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

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ClinicalTrials.gov Identifier: NCT02826525
Recruitment Status : Active, not recruiting
First Posted : July 11, 2016
Last Update Posted : October 22, 2019
Sponsor:
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
T2DM With NAFLD Drug: AZD4076 Drug: Placebo Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
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
Actual Study Start Date : July 18, 2016
Estimated Primary Completion Date : December 28, 2020
Estimated Study Completion Date : December 28, 2020


Arm Intervention/treatment
Experimental: Treatment
Subjects in this arm will receive AZD4076
Drug: AZD4076
Investigational product
Other Name: Study drug

Placebo Comparator: Control
Subjects in this arm will receive placebo
Drug: Placebo
Control
Other Name: Control




Primary Outcome Measures :
  1. The safety and tolerability of AZD4076 by assessing the number of participants with adverse events [ Time Frame: From screening until 26 weeks post first dose ]
    To assess the safety and tolerability of multiple ascending doses of AZD4076

  2. The safety and tolerability of AZD4076 by assessment of blood pressure [ Time Frame: From screening until 26 weeks post first dose ]
    To assess the safety and tolerability of multiple ascending doses of AZD4076

  3. The safety and tolerability of AZD4076 by assessment of pulse [ Time Frame: From screening until 26 weeks post first dose ]
    To assess the safety and tolerability of multiple ascending doses of AZD4076

  4. The safety and tolerability of AZD4076 by assessment of oral temperature [ Time Frame: From day -2 until day 42 ]
    To assess the safety and tolerability of multiple ascending doses of AZD4076

  5. The safety and tolerability of AZD4076 by assessment of electrocardiogram readings [ Time Frame: From screening until 26 weeks post first dose ]
    To assess the safety and tolerability of multiple ascending doses of AZD4076

  6. The safety and tolerability of AZD4076 by assessment of digital electrocardiogram readings [ Time Frame: From predose until 24 hours post-dose on days 1 and 42 ]
    To assess the safety and tolerability of multiple ascending doses of AZD4076

  7. The safety and tolerability AZD4076 by assessment of physical examination [ Time Frame: From screening until 26 weeks post first dose ]
    Percentage of patients with abnormal physical examination

  8. The safety and tolerability of AZD4076 by assessing the injection site [ Time Frame: From day 1 until day 42 ]
    Percentage of patients with dermatological adverse events

  9. The safety and tolerability of AZD4076 by assessing the number of adverse events [ Time Frame: From screening until 26 weeks post first dose ]
    To assess the safety and tolerability of multiple ascending doses of AZD4076

  10. The safety and tolerability of AZD4076 by assessing hematology [ Time Frame: From screening until 26 weeks post first dose ]
    To assess the safety and tolerability of multiple ascending doses of AZD4076

  11. The safety and tolerability of AZD4076 by assessing clinical chemistry [ Time Frame: From screening until 26 weeks post first dose ]
    Percentage of patients with clinically significant changes in laboratory tests.

  12. The safety and tolerability of AZD4076 by assessing urinalysis [ Time Frame: From screening until 26 weeks post-first dose ]
    To assess the safety and tolerability of multiple ascending doses of AZD4076

  13. Glucose infusion rate at hyperinsulinemic clamp [ Time Frame: 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

  14. Reduction in liver fat content (%) per MRI [ Time Frame: Screening and 54 days post first dose ]
    To assess the effect of AZD4076 on liver fat content using magnetic resonance imaging


Secondary Outcome Measures :
  1. 24 hour glucose area under the curve [ Time Frame: Day -2 and day 55 ]
    To assess the effect of AZD4076 on 24-hour glucose.

  2. HOMA-IR [ Time Frame: Day -2 and day 55 ]
    To assess the effect of AZD4076 on homeostatic model assessment insulin resistant (HOMA-IR)

  3. Fasting Endogenous Glucose Production [ Time Frame: Day -1 and day 56 ]
    To assess the effect of AZD4076 on endogenous glucose production (EGP).

