T2DM With NAFLD Clinical Trial
Official title:
Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4076 Following Multiple Ascending Dose Administration to T2DM Subjects With Non-Alcoholic Fatty Liver Disease
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.
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 ;