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

  • STATUS
    Recruiting
  • End date
    Dec 12, 2022
  • participants needed
    60
  • sponsor
    AstraZeneca
Updated on 9 September 2021

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 homozygous for the patatin-like phospholipase domain-containing 3 (PNPLA3) 148M risk allele.

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 homozygous for the PNPLA3 148M risk allele.

The study will comprise of:

  • An optional Pre Screening Visit may be completed to determine PNPLA3 genotype and collect minimal baseline data and only participants homozygous for rs738409 will continue the study and enter the Screening Period. The Pre-Screening Visit is optional and sites may proceed with full screening if this is preferred.
  • A Screening Period with a maximum of 60 days.
  • An 8-week dosing period 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. All study interventions and PD assessments will be administered after a 10 hour fast.
  • Each participant will be followed for 15 weeks post last dose (approximately 5 t; t is estimated to approximately 22 days); however, the length of follow-up may be shortened or extended if the actual t is considerably shorter or longer than predicted.

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 60 participants comprised of male participants and female participants of non-childbearing potential will be randomized into the first 3 cohorts of this study in order to achieve 48 evaluable participants.

Details
Condition Non Alcoholic Steatohepatitis
Treatment Placebo, AZD2693
Clinical Study IdentifierNCT04483947
SponsorAstraZeneca
Last Modified on9 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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
Participant's consent for a liver biopsy or MRE/VCTE at screening, if previous biopsies or MRE/VCTE imaging data are not available
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 9.9 kPa; or
Participants who are homozygous for rs738409 (PNPLA3 148M)
Body weight 50 kg and BMI within the range 25 to 45 kg/m2 (inclusive)
Male, or female of non-childbearing potential
Participants should agree to follow protocol defined contraceptive procedures
Provision of signed, written, and dated informed consent for mandatory Genetic PNPLA3 I148M determination genetic/biomarker, for inclusion or exclusion in the clinical study (this may be checked at the optional Pre-Screening Visit)
Mandatory PNPLA3 Genetic Biomarker and Companion Diagnostic Development Samples (this may be checked at the optional Pre-Screening Visit)
The participant will be excluded from the study if consent for the PNPLA I148M Genetic Biomarker Samples is not given
The mandatory consent will include assessment of PNPLA3 I148M status as well as additional genotyping of gene variants associated with PNPLA3 expression
Provision of 3 blood samples (3 x 4 ml in ethylene-diamine-tetra-acetic acid [EDTA] tubes)
Provision of 3 buccal swabs
Provision of signed and dated written optional genetic research information informed consent prior to collection of samples for optional genetic research for the Genomic Initiative and the clustered regularly interspaced short palindromic repeats (CRISPR) technology (this may be checked at the optional Pre-Screening Visit)

Exclusion Criteria

Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention
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)
If a participant has a positive result at the screening visit for hepatitis C antibody, the investigator will document that the participant has hepatitis C RNA below the limit of detection and has not received curative treatment in the last 3 years
Histological or imaging (MRE or VCTE) evidence of cirrhosis
Any positive result at the Screening Visit for serum hepatitis B surface antigen and human immunodeficiency virus
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) or
urinary albumin-to-creatinine ratio > 3 mg/mol (30 mg/g)
Clinically significant cardiovascular event within the last 6 months prior to the Screening Visit
Participants with a positive SARS-CoV-2 infection test at Screening Visit
Participants with a significant Coronavirus disease 2019 (COVID-19) illness within 6 months of enrolment
Participants with a diagnosis of COVID-19 pneumonia based on radiological assessment
Participants with diagnosis of COVID-19 with significant findings from pulmonary imaging tests
Participants with a diagnosis of COVID-19 requiring hospitalization and/or oxygen supplementation therapy
Suspicion of or known Gilbert's syndrome
Weight loss of more than 5% within the last 6 months prior to randomization. Plans to initiate a weight loss diet or to undergo bariatric surgery
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
Changes to any concomitant medication (initiation, dose change, or cessation) that may impact the study readouts (as judged by the investigator) within 1 month prior to the Screening Visit. This criterion does not apply to medication prescribed for occasional use
Use of anabolic steroids and systemic treatment with glucocorticosteroids within 3 months prior to the Screening Visit
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