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

NCT ID: NCT04483947

Last Updated: 2024-01-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-06
• Study Completion Date: 2023-12-18

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.

Conditions

Non-alcoholic Steatohepatitis (NASH)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Cohort 1

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

Group Type: EXPERIMENTAL

AZD2693

Intervention Type: DRUG

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

Placebo

Intervention Type: OTHER

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

Cohort 2

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

Group Type: EXPERIMENTAL

AZD2693

Intervention Type: DRUG

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

Placebo

Intervention Type: OTHER

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

Cohort 3

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

Group Type: EXPERIMENTAL

AZD2693

Intervention Type: DRUG

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

Placebo

Intervention Type: OTHER

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

Cohort 4

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

Group Type: EXPERIMENTAL

AZD2693

Intervention Type: DRUG

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

Placebo

Intervention Type: OTHER

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

Interventions

AZD2693

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

Intervention Type: DRUG

Placebo

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

Intervention Type: OTHER

Eligibility Criteria

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.

Exclusion Criteria

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).

• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Parexel

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rohit Loomba, MD, MHSc

Role: PRINCIPAL_INVESTIGATOR

Director, NAFLD Research Center Director of Hepatology, Professor of Medicine Vice Chief, Division of Gastroenterology University of California at San Diego ACTRI Building, 1W202 9500 Gilman Drive La Jolla, CA, 92037-0887

Locations

Research Site

Chula Vista, California, United States

Research Site

La Mesa, California, United States

Research Site

Montclair, California, United States

Research Site

San Diego, California, United States

Research Site

Doral, Florida, United States

Research Site

Hialeah, Florida, United States

Research Site

Hialeah, Florida, United States

Research Site

Miami Lakes, Florida, United States

Research Site

Indianapolis, Indiana, United States

Research Site

Morehead City, North Carolina, United States

Research Site

Columbus, Ohio, United States

Research Site

Hershey, Pennsylvania, United States

Research Site

Arlington, Texas, United States

Research Site

Dallas, Texas, United States

Research Site

San Antonio, Texas, United States

Research Site

San Antonio, Texas, United States

Countries

United States

References

Armisen J, Rauschecker M, Sarv J, Liljeblad M, Wernevik L, Niazi M, Knochel J, Eklund O, Sandell T, Sherwood J, Bergenholm L, Hallen S, Wang S, Kamble P, Bhat M, Maxvall I, Wang Y, Lee RG, Bhanot S, Guo S, Romeo S, Lawitz E, Fjellstrom O, Linden D, Blau JE, Loomba R. AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials. J Hepatol. 2025 Jul;83(1):31-42. doi: 10.1016/j.jhep.2024.12.046. Epub 2025 Jan 9.

Reference Type: DERIVED

PMID: 39798707 (View on PubMed)

Lai M, Lai JC, Allegretti AS, Patidar KR, Cullaro G. Investigating the Association between Steatotic Liver Disease and CKD in a Nationally Representative Sample. Kidney360. 2024 Dec 1;5(12):1844-1852. doi: 10.34067/KID.0000000569. Epub 2024 Sep 5.

Reference Type: DERIVED

PMID: 39235870 (View on PubMed)

Other Identifiers

D7830C00002

Identifier Type: -

Identifier Source: org_study_id