<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/NCT03291249</url>
  </required_header>
  <id_info>
    <org_study_id>TZLS-0401-001</org_study_id>
    <nct_id>NCT03291249</nct_id>
  </id_info>
  <brief_title>Assessment of the Safety of Foralumab, an Oral Anti-CD3 Antibody, in Patients With NASH and T2DM</brief_title>
  <official_title>A Randomized, Placebo-controlled ,Double-blind, Phase IIa Assessment of the Safety of Foralumab, an Oral Anti-CD3 Antibody, in Patients With Nonalcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus (T2DM)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tiziana Life Sciences LTD</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tiziana Life Sciences LTD</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized, placebo-controlled, four-arm, double-blind study. Subjects will be&#xD;
      randomized (1:1:1:1) to receive either a daily oral placebo solution or a daily oral dose of&#xD;
      0.5 mg, 2.5 mg or 5.0 mg Foralumab Solution for 30 consecutive days. Subjects will record&#xD;
      adverse events and daily administration of study medication in a subject diary. This will&#xD;
      serve as a measure of compliance and record of safety and tolerability. Subjects will be&#xD;
      followed up for 30 days following completion of treatment.&#xD;
&#xD;
      Study visits performed on Days 14, 30 and 60 of the study, will monitor metabolic parameters&#xD;
      (body mass index [BMI] and waist circumference), serum lipid profiles, immunological markers&#xD;
      (c-reactive protein [CRP] and an array of cytokines), hepatic enzymes and functions&#xD;
      (13C-methacetin breath test [MBT]) and liver steatosis/fibrosis, which will be compared to&#xD;
      baseline levels (Day 1).&#xD;
&#xD;
      The safety and tolerability of the treatment regimen will be determined by monitoring vital&#xD;
      signs, laboratory values, adverse events and physical findings throughout the study. In&#xD;
      addition, its efficacy will be established upon either reduced Day 30 serum alanine&#xD;
      aminotransferase (ALT) levels, reduced hemoglobin A1c (HbA1c) or improved homeostasis model&#xD;
      assessment (HOMA) or HOMA of insulin resistance (HOMA-IR) scores as compared to baseline (Day&#xD;
      1). In addition, to assess the efficacy of the tested Foralumab Solution regimen in improving&#xD;
      overall subject status, a battery of exploratory metabolic, immunologic and hepatic markers&#xD;
      will be evaluated on Days 30 and 60.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A randomized, placebo-controlled, double-blind, phase IIa study for assessment of the safety&#xD;
      of Foralumab, an oral anti-CD3 antibody, in patients with nonalcoholic steatohepatitis (NASH)&#xD;
      and type 2 diabetes mellitus (T2DM).&#xD;
&#xD;
      This is a randomized, placebo-controlled, four-arm, double-blind study. Subjects will be&#xD;
      randomized (1:1:1:1) to receive either a daily oral placebo solution or a daily oral dose of&#xD;
      0.5 mg, 2.5 mg or 5.0 mg Foralumab Solution for 30 consecutive days. Subjects will record&#xD;
      adverse events and daily administration of study medication in a subject diary. This will&#xD;
      serve as a measure of compliance and record of safety and tolerability. Subjects will be&#xD;
      followed up for 30 days following completion of treatment.&#xD;
&#xD;
      Study visits performed on Days 14, 30 and 60 of the study, will monitor metabolic parameters&#xD;
      (body mass index [BMI] and waist circumference), serum lipid profiles, immunological markers&#xD;
      (c-reactive protein [CRP] and an array of cytokines), hepatic enzymes and functions&#xD;
      (13C-methacetin breath test [MBT]) and liver steatosis/fibrosis, which will be compared to&#xD;
      baseline levels (Day 1).&#xD;
&#xD;
      The safety and tolerability of the treatment regimen will be determined by monitoring vital&#xD;
      signs, laboratory values, adverse events and physical findings throughout the study. In&#xD;
      addition, its efficacy will be established upon either reduced Day 30 serum alanine&#xD;
      aminotransferase (ALT) levels, reduced hemoglobin A1c (HbA1c) or improved homeostasis model&#xD;
