AZD4076 in Type 2 Diabetic Subjects With Non-Alcoholic Fatty Liver Disease.

NCT02826525 | Completed Phase 1

• 1 other identifier: D5590C00002
• Study Type: interventional
• Target: 14
• Locations: 0 countries
• Sites: N/A

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.

Conditions

T2DM With NAFLD

Outcome Measures

Primary Outcomes (14)

• The safety and tolerability of AZD4076 by assessing the number of participants with adverse events

  To assess the safety and tolerability of multiple ascending doses of AZD4076

  From screening until 26 weeks post first dose

• The safety and tolerability of AZD4076 by assessment of blood pressure

  To assess the safety and tolerability of multiple ascending doses of AZD4076

  From screening until 26 weeks post first dose

• The safety and tolerability of AZD4076 by assessment of pulse

  To assess the safety and tolerability of multiple ascending doses of AZD4076

  From screening until 26 weeks post first dose

• The safety and tolerability of AZD4076 by assessment of oral temperature

  To assess the safety and tolerability of multiple ascending doses of AZD4076

  From day -2 until day 42

• The safety and tolerability of AZD4076 by assessment of electrocardiogram readings

  To assess the safety and tolerability of multiple ascending doses of AZD4076

  From screening until 26 weeks post first dose

• The safety and tolerability of AZD4076 by assessment of digital electrocardiogram readings

  To assess the safety and tolerability of multiple ascending doses of AZD4076

  From predose until 24 hours post-dose on days 1 and 42

• The safety and tolerability AZD4076 by assessment of physical examination

  Percentage of patients with abnormal physical examination

  From screening until 26 weeks post first dose

• The safety and tolerability of AZD4076 by assessing the injection site

  Percentage of patients with dermatological adverse events

  From day 1 until day 42

• The safety and tolerability of AZD4076 by assessing the number of adverse events

  To assess the safety and tolerability of multiple ascending doses of AZD4076

  From screening until 26 weeks post first dose

• The safety and tolerability of AZD4076 by assessing hematology

  To assess the safety and tolerability of multiple ascending doses of AZD4076

  From screening until 26 weeks post first dose

• The safety and tolerability of AZD4076 by assessing clinical chemistry

  Percentage of patients with clinically significant changes in laboratory tests.

  From screening until 26 weeks post first dose

• The safety and tolerability of AZD4076 by assessing urinalysis

  To assess the safety and tolerability of multiple ascending doses of AZD4076

  From screening until 26 weeks post-first dose

• Glucose infusion rate at hyperinsulinemic clamp

  To assess the effect of AZD4076 on whole body insulin sensitivity using hyperinsulinemic euglycemic clamp with tracer technique

  Day -1 and 56 days post first dose

• Reduction in liver fat content (%) per MRI

  To assess the effect of AZD4076 on liver fat content using magnetic resonance imaging

  Screening and 54 days post first dose

Secondary Outcomes (11)

• 24 hour glucose area under the curve

  Day -2 and day 55

• HOMA-IR

  Day -2 and day 55

• Fasting Endogenous Glucose Production

  Day -1 and day 56

• AUCt of AZD4076 and longmer and shortmer metabolites

  Dosing day 1 and day 42

• Matsuda Index

  Day -2 and day 55

Study Arms (2)

Treatment

EXPERIMENTAL

Subjects in this arm will receive AZD4076

Drug: AZD4076

Control

PLACEBO COMPARATOR

Subjects in this arm will receive placebo

Drug: Placebo

Interventions

AZD4076 DRUG

Investigational product

Also known as: Study drug

Treatment

Placebo DRUG

Control

Also known as: Control

Control

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Males or females of non-child bearing potential.
• Age 18-70 years with suitable veins for cannulation or repeated venipuncture.
• BMI 23-40 kg/m2 inclusive.
• Diagnosed T2D (HbA1c 7-11%) treated with a stable dose of metformin for at least one month prior to screening.
• Hepatic steatosis of ≥8%.

You may not qualify if:

• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
• History or presence of hepatic or renal disease (with the exception of hepatic steatosis).
• Presence of acute proliferative retinopathy or maculopathy, severe gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy.
• Clinically significant cardiovascular event within the last 6 months prior to screening.
• History or presence of significant neurological or psychiatric disease/mental illness (as assessed using the C-SSRS).
• History of malignancy within the last 5 years, excluding successful treatment of basal cell skin carcinoma or in situ carcinoma of cervix.
• Suspicion of or known Gilbert's syndrome.
• Supine systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 95 mmHg confirmed in the screening period.
• Changes in any current medication (initiation, dose change or cessation) that may impact the study readouts (as judged by the Investigator) within three months prior to MRI assessment of steatosis screening. The criterion does not apply to medication prescribed for occasional use.
• Treatment with antidiabetics (except for metformin) during the last three months prior to screening or treatment with sulfonylurea (SU) drugs within the 4 weeks prior to screening.
• \. Used or plan to use drugs that cause weight loss, participating in, or have participated in weight loss program within the last 3 months.
• \. Use of anabolic steroids and systemic treatment with glucosteroids within three months prior to screening. Intra articular, topical, and inhaled steroids are permissible.
• \. Any confirmed clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the Investigator.
• \. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).
• \. Confirmed serum creatinine greater than the ULN. 16. A confirmed eGFR \<60 calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

Sponsors & Collaborators

• AstraZeneca: lead

MeSH Terms

Interventions

Drug Evaluation

Intervention Hierarchy (Ancestors)

Drug Development; Investigative Techniques; Evaluation Studies as Topic

Study Officials

• Linda Morrow, MD

  ProSciento, Inc.

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 29, 2016
• First Posted: July 11, 2016
• Study Start: July 18, 2016
• Primary Completion: October 11, 2019
• Study Completion: October 11, 2019
• Last Updated: April 1, 2021

Record last verified: 2021-03