AZD4076 in Type 2 Diabetic Subjects With Non-Alcoholic Fatty Liver Disease.
- Registration Number
- NCT02826525
- Lead Sponsor
- AstraZeneca
- Brief 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 14
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control Placebo Subjects in this arm will receive placebo Treatment AZD4076 Subjects in this arm will receive AZD4076
- Primary Outcome Measures
Name Time Method The safety and tolerability of AZD4076 by assessment of blood pressure From screening until 26 weeks post first dose To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessment of pulse From screening until 26 weeks post first dose To assess the safety and tolerability of multiple ascending doses of AZD4076
Reduction in liver fat content (%) per MRI Screening and 54 days post first dose To assess the effect of AZD4076 on liver fat content using magnetic resonance imaging
The safety and tolerability of AZD4076 by assessing the number of participants with adverse events From screening until 26 weeks post first dose To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessment of oral temperature From day -2 until day 42 To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessing clinical chemistry From screening until 26 weeks post first dose Percentage of patients with clinically significant changes in laboratory tests.
The safety and tolerability of AZD4076 by assessment of digital electrocardiogram readings From predose until 24 hours post-dose on days 1 and 42 To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability AZD4076 by assessment of physical examination From screening until 26 weeks post first dose Percentage of patients with abnormal physical examination
The safety and tolerability of AZD4076 by assessing the injection site From day 1 until day 42 Percentage of patients with dermatological adverse events
The safety and tolerability of AZD4076 by assessing the number of adverse events From screening until 26 weeks post first dose To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessing urinalysis From screening until 26 weeks post-first dose To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessing hematology From screening until 26 weeks post first dose To assess the safety and tolerability of multiple ascending doses of AZD4076
The safety and tolerability of AZD4076 by assessment of electrocardiogram readings From screening until 26 weeks post first dose To assess the safety and tolerability of multiple ascending doses of AZD4076
Glucose infusion rate at hyperinsulinemic clamp Day -1 and 56 days post first dose To assess the effect of AZD4076 on whole body insulin sensitivity using hyperinsulinemic euglycemic clamp with tracer technique
- Secondary Outcome Measures
Name Time Method Fasting Endogenous Glucose Production Day -1 and day 56 To assess the effect of AZD4076 on endogenous glucose production (EGP).
AUC0-24 of AZD4076 and longmer and shortmer metabolites Dosing day 1 and day 42 To characterize pharmacokinetics of AZD4076 by area under the curve to 24 hours
Cmax of AZD4076 and longmer and shortmer metabolites Dosing day 1 and day 42 To characterize pharmacokinetics of AZD4076 by peak concentration
24 hour glucose area under the curve Day -2 and day 55 To assess the effect of AZD4076 on 24-hour glucose.
Matsuda Index Day -2 and day 55 To assess the effect of AZD4076 on Matusda Index
Tmax of AZD4076 and longmer and shortmer metabolites Dosing day 1 and day 42 To characterize pharmacokinetics of AZD4076 by time to peak concentration
Ae of AZD4076 and longmer and shortmer metabolites Dosing day 1 and day 42 To characterize pharmacokinetics of AZD4076 by amount excreted in urine
AUCt of AZD4076 and longmer and shortmer metabolites Dosing day 1 and day 42 To characterize pharmacokinetics of AZD4076 by area under the curve to time
HOMA-IR Day -2 and day 55 To assess the effect of AZD4076 on homeostatic model assessment insulin resistant (HOMA-IR)
CLR of AZD4076 and longmer and shortmer metabolites Day 1 and 42 To characterize pharmacokinetics of AZD4076 by clearance
fe% of AZD4076 and longmer and shortmer metabolites Dosing day 1 and day 42 To characterize pharmacokinetics of AZD4076 by fraction excreted in urine