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

NCT04483947 | Completed Phase 1 FDA Drug FDA Device

• 1 other identifier: D7830C00002
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 16

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.

Conditions

Non-alcoholic Steatohepatitis (NASH)

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Number of participants with adverse events

  Up to 32 weeks (From Screening to Final Visit)

Secondary Outcomes (48)

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

  Baseline (Day 1), Week 8, Week 12

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

  Baseline (Day 1), Week 8, Week 12

• Absolute change from baseline in Alanine Aminotransferase

  Up to 32 weeks (From Pre-Screening to Final Visit)

• Percent change from baseline in Alanine Aminotransferase

  Up to 32 weeks (From Pre-Screening to Final Visit)

• Absolute change from baseline in Aspartate Aminotransferase

  Up to 32 weeks (From Pre-Screening to Final Visit)

Study Arms (4)

Cohort 1

EXPERIMENTAL

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

Drug: AZD2693; Other: Placebo

Cohort 2

EXPERIMENTAL

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

Drug: AZD2693; Other: Placebo

Cohort 3

EXPERIMENTAL

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

Drug: AZD2693; Other: Placebo

Cohort 4

EXPERIMENTAL

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

Drug: AZD2693; Other: Placebo

Interventions

AZD2693 DRUG

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

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Placebo OTHER

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

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (16)

Research Site

Chula Vista, California, 91911, United States

Location

Research Site

La Mesa, California, 91942, United States

Location

Research Site

Montclair, California, 91763, United States

Location

Research Site

San Diego, California, 92103, United States

Location

Research Site

Doral, Florida, 33166, United States

Location

Research Site

Hialeah, Florida, 33014, United States

Location

Research Site

Hialeah, Florida, 33016, United States

Location

Research Site

Miami Lakes, Florida, 33014, United States

Location

Research Site

Indianapolis, Indiana, 46202, United States

Location

Research Site

Morehead City, North Carolina, 28557, United States

Location

Research Site

Columbus, Ohio, 43213, United States

Location

Research Site

Hershey, Pennsylvania, 17033, United States

Location

Research Site

Arlington, Texas, 76012, United States

Location

Research Site

Dallas, Texas, 75203, United States

Location

Research Site

San Antonio, Texas, 78215, United States

Location

Research Site

San Antonio, Texas, 78229, United States

Location

Related Publications (2)

• 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.

  PMID: 39798707 DERIVED

• 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.

  PMID: 39235870 DERIVED

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Obesity

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Rohit Loomba, MD, MHSc

  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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2020
• First Posted: July 23, 2020
• Study Start: November 6, 2020
• Primary Completion: December 18, 2023
• Study Completion: December 18, 2023
• Last Updated: January 17, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

US (16)