AZD4076 in Type 2 Diabetic Subjects With Non-Alcoholic Fatty Liver Disease.
Condition: T2DM With NAFLD
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a phase I/IIa, randomized, single-blind, placebo-controlled, multiple-ascending dose
      study conducted at a single site. The study plans to include up to approximately 46 evaluable
      subjects with Type 2 Diabetes Mellitus (HbA1c 7-11%) and Non-Alcoholic Fatty Liver disease
      (liver fat content > = 8%) on metformin monotherapy.

      Three initial cohorts are planned:

        -  Cohort 1: 6 subjects receiving AZD4076 and 4 subjects receiving placebo

        -  Cohort 2: 12 subjects receiving AZD4076 and 10 subjects receiving placebo

        -  Cohort 3: 10 subjects receiving AZD4076 and 10 subjects receiving placebo, with the
           possibility to add additional subjects if drop-out rates are higher than expected

      Pending review by SRC, an additional 2 cohorts, each consisting of 18 evaluable subjects may
      be included in the study.

      The primary objectives of this clinical trial are to investigate the safety and tolerability
      of AZD4076 following subcutaneous administration of multiple ascending doses; to assess the
      effect of AZD4076 on whole body insulin sensitivity using hyperinsulinemic euglycemic clamp
      with tracer technique; and to assess the effect of AZD4076 on liver fat content using
      magnetic resonance imaging. Secondary objectives of this trial are to characterize multiple
      dose PK of AZD4076 and its longmer and shortmer metabolites and assess the time required to
      reach steady state and the degree of accumulation; to assess the efficacy of AZD4076 on
      24-hour glucose; and to assess the effect of AZD4076 on homeostatic model assessment insulin
      resistant (HOMA-IR) and Matsuda index.
    

Detailed description: 
      This is a phase I/IIa, randomized, single-blind, placebo-controlled, multiple-ascending dose
      study conducted at a single site. The study plans to include up to approximately 46 evaluable
      subjects with Type 2 Diabetes Mellitus (HbA1c 7-11%) and Non-Alcoholic Fatty Liver disease
      (liver fat content > = 8%) on metformin monotherapy

      Three initial cohorts are planned:

        -  Cohort 1: 6 subjects receiving AZD4076 and 4 subjects receiving placebo

        -  Cohort 2: 12 subjects receiving AZD4076 and 10 subjects receiving placebo

        -  Cohort 3: 10 subjects receiving AZD4076 and 10 subjects receiving placebo, with the
           possibility to add additional subjects if drop-out rates are higher than expected.

      Pending review by SRC, an additional 2 cohorts, each consisting of 18 evaluable subjects may
      be included in the study.

      The planned study consists of a screening visit, followed by 12 subsequent study visits.
      There will be a total of three residential periods: (1) Loading phase of the treatment (visit
      2, days -4 to 14), (2) maintenance phase of treatment (visit 6, days 42-43), and (3) 8 weeks
      post-first dose of study drug (visit 9, days 53-56). Dosing of study drug will take place on
      days 1, 3, 5, 7, and 9 in the loading phase; and on days 14, 21, 28, 35, and 42 during the
      maintenance phase. Following the maintenance phase, subjects will have four follow-up visits.

      Study Objectives:

      The primary objectives of this clinical trial are to investigate the safety and tolerability
      of AZD4076 following subcutaneous administration of multiple ascending doses; to assess the
      effect of AZD4076 on whole body insulin sensitivity using hyperinsulinemic euglycemic clamp
      with tracer technique; and to assess the effect of AZD4076 on liver fat content using
      magnetic resonance imaging. Secondary objectives of this trial are to characterize multiple
      dose PK of AZD4076 and its longmer and shortmer metabolites and assess the time required to
      reach steady state and the degree of accumulation; to assess the efficacy of AZD4076 on
      24-hour glucose; and to assess the effect of AZD4076 on homeostatic model assessment insulin
      resistant (HOMA-IR) and Matsuda index.

      Study Population:

      Subjects participating in this study are adult males and females of non-child bearing
      potential, who are 18-70 years of age, body mass index 23-40 kg/m2, diagnosed with T2DM who
      are inadequately controlled (HbA1C 7-11%) on a stable metformin regimen, and who have hepatic
      steatosis (defined as liver fat content of >=8% per MRI).

      Duration of treatment:

      The screening visit will occur within 42 days prior to the administration of the study drug.
      Total length of the treatment period is 6 weeks. The treatment period is divided in two
      phases: the loading phase, in which participants will receive the study drug every other day
      for 9 days (Days 1, 3, 5 , 7 and 9); thereafter subjects will enter the maintenance phase,
      where dosing will occur once weekly for four weeks (Days 14, 21, 28, 35 and 42). To ensure
      safety, subjects will be followed for approximately 5 months post the last dose of study
      drug.

      Investigational product, dosage and mode of administration:

      The study will utilize two study drugs: AZD4076 and placebo. Both drugs will be administered
      subcutaneously in the abdomen.

      Safety analysis:

      The key outcomes for the safety analyses are: adverse events, vital signs, safety laboratory
      parameters, ECGs, telemetry; and structured neurological and physical examination, as well as
      injection site assessment. Pharmacodynamic parameters will be derived from data generated
      from the clamp procedure, MRI, HOMA, OGTT and 24-hour glucose AUC. For pharmacokinetic
      parameters, plasma and urine concentrations of AZD4076 and its metabolites will be measured
    

Intervention name(s): AZD4076; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Investigational product; Control
Other intervention name(s): Study drug; Control
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment