<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02194894</url>
  </required_header>
  <id_info>
    <org_study_id>HS-13-00771</org_study_id>
    <nct_id>NCT02194894</nct_id>
  </id_info>
  <brief_title>The Effect of Acetaminophen on Non-alcoholic Fatty Liver Disease Patients</brief_title>
  <official_title>The Effect of Daily Acetaminophen on Patients With Non-alcoholic Fatty Liver Disease (NAFLD) Compared to Healthy Controls</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Southern California</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Southern California</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this first pilot study, we will examine the effects of acetaminophen dosing in adult&#xD;
      patients with NAFLD in comparison to the effects in a healthy control group. Both groups will&#xD;
      receive 3 grams (g) of acetaminophen, the maximum recommended daily dose, daily for 14 days.&#xD;
      We hypothesize that NAFLD patients are more prone to APAP toxicity than normal&#xD;
      controls.Treatment will be stopped after two weeks or in the following conditions:&#xD;
&#xD;
      Treatment with APAP will be stopped in healthy volunteers if ALT and/or AST reached three&#xD;
      times the ULN. In patients with NAFLD, treatment will be stopped if: ALT or AST reach ≥ three&#xD;
      times the upper limit of entry value or ≥ 5 times the ULN; or if there is ALT or AST &gt;3 times&#xD;
      ULN and TBili &gt;2xULN or INR &gt;1.5; or if there is ALT or AST &gt;3 times ULN with the appearance&#xD;
      of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or&#xD;
      eosinophilia (&gt;5%). We follow a conservative approach derived from the FDA guidelines for&#xD;
      stopping medications expected to cause drug induced liver injury (DILI). Indeed, the FDA&#xD;
      allows continuation of the medication until ALT or AST are &gt;8x ULN in the absence of elevated&#xD;
      Tbili or INR. Patients who have hepatotoxicity will have close monitoring of their liver&#xD;
      enzymes until they normalize. Taking acetaminophen up to 3g daily has been shown to be safe&#xD;
      and acceptable. We have followed very strict criteria for monitoring and stopping rules&#xD;
      however in the usually cases of toxicity the patient will be admitted for monitoring.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    No patients enrolled&#xD;
  </why_stopped>
  <start_date>June 2014</start_date>
  <completion_date type="Actual">March 19, 2015</completion_date>
  <primary_completion_date type="Actual">March 19, 2015</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <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.</measure>
    <time_frame>14 days</time_frame>
    <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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Exploring possible mechanism of acetaminophen liver injury in NAFLD patients</measure>
    <time_frame>14 days</time_frame>
    <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).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Non-alcoholic Fatty Liver Disease (NAFLD)</condition>
  <arm_group>
    <arm_group_label>NAFLD patients</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy controls</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetaminophen</intervention_name>
    <description>acetaminophen will be given for patient for both arms for 14 days</description>
    <arm_group_label>Healthy controls</arm_group_label>
    <arm_group_label>NAFLD patients</arm_group_label>
    <other_name>APAP</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        NAFLD patients:&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          1. &quot;Presence of NAFLD&quot;: This will be defined by the presence of at least two of the&#xD;
             following criteria: (a) suggestion of liver fat by an imaging study (ultrasound, CT&#xD;
             scan, MRI or MR spectroscopy) performed in the 6 months prior to enrollment; (b)&#xD;
             elevated aminotransferase levels (ALT &gt; 31 U/L for men or &gt; 19 U/L for women, or AST &gt;&#xD;
             30 U/L) on at least two occasions in the 6 months preceding enrollment; and (c)&#xD;
             presence of the metabolic syndrome, defined according to the modified AHA/NCEP&#xD;
             criteria. Biopsies are not required; however, previous biopsy done within the 6 months&#xD;
             prior to the initiation of the study will be considered diagnostic if typical findings&#xD;
             of NAFLD are described and other causes of liver disease are ruled out;&#xD;
&#xD;
          2. Individuals who are 18-70 years old;&#xD;
&#xD;
          3. Written informed consent.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Serum ALT &gt; 3 times ULN at baseline.&#xD;
&#xD;
          2. Evidence of another form of liver disease including viral hepatitis, autoimmune&#xD;
             hepatitis, cholestatic liver disease, Wilson's disease, Alpha-1-antitrypsin&#xD;
             deficiency, hemochromatosis or DILI.&#xD;
&#xD;
          3. History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day)&#xD;
             in the previous 10 years, or history of alcohol intake averaging greater than 10&#xD;
             gm/day (1 drink per day: 7 drinks per week) in the previous one year.&#xD;
&#xD;
          4. Evidence of liver cirrhosis on labs or imaging.&#xD;
&#xD;
          5. History of gastrointestinal bypass surgery or ingestion of drugs known to produce&#xD;
             hepatic steatosis in the previous 6 months.&#xD;
&#xD;
          6. Significant systemic or major illnesses other than liver disease.&#xD;
&#xD;
          7. Positive test for anti-HIV.&#xD;
&#xD;
          8. Active substance abuse.&#xD;
&#xD;
          9. Pregnancy or inability to practice adequate contraception in women of childbearing&#xD;
             potential&#xD;
&#xD;
         10. Evidence of hepatocellular carcinoma.&#xD;
&#xD;
         11. Any other condition which, in the opinion of the investigators, would impede&#xD;
             competence or compliance.&#xD;
&#xD;
         12. Serum creatinine &gt;1.5 mg/dl.&#xD;
&#xD;
         13. Starting medications that have been shown to cause drug induced liver injury (eg,&#xD;
             augmentin, statins.) within one month prior to enrollment. Medications that have been&#xD;
             known to cause DILI but have taken for more than one month prior to enrollment (such&#xD;
             as statins) should not be an exclusion.&#xD;
&#xD;
        Healthy Controls:&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          1. Individuals who are 18-70 years old&#xD;
&#xD;
          2. Normal Liver enzymes&#xD;
&#xD;
          3. Negative hepatitis B surface antigen, and hepatitis C antibody&#xD;
&#xD;
          4. BMI (18.5 - 24.9) kg/m2&#xD;
&#xD;
          5. Written informed consent.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Presence of the metabolic syndrome, defined according to the modified AHA/NCEP&#xD;
             criteria&#xD;
&#xD;
          2. Taking concomitant medications&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mazen Noureddin</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southern California</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>USC</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>USC HCC II (Fatty Liver Clinic)</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>91105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2014</verification_date>
  <study_first_submitted>June 7, 2014</study_first_submitted>
  <study_first_submitted_qc>July 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 18, 2014</study_first_posted>
  <last_update_submitted>March 28, 2017</last_update_submitted>
  <last_update_submitted_qc>March 28, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 30, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Acetaminophen, Non-alcoholic Fatty Liver Disease (NAFLD)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetaminophen</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02194894
org study id: HS-13-00771
nct id: NCT02194894
lead sponsor: 
has dmc: Yes
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.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
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.
time frame: 14 days
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.
measure: Exploring possible mechanism of acetaminophen liver injury in NAFLD patients
time frame: 14 days
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).
arm group label: NAFLD patients
arm group type: Active Comparator
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 group label: Healthy controls
arm group type: Active Comparator
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: Acetaminophen
description: acetaminophen will be given for patient for both arms for 14 days
arm group label: Healthy controls
arm group label: NAFLD patients
other name: APAP
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Mazen Noureddin
role: Principal Investigator
affiliation: University of Southern California
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Acetaminophen