      assessment (HOMA) or HOMA of insulin resistance (HOMA-IR) scores as compared to baseline (Day&#xD;
      1). In addition, to assess the efficacy of the tested Foralumab Solution regimen in improving&#xD;
      overall subject status, a battery of exploratory metabolic, immunologic and hepatic markers&#xD;
      will be evaluated on Days 30 and 60.&#xD;
&#xD;
      Primary: To assess the safety and tolerability of the tested Foralumab Solution regimen in&#xD;
      subjects with both T2DM and NASH/NAFLD Secondary: To assess the efficacy of the tested&#xD;
      Foralumab Solution regimen in improving serum ALT levels, HbA1c, HOMA or HOMA-IR scores in&#xD;
      subjects with both T2DM and NASH/NAFLD.&#xD;
&#xD;
      Exploratory: To assess the efficacy of the tested Foralumab Solution regimen in improving&#xD;
      overall subject status, as measured by a battery of metabolic, immunologic and hepatic&#xD;
      markers.&#xD;
&#xD;
      48 adult subjects (≥18 years) with T2DM and who meet the inclusion criteria for NASH or NAFLD&#xD;
      2a Up to 25 Foralumab (TZLS-0401) is a fully human IgG1 monoclonal antibody directed against&#xD;
      the CD3-epsilon (or CD3ε) antigen expressed on the surface of a type of white blood cell&#xD;
      called T-cells, or T-lymphocytes. The Fc region of the antibody is mutated to reduce the&#xD;
      cytokine release syndrome associated with parenteral administration of anti CD3. When&#xD;
      administered orally, Foralumab is not absorbed and induces a signal at the level of the gut&#xD;
      immune system to promote regulatory T cells systemically.&#xD;
&#xD;
      A once-daily oral dose of Foralumab solution (0.5, 2.5 or 5.0 mg) or placebo solution will be&#xD;
      taken in the morning on an empty stomach for 30 consecutive days.&#xD;
&#xD;
      Group A will receive placebo solution for 30 days (n=12) Group B will receive 0.5 mg&#xD;
      Foralumab Solution daily for 30 days (n=12) Group C will receive 2.5 mg Foralumab Solution&#xD;
      daily for 30 days (n=12) Group D will receive 5.0 mg Foralumab Solution daily for 30 days&#xD;
      (n=12)&#xD;
&#xD;
      A single 20 mg omeprazole pill will be concomitantly administered daily.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Due to MOH request.&#xD;
  </why_stopped>
  <start_date type="Anticipated">December 1, 2017</start_date>
  <completion_date type="Anticipated">June 1, 2019</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>severity and duration for all adverse events</measure>
    <time_frame>30 days after last dose</time_frame>
    <description>Incidence, severity, and duration for all adverse events (AEs), and abnormal laboratory and physical findings up until 30 days after last dose</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Abnormal laboratory findings</measure>
    <time_frame>30 days after last dose</time_frame>
    <description>Incidence, severity, and duration for all adverse events (AEs), and abnormal laboratory and physical findings up until 30 days after last dose</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Abnormal physical findings</measure>
    <time_frame>30 days after last dose</time_frame>
    <description>Incidence, severity, and duration for all adverse events (AEs), and abnormal laboratory and physical findings up until 30 days after last dose</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change ALT levels</measure>
    <time_frame>Day 30 versus Day 1 serum ALT levels</time_frame>
    <description>Day 30 versus Day 1 serum ALT levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in HbA1c levels</measure>
    <time_frame>Day 30 versus Day 1</time_frame>
    <description>HbA1c levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>change in HOMA/HOMA-IR scores</measure>
    <time_frame>Day 30 versus Day 1</time_frame>
    <description>Day 30 versus Day 1 change in HOMA/HOMA-IR scores. Insulin and fasting plasma glucose will be measured to calculate HOMA/HOMA-IR</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Body mass index (BMI)</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>Measurment of BMI (kg/m^2) Serum lipid profile: total cholesterol, triglycerides, low density lipoprotein (LDL) and high density lipoprotein (HDL) fractions.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Immunological markers</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>C-reactive protein (CRP) b. T cell-associated cytokine levels (IL2, 4, 5, 6, 8,10,12, 13, IFN, TNF, TGF c. Regulatory T cell (Tregs) levels (cells positive for: CD4, CD25, CD8, CD56, CD3, CD62, CD127, NKT, FoxP3, LAP)</description>
  </other_outcome>
  <other_outcome>
    <measure>Cytokine levels</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>Measurement of Cytokine levels Mean serum concentrations of, cytokeratin (CK)-18 fragments, C-peptide, glucagon-like peptide-1 (GLP-1), adiponectin c. 13C-Methacetin breath test (MBT) Hepatic steatosis and fibrosis</description>
  </other_outcome>
  <other_outcome>
    <measure>waist circumference</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>measurement of waist circumference (cm)</description>
  </other_outcome>
  <other_outcome>
    <measure>Serum lipid profile</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>Serum lipid concentration will be measured</description>
  </other_outcome>
  <other_outcome>
    <measure>Regulatory T cell</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>Measurement of Regulatory T cell</description>
  </other_outcome>
  <other_outcome>
    <measure>Liver enzymes</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>Measurement of Liver enzymes</description>
  </other_outcome>
  <other_outcome>
    <measure>Mean serum concentrations of cytokeratin (CK)-18 fragments</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>Measurement of (CK)-18 fragments concentration</description>
  </other_outcome>
  <other_outcome>
    <measure>Mean serum concentrations of C-peptide</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>Measurement of C-peptide concentration</description>
  </other_outcome>
  <other_outcome>
    <measure>Mean serum concentrations of glucagon-like peptide-1 (GLP-1)</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>Measurement of glucagon-like peptide-1 (GLP-1) concentration</description>
  </other_outcome>
  <other_outcome>
    <measure>Mean serum concentrations of adiponectin</measure>
    <time_frame>Day 1 versus day 30 and 60</time_frame>
    <description>Measurement of adiponectin concentration</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>NASH - Nonalcoholic Steatohepatitis</condition>
  <condition>NAFLD</condition>
  <condition>T2DM (Type 2 Diabetes Mellitus)</condition>
  <arm_group>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Group A will receive placebo solution for 30 consecutive days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group B will receive 0.5 mg Foralumab Solution daily for 30 consecutive days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group C</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group B will receive 2.5 mg Foralumab Solution daily for 30 consecutive days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group D</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group B will receive 5.0 mg Foralumab Solution daily for 30 consecutive days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Foralumab</intervention_name>
    <description>Anti CD3 mAb</description>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_label>Group C</arm_group_label>
    <arm_group_label>Group D</arm_group_label>
    <other_name>Anti CD3</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>Placebo oral solution</description>
    <arm_group_label>Group A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Omeprazole 20mg</intervention_name>
    <description>Omeprazole is a proton pump inhibitor used to neutralize stomach PH</description>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_label>Group C</arm_group_label>
    <arm_group_label>Group D</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Provision of written informed consent&#xD;
&#xD;
          -  Diagnosis of T2DM&#xD;
&#xD;
          -  HbA1c &lt; 9.0 while on standard of care&#xD;
&#xD;
          -  Historical histology-based confirmation of NASH within 12 months prior to screening OR&#xD;
&#xD;
        Diagnosis of NAFLD based on all the following:&#xD;
&#xD;
          -  Presentation of at least one other parameter of the metabolic syndrome from the&#xD;
