 2, 4, 7, 9, 11, 14 and on follow up day 17
Arm Title
Healthy controls
Arm Type
Active Comparator
Arm Description
Twenty healthy controls will take 3g of APAP daily for 14 days. Serum liver chemistries and trough acetaminophen (APAP) concentrations will be measured on treatment days 0, 2, 4, 7, 9, 11, 14 and on follow up day 17
Intervention Type
Drug
Intervention Name(s)
Acetaminophen
Other Intervention Name(s)
APAP
Intervention Description
acetaminophen will be given for patient for both arms for 14 days
Primary Outcome Measure Information:
Title
This pilot study will seek to answer the question of whether or not NAFLD patients are more prone to APAP toxicity and whether or not lower doses should be recommended.
Description
Liver injury in controls will be defined as an increase in the alanine aminotransferase (ALT) level and/or Aspartae aminotransferase (AST) ≥ three times the upper limit of normal (ULN). Liver Injury in NAFLD patients will be defined as rise of ALT and/or AST ≥3 times baseline levels (which are likely to be elevated) and reaching 5 times ULN. Acetaminophen will be immediately discontinued once the ALT and/or AST reache the defined liver injury level and patients will continue to be monitored. Comparison between the two groups will assess whether or not NAFLD patients are more prone to liver injury than controls.
Time Frame
14 days
Secondary Outcome Measure Information:
Title
Exploring possible mechanism of acetaminophen liver injury in NAFLD patients
Description
We plan to measure the serum and urine levels of APAP metabolites including serum levels of acetaminophen-glucuronide (APAP-G) and acetaminophen-sulfate (APAP-S) and the urine levels of cysteine and mercapturic acid conjugates (APAP-C and APAP-M). We also plan to measure APAP protein adducts which are biomarkers of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite NAPQI. We will measure the serum glutathione level and serum markers of mitochondrial injury, including glutamate dehydrogenase (GLDH) and acylcarnitine, as well as markers of necrosis such as miR-122, high-mobility group box-1 protein (HMGB1), full-length keratin 18 and apoptosis marker keratin 18 fragments. The activity of UGT will be estimated by the plasma ratio of APAP-G to APAP at 4 hours (when the first sample is drawn). Expression of CYP2E1 in the peripheral lymphocytes will be assessed using reverse transcription polymerase chain reaction (RT-PCR).
Time Frame
14 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
NAFLD patients:
Inclusion criteria:
"Presence of NAFLD": This will be defined by the presence of at least two of the following criteria: (a) suggestion of liver fat by an imaging study (ultrasound, CT scan, MRI or MR spectroscopy) performed in the 6 months prior to enrollment; (b) elevated aminotransferase levels (ALT > 31 U/L for men or > 19 U/L for women, or AST > 30 U/L) on at least two occasions in the 6 months preceding enrollment; and (c) presence of the metabolic syndrome, defined according to the modified AHA/NCEP criteria. Biopsies are not required; however, previous biopsy done within the 6 months prior to the initiation of the study will be considered diagnostic if typical findings of NAFLD are described and other causes of liver disease are ruled out;
Individuals who are 18-70 years old;
Written informed consent.
Exclusion criteria:
Serum ALT > 3 times ULN at baseline.
Evidence of another form of liver disease including viral hepatitis, autoimmune hepatitis, cholestatic liver disease, Wilson's disease, Alpha-1-antitrypsin deficiency, hemochromatosis or DILI.
History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol intake averaging greater than 10 gm/day (1 drink per day: 7 drinks per week) in the previous one year.
Evidence of liver cirrhosis on labs or imaging.
History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis in the previous 6 months.
Significant systemic or major illnesses other than liver disease.
Positive test for anti-HIV.
Active substance abuse.
Pregnancy or inability to practice adequate contraception in women of childbearing potential
Evidence of hepatocellular carcinoma.
Any other condition which, in the opinion of the investigators, would impede competence or compliance.
Serum creatinine >1.5 mg/dl.
Starting medications that have been shown to cause drug induced liver injury (eg, augmentin, statins.) within one month prior to enrollment. Medications that have been known to cause DILI but have taken for more than one month prior to enrollment (such as statins) should not be an exclusion.
Healthy Controls:
Inclusion criteria:
Individuals who are 18-70 years old
Normal Liver enzymes
Negative hepatitis B surface antigen, and hepatitis C antibody
BMI (18.5 - 24.9) kg/m2
Written informed consent.
Exclusion criteria:
Presence of the metabolic syndrome, defined according to the modified AHA/NCEP criteria
Taking concomitant medications
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mazen Noureddin
Organizational Affiliation
University of Southern California
Official's Role
Principal Investigator
Facility Information:
Facility Name
USC
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
USC HCC II (Fatty Liver Clinic)
City
Los Angeles
State/Province
California
ZIP/Postal Code
91105
Country
United States
12. IPD Sharing Statement
Learn more about this trial
The Effect of Acetaminophen on Non-alcoholic Fatty Liver Disease Patients
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