  4. AUCt of AZD4076 and longmer and shortmer metabolites [ Time Frame: Dosing day 1 and day 42 ]
    To characterize pharmacokinetics of AZD4076 by area under the curve to time

  5. Matsuda Index [ Time Frame: Day -2 and day 55 ]
    To assess the effect of AZD4076 on Matusda Index

  6. AUC0-24 of AZD4076 and longmer and shortmer metabolites [ Time Frame: Dosing day 1 and day 42 ]
    To characterize pharmacokinetics of AZD4076 by area under the curve to 24 hours

  7. Cmax of AZD4076 and longmer and shortmer metabolites [ Time Frame: Dosing day 1 and day 42 ]
    To characterize pharmacokinetics of AZD4076 by peak concentration

  8. Tmax of AZD4076 and longmer and shortmer metabolites [ Time Frame: Dosing day 1 and day 42 ]
    To characterize pharmacokinetics of AZD4076 by time to peak concentration

  9. CLR of AZD4076 and longmer and shortmer metabolites [ Time Frame: Day 1 and 42 ]
    To characterize pharmacokinetics of AZD4076 by clearance

  10. fe% of AZD4076 and longmer and shortmer metabolites [ Time Frame: Dosing day 1 and day 42 ]
    To characterize pharmacokinetics of AZD4076 by fraction excreted in urine

  11. Ae of AZD4076 and longmer and shortmer metabolites [ Time Frame: Dosing day 1 and day 42 ]
    To characterize pharmacokinetics of AZD4076 by amount excreted in urine



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

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

Exclusion criteria

  1. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
  2. History or presence of hepatic or renal disease (with the exception of hepatic steatosis).
  3. Presence of acute proliferative retinopathy or maculopathy, severe gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy.
  4. Clinically significant cardiovascular event within the last 6 months prior to screening.
  5. History or presence of significant neurological or psychiatric disease/mental illness (as assessed using the C-SSRS).
  6. History of malignancy within the last 5 years, excluding successful treatment of basal cell skin carcinoma or in situ carcinoma of cervix.
  7. Suspicion of or known Gilbert's syndrome.
  8. Supine systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 95 mmHg confirmed in the screening period.
  9. 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.

10 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.

11. Used or plan to use drugs that cause weight loss, participating in, or have participated in weight loss program within the last 3 months.

12. Use of anabolic steroids and systemic treatment with glucosteroids within three months prior to screening. Intra articular, topical, and inhaled steroids are permissible.

13. Any confirmed clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the Investigator.

14. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).

15. Confirmed serum creatinine greater than the ULN. 16. A confirmed eGFR <60 calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

17. Confirmed platelet count outside the normal range. 18. Confirmed ALT or AST greater than 1.5x ULN. 19. Confirmed total bilirubin greater than ULN 20. Any clinically significant abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead, or left ventricular hypertrophy.

21. Prolonged QTcF > 450 ms for males and > 470 ms for females or family history of long QT syndrome.

22. PR(PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation.

23. PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation.

24. Persistent or intermittent complete bundle branch block (BBB) with QRS > 120 ms.

25. Known or suspected history of drug abuse within the past 5 years, as judged by the Investigator.

26. Smokes >10 cigarettes/day and unable to comply with the nicotine restriction during the study.

27. History of alcohol abuse or excessive intake of alcohol. Definition of excessive intake: an average weekly intake of >14 drinks/week for men or >7 drinks/week for women. One drink is equivalent to (12 g alcohol) = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of 80 proof distilled spirits.

28. Positive screen for drugs of abuse at screening or admission to the unit or positive screen for alcohol at screening or on admission to the unit prior to the first administration of IMP.

29. History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD4076.

30. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea), as judged by the Investigator.

31. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.

32. Plasma donation within one month of screening or any blood donation/blood loss > 500 mL during the 56 days prior to screening.

33. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within one month of the administration of IMP in this study. The period of exclusion begins one month after the final dose or one month after the last visit whichever is the longest.

34. Use of implants or devices that are incompatible with the MRI procedure. 35. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

36. Involvement of any Astra Zeneca, PROFIL INSTITUTE or study site employee or their close relatives.

37. Judgment by the Investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.

38. Subjects not willing to comply with the dietary requirements in the study as judged by the Investigator.

39. Subjects who cannot communicate reliably with the Investigator or designee. 40. Previous bone marrow transplant. 41. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02826525


Sponsors and Collaborators
AstraZeneca
Investigators
Layout table for investigator information
Principal Investigator: Linda Morrow, MD ProSciento, Inc.

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02826525     History of Changes
Other Study ID Numbers: D5590C00002
First Posted: July 11, 2016    Key Record Dates
Last Update Posted: October 22, 2019
Last Verified: October 2019
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases