The Effect of Acetaminophen on Non-alcoholic Fatty Liver Disease Patients

NCT02194894 | Withdrawn DMC

• 1 other identifier: HS-13-00771
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 2

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.

Conditions

Non-alcoholic Fatty Liver Disease (NAFLD)

Keywords

Acetaminophen, Non-alcoholic Fatty Liver Disease (NAFLD)

Outcome Measures

Primary Outcomes (1)

• 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.

  14 days

Secondary Outcomes (1)

• Exploring possible mechanism of acetaminophen liver injury in NAFLD patients

  14 days

Study Arms (2)

NAFLD patients

ACTIVE COMPARATOR

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

Drug: Acetaminophen

Healthy controls

ACTIVE COMPARATOR

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

Drug: Acetaminophen

Interventions

Acetaminophen DRUG

acetaminophen will be given for patient for both arms for 14 days

Also known as: APAP

Healthy controls; NAFLD patients

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• "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.

You may not qualify if:

• 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.
• Healthy Controls:
• Individuals who are 18-70 years old
• Normal Liver enzymes

Sponsors & Collaborators

• University of Southern California: lead

Study Sites (2)

USC

Los Angeles, California, 90033, United States

Location

USC HCC II (Fatty Liver Clinic)

Los Angeles, California, 91105, United States

Location

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

Acetaminophen

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Study Officials

• Mazen Noureddin

  University of Southern California

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2014
• First Posted: July 18, 2014
• Study Start: June 1, 2014
• Primary Completion: March 19, 2015
• Study Completion: March 19, 2015
• Last Updated: March 30, 2017

Record last verified: 2014-06

Locations

US (2)