             following list of three:&#xD;
&#xD;
             (i) hypertension [≥130/85 mmHg or regularly taking an antihypertensive], (ii)&#xD;
             dyslipidemia with high serum triglycerides [≥150 mg/dL or regularly taking medicines&#xD;
             to lower high triglyceride levels] or low serum HDL [&lt;50 mg/dL for women and &lt;40 mg/dL&#xD;
             for men], (iii) obesity (BMI &gt; 30 kg/m2) or central obesity [waistline measurement ≥&#xD;
             89 cm for women and ≥ 102 cm for men])&#xD;
&#xD;
          -  ALT &gt; 40 IU&#xD;
&#xD;
          -  Fat fraction &gt;10% in MRI performed during screening or up to 3 months prior to&#xD;
             screening.&#xD;
&#xD;
          -  Agree to the use of effective contraceptive measures, as defined in the protocol, if&#xD;
             either male or female with child-bearing potential.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Subject with cirrhosis per biopsy (fibrosis staging score &gt;= 4) or Fibroscan® &gt;14 kPa&#xD;
             within 12 months of screening.&#xD;
&#xD;
          -  Presence of vascular liver disease&#xD;
&#xD;
          -  Any history or evidence of decompensated liver disease such as recurrent variceal&#xD;
             bleeding, refractory ascites or hepatic encephalopathy&#xD;
&#xD;
          -  Known history of chronic alcoholic liver disease, chronic hepatitis B or C infection,&#xD;
             drug-induced liver injury (DILI), hemochromatosis, Wilson's disease, 1-antitrypsin&#xD;
             deficiency, primary biliary cirrhosis or secondary sclerosing cholangitis, autoimmune&#xD;
             hepatitis&#xD;
&#xD;
          -  Known HIV antibody-positive&#xD;
&#xD;
          -  History of liver transplantation&#xD;
&#xD;
          -  BMI &lt;25kg/m2&#xD;
&#xD;
          -  Clinically significant alcohol use&#xD;
&#xD;
          -  Score of ≥ 2 on the CAGE questionnaire, OR&#xD;
&#xD;
          -  Any subject with current significant alcohol consumption or a history of significant&#xD;
             alcohol consumption for a period of more than 3 consecutive months any time within 1&#xD;
             year prior to screening, as determined by medical history (medical chart review and/or&#xD;
             interview). Significant alcohol consumption is defined as: females: &gt;20 g/day; males:&#xD;
             &gt;30 g/day, with a standard drink in the US averaging 14 g alcohol.&#xD;
&#xD;
          -  Type 1 diabetes&#xD;
&#xD;
          -  Bariatric surgery within the last 5 years&#xD;
&#xD;
          -  Weight loss or gain of ≥5 kg in the past 6 months or &gt;10% change in bodyweight in the&#xD;
             past 12 months&#xD;
&#xD;
          -  Inadequate vascular access on physical examination&#xD;
&#xD;
          -  Lactating/breastfeeding/pregnant at screening&#xD;
&#xD;
          -  On an elemental diet or parenteral nutrition&#xD;
&#xD;
          -  Concurrent conditions&#xD;
&#xD;
          -  Inflammatory bowel disease&#xD;
&#xD;
          -  Unstable angina, myocardial infarction, transient ischemic events, or stroke within 24&#xD;
             weeks of screening&#xD;
&#xD;
          -  Ongoing infectious disease, excluding recurrent urinary tract infection treated with&#xD;
             long-term antibiotic prophylaxis&#xD;
&#xD;
          -  Any type of immune-mediated and/or malignant disease&#xD;
&#xD;
          -  Any other concurrent condition which, in the opinion of the investigator, could impact&#xD;
             adversely on the participating subject or on the interpretation of the study data&#xD;
&#xD;
          -  Concurrent medications including:&#xD;
&#xD;
          -  Amiodarone taken within 30 days of Day 1 (MBT contraindication)&#xD;
&#xD;
          -  Beta-blockers: must be on a stable dose for at least 30 days prior to Day 1 (MBT&#xD;
             contraindication)&#xD;
&#xD;
          -  Statins: must be on a stable dose for at least 30 days prior to Day 1 (MBT&#xD;
             contraindication)&#xD;
&#xD;
          -  The following medications taken every day for more than 1 week over the last three&#xD;
             months: S-adenosyl methionine (SAM-e), betaine, milk thistle and probiotic supplements&#xD;
             (other than yoghurt) with the exception of vitamin E or gemfibrozil, which are allowed&#xD;
&#xD;
             ** If &gt;= 400 IU vitamin E on a regular basis or gemfibrozil, at any dose, are used,&#xD;
             the dose must be stable for more than 3 months;&#xD;
&#xD;
          -  immunomodulatory agents including In the last 4 weeks&#xD;
&#xD;
               -  oral or parenteral antibiotics&#xD;
&#xD;
               -  daily treatment with non-steroidal anti-inflammatory drugs (e.g., aspirin (&gt;100&#xD;
                  mg/day), ibuprofen, naproxen, imeloxicam, celecoxib)&#xD;
&#xD;
        In the last 3 months&#xD;
&#xD;
          -  systemic steroids&#xD;
&#xD;
          -  daily treatment with non-steroidal anti-inflammatory drugs (e.g., aspirin&#xD;
             (&gt;100mg/day), ibuprofen, naproxen, meloxicam, celecoxib) over 4 or more weeks in the&#xD;
             last 3 months&#xD;
&#xD;
          -  variable dose of antilipidemic agents (HMG Co-A reductase inhibitors - &quot;statins&quot;).&#xD;
             Subjects on stable dose of statins are eligible if missed no more than one week of&#xD;
             dosing over the last 3 months&#xD;
&#xD;
        In the last 12 months&#xD;
&#xD;
        o azathioprine, 6-mercaptopurine, methotrexate, cyclosporin, anti-TNF alpha therapies&#xD;
        (infliximab, adalimumab, etanercept) or anti-integrin therapies&#xD;
&#xD;
          -  Any of the following laboratory abnormalities:&#xD;
&#xD;
          -  Neutrophil count ≤1.0 x 109/L&#xD;
&#xD;
          -  Platelets &lt;100 x 109/L&#xD;
&#xD;
          -  Hemoglobin &lt;10g/dL&#xD;
&#xD;
          -  Albumin &lt;3.5g&#xD;
&#xD;
          -  International Normalized Ratio (INR) &gt;1.5&#xD;
&#xD;
          -  Total bilirubin &gt;1.5 x upper limit of reference range (unless Gilbert's syndrome or&#xD;
             extrahepatic source as denoted by increased indirect bilirubin fraction)&#xD;
&#xD;
          -  Either creatinine clearance ≤60mL/minute, calculated by Cockroft Gault, or creatinine&#xD;
             &gt;1.5x upper limit of reference range&#xD;
&#xD;
          -  Regular use of marijuana or marijuana-related products, or use of cocaine, or street&#xD;
             drugs, as determined by medical history (medical chart review and/or interview).&#xD;
&#xD;
          -  Subjects with symptoms of significant mental illness, inability to cooperate or&#xD;
             communicate with the investigator, who are unlikely to comply with the study&#xD;
             requirements, or who are unable to provide informed consent.&#xD;
&#xD;
          -  Hypersensitivity to methacetin and/or its metabolites (i.e., paracetamol,&#xD;
             acetaminophen)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>120 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 21, 2017</study_first_submitted>
  <study_first_submitted_qc>September 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <last_update_submitted>September 10, 2019</last_update_submitted>
  <last_update_submitted_qc>September 10, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 12, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Omeprazole</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/NCT03291249
org study id: TZLS-0401-001
nct id: NCT03291249
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a randomized, placebo-controlled, four-arm, double-blind study. Subjects will be
      randomized (1:1:1:1) to receive either a daily oral placebo solution or a daily oral dose of
      0.5 mg, 2.5 mg or 5.0 mg Foralumab Solution for 30 consecutive days. Subjects will record
      adverse events and daily administration of study medication in a subject diary. This will
      serve as a measure of compliance and record of safety and tolerability. Subjects will be
      followed up for 30 days following completion of treatment.

      Study visits performed on Days 14, 30 and 60 of the study, will monitor metabolic parameters
      (body mass index [BMI] and waist circumference), serum lipid profiles, immunological markers
      (c-reactive protein [CRP] and an array of cytokines), hepatic enzymes and functions
      (13C-methacetin breath test [MBT]) and liver steatosis/fibrosis, which will be compared to
      baseline levels (Day 1).

      The safety and tolerability of the treatment regimen will be determined by monitoring vital
      signs, laboratory values, adverse events and physical findings throughout the study. In
      addition, its efficacy will be established upon either reduced Day 30 serum alanine
      aminotransferase (ALT) levels, reduced hemoglobin A1c (HbA1c) or improved homeostasis model
      assessment (HOMA) or HOMA of insulin resistance (HOMA-IR) scores as compared to baseline (Day
      1). In addition, to assess the efficacy of the tested Foralumab Solution regimen in improving
      overall subject status, a battery of exploratory metabolic, immunologic and hepatic markers
      will be evaluated on Days 30 and 60.
A randomized, placebo-controlled, double-blind, phase IIa study for assessment of the safety
      of Foralumab, an oral anti-CD3 antibody, in patients with nonalcoholic steatohepatitis (NASH)
      and type 2 diabetes mellitus (T2DM).

      This is a randomized, placebo-controlled, four-arm, double-blind study. Subjects will be
      randomized (1:1:1:1) to receive either a daily oral placebo solution or a daily oral dose of
      0.5 mg, 2.5 mg or 5.0 mg Foralumab Solution for 30 consecutive days. Subjects will record
      adverse events and daily administration of study medication in a subject diary. This will
      serve as a measure of compliance and record of safety and tolerability. Subjects will be
      followed up for 30 days following completion of treatment.

      Study visits performed on Days 14, 30 and 60 of the study, will monitor metabolic parameters
      (body mass index [BMI] and waist circumference), serum lipid profiles, immunological markers
      (c-reactive protein [CRP] and an array of cytokines), hepatic enzymes and functions
      (13C-methacetin breath test [MBT]) and liver steatosis/fibrosis, which will be compared to
      baseline levels (Day 1).

      The safety and tolerability of the treatment regimen will be determined by monitoring vital
      signs, laboratory values, adverse events and physical findings throughout the study. In
      addition, its efficacy will be established upon either reduced Day 30 serum alanine
      aminotransferase (ALT) levels, reduced hemoglobin A1c (HbA1c) or improved homeostasis model
      assessment (HOMA) or HOMA of insulin resistance (HOMA-IR) scores as compared to baseline (Day
      1). In addition, to assess the efficacy of the tested Foralumab Solution regimen in improving
      overall subject status, a battery of exploratory metabolic, immunologic and hepatic markers
      will be evaluated on Days 30 and 60.

      Primary: To assess the safety and tolerability of the tested Foralumab Solution regimen in
      subjects with both T2DM and NASH/NAFLD Secondary: To assess the efficacy of the tested
      Foralumab Solution regimen in improving serum ALT levels, HbA1c, HOMA or HOMA-IR scores in
      subjects with both T2DM and NASH/NAFLD.

      Exploratory: To assess the efficacy of the tested Foralumab Solution regimen in improving
      overall subject status, as measured by a battery of metabolic, immunologic and hepatic
      markers.

      48 adult subjects (≥18 years) with T2DM and who meet the inclusion criteria for NASH or NAFLD
      2a Up to 25 Foralumab (TZLS-0401) is a fully human IgG1 monoclonal antibody directed against
      the CD3-epsilon (or CD3ε) antigen expressed on the surface of a type of white blood cell
      called T-cells, or T-lymphocytes. The Fc region of the antibody is mutated to reduce the
      cytokine release syndrome associated with parenteral administration of anti CD3. When
      administered orally, Foralumab is not absorbed and induces a signal at the level of the gut
      immune system to promote regulatory T cells systemically.

      A once-daily oral dose of Foralumab solution (0.5, 2.5 or 5.0 mg) or placebo solution will be
      taken in the morning on an empty stomach for 30 consecutive days.

      Group A will receive placebo solution for 30 days (n=12) Group B will receive 0.5 mg
      Foralumab Solution daily for 30 days (n=12) Group C will receive 2.5 mg Foralumab Solution
      daily for 30 days (n=12) Group D will receive 5.0 mg Foralumab Solution daily for 30 days
      (n=12)

      A single 20 mg omeprazole pill will be concomitantly administered daily.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: severity and duration for all adverse events
time frame: 30 days after last dose
description: Incidence, severity, and duration for all adverse events (AEs), and abnormal laboratory and physical findings up until 30 days after last dose
measure: Abnormal laboratory findings
time frame: 30 days after last dose
description: Incidence, severity, and duration for all adverse events (AEs), and abnormal laboratory and physical findings up until 30 days after last dose
measure: Abnormal physical findings
time frame: 30 days after last dose
description: Incidence, severity, and duration for all adverse events (AEs), and abnormal laboratory and physical findings up until 30 days after last dose
measure: Change ALT levels
time frame: Day 30 versus Day 1 serum ALT levels
description: Day 30 versus Day 1 serum ALT levels
measure: Change in HbA1c levels
time frame: Day 30 versus Day 1
description: HbA1c levels
measure: change in HOMA/HOMA-IR scores
time frame: Day 30 versus Day 1
description: Day 30 versus Day 1 change in HOMA/HOMA-IR scores. Insulin and fasting plasma glucose will be measured to calculate HOMA/HOMA-IR
measure: Body mass index (BMI)
time frame: Day 1 versus day 30 and 60
description: Measurment of BMI (kg/m^2) Serum lipid profile: total cholesterol, triglycerides, low density lipoprotein (LDL) and high density lipoprotein (HDL) fractions.
measure: Change in Immunological markers
time frame: Day 1 versus day 30 and 60
description: C-reactive protein (CRP) b. T cell-associated cytokine levels (IL2, 4, 5, 6, 8,10,12, 13, IFN, TNF, TGF c. Regulatory T cell (Tregs) levels (cells positive for: CD4, CD25, CD8, CD56, CD3, CD62, CD127, NKT, FoxP3, LAP)
measure: Cytokine levels
time frame: Day 1 versus day 30 and 60
description: Measurement of Cytokine levels Mean serum concentrations of, cytokeratin (CK)-18 fragments, C-peptide, glucagon-like peptide-1 (GLP-1), adiponectin c. 13C-Methacetin breath test (MBT) Hepatic steatosis and fibrosis
measure: waist circumference
time frame: Day 1 versus day 30 and 60
description: measurement of waist circumference (cm)
measure: Serum lipid profile
time frame: Day 1 versus day 30 and 60
description: Serum lipid concentration will be measured
measure: Regulatory T cell
time frame: Day 1 versus day 30 and 60
description: Measurement of Regulatory T cell
measure: Liver enzymes
time frame: Day 1 versus day 30 and 60
description: Measurement of Liver enzymes
measure: Mean serum concentrations of cytokeratin (CK)-18 fragments
time frame: Day 1 versus day 30 and 60
description: Measurement of (CK)-18 fragments concentration
measure: Mean serum concentrations of C-peptide
time frame: Day 1 versus day 30 and 60
description: Measurement of C-peptide concentration
measure: Mean serum concentrations of glucagon-like peptide-1 (GLP-1)
time frame: Day 1 versus day 30 and 60
description: Measurement of glucagon-like peptide-1 (GLP-1) concentration
measure: Mean serum concentrations of adiponectin
time frame: Day 1 versus day 30 and 60
description: Measurement of adiponectin concentration
arm group label: Group A
arm group type: Placebo Comparator
description: Group A will receive placebo solution for 30 consecutive days
arm group label: Group B
arm group type: Experimental
description: Group B will receive 0.5 mg Foralumab Solution daily for 30 consecutive days
arm group label: Group C
arm group type: Experimental
description: Group B will receive 2.5 mg Foralumab Solution daily for 30 consecutive days
arm group label: Group D
arm group type: Experimental
description: Group B will receive 5.0 mg Foralumab Solution daily for 30 consecutive days
intervention type: Drug
intervention name: Foralumab
description: Anti CD3 mAb
arm group label: Group B
arm group label: Group C
arm group label: Group D
other name: Anti CD3
intervention type: Other
intervention name: placebo
description: Placebo oral solution
arm group label: Group A
intervention type: Drug
intervention name: Omeprazole 20mg
description: Omeprazole is a proton pump inhibitor used to neutralize stomach PH
arm group label: Group A
arm group label: Group B
arm group label: Group C
arm group label: Group D
criteria: 
gender: All
minimum age: 18 Years
maximum age: 120 Years
healthy volunteers: No
responsible party type: Sponsor
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Omeprazole