Back to results

A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients

Primary Purpose

Non-alcoholic Steatohepatitis (NASH)

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

AZD2693

Placebo

About this trial

This is an interventional treatment trial for Non-alcoholic Steatohepatitis (NASH) focused on measuring Pharmacokinetics, Pharmacodynamics, Obese, PNPLA3 148M Risk Alleles, Multiple Ascending Dose

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

For Cohorts 1 to 3:

An MRI-PDFF ≥7% and one of the following:
- Previous liver biopsy: Acceptable if taken in the previous 3 years for fibrosis stages F0 to F2, or within the previous 1 year for stage F3; or
- Previous imaging results taken in the previous 2 years: An MRE between 2.55 kPa and 3.63 kPa, or a vibration-controlled transient elastography (VCTE) between 7.1 kPa and 11.9 kPa;
Participants who are homozygous for rs738409 (PNPLA3 148M). Cohort 2 will enroll participants who are heterozygous for PNPLA3 148M.

For Cohort 4:

• An MRI-PDFF ≥ 7% and participant's consent for a liver biopsy.

Participants with suspected or confirmed Non-alcoholic fatty liver disease (NAFLD) or NASH are eligible for the Screening liver biopsy if they meet main protocol inclusion/exclusion criteria AND have any of the following:

Alanine aminotransferase > Upper Limit of Normal (ULN) but < 3 × ULN, OR Imaging demonstrating hepatic steatosis including attenuation parameter (CAP) > 290dB/m, OR A Magnetic resonance elastography (MRE) between 2.55 kPa and 3.63 kPa, or a vibration-controlled transient elastography (VCTE) between 7.1 kPa and 11.9 kPa.

Histologic evidence of NAFLD or NASH with a NASH Activity Score (NAS) ≥ 3 (independent of subcategory scoring) following Screening liver biopsy.
Participants who are homozygous for rs738409 (PNPLA3 148M).

Exclusion Criteria:

History of liver transplant, or current placement on a liver transplant list (this may be checked at the optional Pre-Screening Visit).
History or presence of hepatic disease (with the exception of hepatic steatosis, NASH) or evidence of other known forms of known chronic liver disease such as alcoholic liver disease, hepatitis B, primary biliary cirrhosis, primary sclerotic cirrhosis, autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (this may be checked at the optional Pre-Screening Visit).
Histological or imaging (MRE or VCTE) evidence of cirrhosis.
Participants with history or pre-existing renal disease, as defined below:
- estimated glomerular filtration rate < 60 mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula)
Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gums or nose bleeds).
History of major bleed or high-risk of bleeding diathesis.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Arm Description

15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo

15 participants will receive AZD2693 dose 2 and 5 participants will receive placebo

15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo

15 participants will receive AZD2693 dose 3 and 5 participants will receive placebo

Outcomes

Primary Outcome Measures

Number of participants with adverse events

Secondary Outcome Measures

Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC)

Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC)

Absolute change from baseline in Alanine Aminotransferase

Percent change from baseline in Alanine Aminotransferase

Absolute change from baseline in Aspartate Aminotransferase

Percent change from baseline in Aspartate Aminotransferase

Absolute change from baseline in Gamma Glutamyl Transferase

Percent change from baseline in Gamma Glutamyl Transferase

Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score

Percent change from baseline in ELF score

Absolute change from baseline in plasma pharmacodynamic biomarker

Percent change from baseline in plasma pharmacodynamic biomarker

Absolute change from baseline in disease-specific biomarkers

Percentage change from baseline in disease-specific biomarkers

Absolute change from baseline β-Hydroxybutyrate and lipid profile

Percent change from baseline β-Hydroxybutyrate and lipid profile

Maximum observed plasma drug concentration (Cmax)

Time to reach maximum observed plasma concentration (tmax)

Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz)

Apparent terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic concentration-time curve, estimated as (ln2)/λz (t½λz)

Area under the plasma concentration-time curve from time zero to 48 hours after dosing (AUC(0-48h))

Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)

Area under the concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC)

Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F)

Mean residence time (MRT)

Time delay between drug administration and the first observed concentration in plasma (tlag)

Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz (Vz/F)

Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D)

Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)

Observed maximum plasma concentration divided by the dose administered (Cmax/D)

Time of the last quantifiable concentration (tlast)

Maximum observed plasma drug concentration at steady state (Cssmax)

Minimum observed drug concentration at steady state (Cssmin)

Time to reach maximum observed plasma concentration at steady state (tssmax)

Area under the concentration-time curve in the dose interval (AUCss)

Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F)

Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUCss/D)

Observed maximum plasma concentration divided by the dose administered (Cssmax/D)

Accumulation ratio based on Cmax (RacCmax)

Accumulation ratio based on AUC (RacAUC)

Temporal change parameter in systemic exposure (TCP)

Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2))

Cumulative amount of analyte excreted from time zero through the last sampling interval (Ae(0-last))

Fraction of dose excreted unchanged into the urine from time t1 to t2 (fe(t1-t2))

Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point (fe(0-last))

Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC (CLR)

Change from placebo to Week 10 in PNPLA3 messenger ribonucleic acid (mRNA) and protein expression (Cohort 4 only)

Change from baseline to Week 10 in PNPLA3 mRNA and protein expression (Cohort 4 only)

Full Information

NCT ID

NCT04483947

First Posted

July 6, 2020

Last Updated

October 13, 2023

Sponsor

AstraZeneca

Collaborators

Parexel

1. Study Identification

Unique Protocol Identification Number

NCT04483947

Brief Title

A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients

Official Title

A Phase 1, Double Blind, Randomised, Placebo-Controlled, Multi-centre, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD2693 in Patients With Non-alcoholic Steatohepatitis (NASH) With Fibrosis Stage 0-3 and Carriers of the PNPLA3 148M Risk Alleles

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

November 6, 2020 (Actual)

Primary Completion Date

December 18, 2023 (Anticipated)

Study Completion Date

December 18, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AstraZeneca

Collaborators

Parexel

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

5. Study Description

Brief Summary

This study is intended to investigate the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD2693, following subcutaneous (SC) administration of multiple ascending doses in participants with Non-alcoholic Steatohepatitis (NASH) with fibrosis Stage 0 to 3 and who are carriers of the patatin-like phospholipase domain-containing 3 (PNPLA3) 148M risk alleles.

Detailed Description

This study is a double blind, randomised, placebo-controlled, multi-centre study in participants with NASH and fibrosis stage between F0 (no fibrosis) and F3 (bridging fibrosis), and who are carriers of the PNPLA3 148M risk alleles. The study will comprise of: An optional Pre-Screening Visit may be completed to determine PNPLA3 genotype and collect minimal baseline data and participants who are carriers of the PNPLA3 148M risk allele(s) will continue the study and enter the Screening Period. A Screening Period with a maximum of 60 days. For participants in all Cohorts, the dosing period will be 8 weeks during which participants will be resident of the study site for Dose 1 and Dose 3. Dose 1 will have participants reside at the study site from the day prior to study intervention administration (Day -1) until at least 2 days after study intervention administration with discharge on Day 3. Dose 2 will be administered at the study site on Day 29 with no overnight stay. Dose 3 will have participants reside at the study site from the day prior to study intervention administration (Day 56) until at least 2 days after study intervention administration with discharge on Day 59. Each participant will be followed for approximately 15 weeks post last dose. The study will be performed at up to 30 study sites in the United States (US) and up to 5 study sites in Mexico. Approximately 80 participants comprising of male and female participants of non-childbearing potential may be enrolled into the first 4 cohorts of this study in order to achieve a target of 56 to 64 evaluable participants.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Non-alcoholic Steatohepatitis (NASH)

Keywords

Pharmacokinetics, Pharmacodynamics, Obese, PNPLA3 148M Risk Alleles, Multiple Ascending Dose

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

ParticipantInvestigator

Masking Description

The study will be blinded for all study site personal including the principal investigator during the clinical conduct of a given cohort. Investigators will remain blinded to each participant's assigned study intervention throughout the course of the study.

Allocation

Randomized

Enrollment

74 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

15 participants will receive AZD2693 dose 2 and 5 participants will receive placebo

Arm Title

Cohort 3

Arm Type

Experimental

Arm Description

15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo

Arm Title

Cohort 4

Arm Type

Experimental

Arm Description

15 participants will receive AZD2693 dose 3 and 5 participants will receive placebo

Intervention Type

Drug

Intervention Name(s)

AZD2693

Intervention Description

Subcutaneous administration of AZD2693 multiple ascending doses in participants with NASH and who are carriers of the PNPLA3 148M risk allele(s).

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Participants randomised to placebo will receive the corresponding dose volume of solution as participants receiving AZD2693 within the same cohort

Primary Outcome Measure Information:

Title

Number of participants with adverse events

Time Frame

Up to 32 weeks (From Screening to Final Visit)

Secondary Outcome Measure Information:

Title

Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC)

Time Frame

Baseline (Day 1), Week 8, Week 12

Title

Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC)

Time Frame

Baseline (Day 1), Week 8, Week 12

Title

Absolute change from baseline in Alanine Aminotransferase

Time Frame