Clinical trial NCT02194894: 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
Overall status: WITHDRAWN
Phase: NA
Conditions: Non-alcoholic Fatty Liver Disease (NAFLD)
Keywords: Acetaminophen, Non-alcoholic Fatty Liver Disease (NAFLD)
Lead sponsor: University of Southern California
Sponsor class: OTHER
First posted: 2014-07-18
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.


Eligibility criteria: NAFLD patients:

Inclusion criteria:

1. "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;
2. Individuals who are 18-70 years old;
3. Written informed consent.

Exclusion criteria:

1. Serum ALT \> 3 times ULN at baseline.
2. 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.
3. 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.
4. Evidence of liver cirrhosis on labs or imaging.
5. History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis in the previous 6 months.
6. Significant systemic or major illnesses other than liver disease.
7. Positive test for anti-HIV.
8. Active substance abuse.
9. Pregnancy or inability to practice adequate contraception in women of childbearing potential
10. Evidence of hepatocellular carcinoma.
11. Any other condition which, in the opinion of the investigators, would impede competence or compliance.
12. Serum creatinine \>1.5 mg/dl.
13. 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:

1. Individuals who are 18-70 years old
2. Normal Liver enzymes
3. Negative hepatitis B surface antigen, and hepatitis C antibody
4. BMI (18.5 - 24.9) kg/m2
5. Written informed consent.

Exclusion criteria:

1. Presence of the metabolic syndrome, defined according to the modified AHA/NCEP criteria
2. Taking concomitant medications

Primary outcomes:
measure: 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.
timeFrame: 14 days
Secondary outcomes:
measure: Exploring possible mechanism of acetaminophen liver injury in NAFLD patients
timeFrame: 14 days
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC
state: California
city: Los Angeles
country: United States
facility: USC HCC II (Fatty Liver Clinic)
state: California
Study officials:
affiliation: University of Southern California
name: Mazen Noureddin
role: PRINCIPAL_INVESTIGATOR
References: