Aramchol for HIV-associated Nonalcoholic Fatty Liver Disease and Lipodystrophy
Condition: Nonalcoholic Fatty Liver Disease; HIV
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Lipodystrophy
Intervention: Aramchol; Placebo
Intervention description: Aramchol, a conjugate of Cholic acid and Arachidic acid, is a first in class member of a novel family of synthetic Fatty-Acid / Bile-Acid Conjugates (FABACs). FABACs are composed of endogenic compounds, orally administrated with potentially good safety and tolerability parameters; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      A subset of patients with NAFLD that have not been extensively studied are those infected
      with human immunodeficiency virus (HIV). Currently, there is no FDA approved treatment for
      NAFLD or NASH. Additionally, there have been no significant clinical trials for HIV patients
      with NAFLD and there are no approved treatment options. We plan to conduct a randomized,
      double-blinded, placebo-controlled clinical trial to examine the efficacy of 600 mg of
      Aramchol daily (including 200 mg tablet and 400 mg tablet) versus identical placebo given
      over 12 weeks to improve HIV-associated hepatic steatosis as measured by a validated and
      accurate magnetic resonance imaging (MRI)-based technique.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age at entry at least 18 years.

          2. And at least one of the following risk factor for more severe liver disease:
             Hypertriglyceridemia based upon ATP-III guidelines, Increased LDL cholesterol or
             increased total cholesterol based upon ATP-III guidelines, Decreased HDL cholesterol
             based upon ATP-III guidelines, Serum alanine (ALT) or aspartate (AST) aminotransferase
             activities that are above the upper limits of normal. 19 or more in women and 30 or
             more in men, Overweight as defined as BMI: 25 < 30 kg/m2, Obesity as defined BMI ≥ 30
             kg/m2, Hyperuricemia based upon ATP-III guidelines, Prediabetes or Diabetes by
             American Diabetes Association Criteria

          3. Lipodystrophy will be confirmed on both clinical and radiologic assessment and defined
             as: Clinical history and/or exam by the study physician with signs of either
             facial,temporal, upper or lower extremity lipo-atrophy, Documented abdominal fat
             accumulation with presence of hepatic steatosis on MRI

          4. An MRI-determined fat fraction classification threshold (≥5%) will be used to confirm
             subjects. MR examinations will include four research sequences (three imaging
             sequences and one single-voxel spectroscopy sequence) that have been developed and
             refined by Dr. Sirlin, allowing for the measurement of liver fat fraction and newer
             candidate MR biomarkers for future NAFLD studies. MR examinations will last 20-30
             minutes and will be performed without contrast agents. Subjects will be scanned at
             1.5T. To assess sequence repeatability, two sequences per subject, block randomized,
             will be run three times. For MR elastography, MR imaging will be done which will
             include placing a vibrating paddle over the abdomen while images are obtained. A
             comprehensive screening questionnaire will be utilized prior to subjects having an
             MRI. Experienced research MR technologists will perform MR examinations under the
             supervision of Dr. Sirlin.

          5. History of HIV documented by a previously positive HIV Elisa or PCR.

          6. Stable antiretroviral (ART) regimen for at least 12 weeks prior to study inclusion.

          7. Written informed consent.

        Exclusion Criteria:

          1. Evidence of another form of liver disease: Hepatitis B as defined as presence of
             hepatitis B surface antigen (HBsAg), Hepatitis C as defined by presence of hepatitis C
             virus (HCV) RNA in serum, Autoimmune hepatitis as defined by anti-nuclear antibody
             (ANA) of 1:160 or greater and liver histology consistent with autoimmune hepatitis or
             previous response to immunosuppressive therapy, Autoimmune cholestatic liver disorders
             as defined by elevation of alkaline phosphatase and anti-mitochondrial antibody of
             greater than 1:80 or liver histology consistent with rimary biliary cirrhosis or
             elevation of alkaline phosphatase and liver histology consistent with sclerosing
             cholangitis, Wilsons disease as defined by ceruloplasmin below the limits of normal
             and liver histology consistent with Wilsons disease Alpha-1-antitrypsin deficiency as
             defined by alpha-1-antitrypsin level less than normal and liver histology consistent
             with alpha-1-antitrypsin deficiency hemochromatosis as defined by presence of 3+ or 4+
             stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity
             for C282Y/H63D, Drug-induced liver disease as defined on the basis of typical exposure
             and history,Bile duct obstruction as shown by imaging studies.

          2. Evidence of liver cirrhosis based upon clinical assessment, imaging or any of the
             following lab abnormalities: INR >1.4, albumin <3.2 g/dL, platelet count <90 x
             103/microliter

          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 or 7 drinks per week) in the previous one year.

          4. Contraindications to MRI: The subject has any contraindication to MR imaging, such as
             patients with pacemakers, metallic cardiac valves, magnetic material such as surgical
             clips, implanted electronic infusion pumps or other conditions that would preclude
             proximity to a strong magnetic field, the subject has a history of extreme
             claustrophobia, The subject cannot fit inside the MR scanner cavity, decompensated
             liver disease, Child-Pugh score greater than or equal to 7 points

        6. History of gastrointestinal bypass surgery or ingestion of drugs known to produce
        hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate,
        tetracycline or amiodarone in the previous 6 months. 7. Recent use (within the last 90
        days) of medications to treat hepatic steatosis such as pioglitazone (or medications in the
        same class) or vitamin E. 8. Use of Aramchol or agents in the same class. 9. Recent use
        (within the last 90 days) of insulin as an outpatient for management of diabetes.

        10. HbA1c > 9 or uncontrolled diabetes. 11. Significant systemic or major illnesses other
        than liver disease, including congestive heart failure, coronary artery disease,
        cerebrovascular disease, pulmonary disease with hypoxia, renal failure, organ
        transplantation, serious psychiatric disease, malignancy that, in the opinion of the
        investigator would preclude treatment with Aramchol and adequate follow up.

        12. Active substance abuse, such as alcohol, inhaled or injection drugs within the previous
        one year. 13. Pregnancy or inability to practice adequate contraception in women of
        childbearing potential.

        14. Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml
        and/or liver mass on imaging study that is suggestive of liver cancer.

        15. HIV specific exclusions: CD4 count of less than 200 cells/μL, Detectable viral
        load,Changes to ART regimen in the preceding 12 weeks,Lack of alternative ART regimens
        should the patient experience virologic breakthrough,History of opportunistic infection in
        the preceding 12 months

        16. Symptoms of uncontrolled gastrointestinal disorders involving motility, gastric acid or
        gastric emptying malabsorption ,Disorders including but not limited to peptic ulcer
        disease, gastroesophageal reflux, dyspepsia, gastroparesis, chronic diarrhea, chromic
        constipation, gall bladder disease,pancreatitis, lactose intolerance and celiac
        disease.Patients who have used anticholinergic or other drugs known to affect
        gastrointestinal motility within 7 days prior to dosing and throughout the study will also
        be excluded

        17. Patients with hypersensitivity to Aramchol or to any of the excipients in the tablets
        or with hypersensitivity to cholic acid or bile acid sequestrants

        18. Any other condition, which, in the opinion of the investigators would impede competence
        or compliance or possibility hinder completion of the study.