A Study to Evaluate AZD2693 in Participants Who Are Carriers of the PNPLA3 148M Risk Allele With Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis

Study Overview
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Brief Summary
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A Study to Evaluate the Efficacy, Safety and Tolerability of AZD2693 given by subcutaneous injection in adult participants with non-cirrhotic non-alcoholic steatohepatitis with fibrosis and who are carriers of the PNPLA3 148M Risk Allele

Official Title
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A Randomised, Double-blind, Placebo-controlled, Multi-centre Phase 2b Study to Evaluate the Efficacy, Safety and Tolerability of AZD2693 in Participants With Non-cirrhotic Non-alcoholic Steatohepatitis (NASH) With Fibrosis Who Are Carriers of the PNPLA3 rs738409 148M Risk Allele

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: AZD2693
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria : Participants are eligible to be included in the study only if all the following criteria apply: Age Participant must be 18 to 75 years of age (inclusive) at the time of signing the informed consent. Type of Participant and Disease Characteristics Participants who are carriers for the PNPLA3 rs738409 148M risk allele. Participants with histological evidence of NASH based on central pathologist evaluation of a liver biopsy obtained up to 6 months before randomisation, or during screening, fulfilling both criteria: Definitive NASH with NAS ≥ 4 with ≥ 1 in each component (ie, steatosis, lobular inflammation, and ballooning). Presence of fibrosis stage F2 or F3 according to the NASH CRN fibrosis staging system based on central pathologist evaluation. Key Exclusion Criteria : Participants are excluded from the study if any of the following criteria apply: Medical Conditions Liver disease of other aetiologies (eg, alcoholic steatohepatitis; drug-induced, viral or autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; hemochromatosis; alpha-1 antitrypsin deficiency; Wilson's disease) History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy, or variceal bleeding. Historical persistent or pre-existing renal disease marked by eGFR < 40 mL/min/1.73 m2 (as defined by Kidney Disease Improving Global Outcomes guidelines). Confirmed platelet count outside the normal range at the screening visit. Any of the following confirmed at the screening visit: ALT > 5.0 × ULN TBL > 1.5 mg/dL (TBL > 1.5 mg/dL is allowed if conjugated bilirubin is < 1.5 × ULN) INR > 1.3 ALP > 1.5 × ULN (unless the ALP elevation is not from hepatic origin as determined by a bone-specific ALP)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised, Double-blind, Placebo-controlled, Multi-centre Phase 2b Study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD2693 dose 1<br>Participants will receive AZD2693 dose 1 | Drug: AZD2693<br>* AZD2693 solution SC once per month<br>|
| Experimental: AZD2693 dose 2<br>Participants will receive AZD2693 dose 2 | Drug: AZD2693<br>* AZD2693 solution SC once per month<br>|
| Placebo Comparator: Placebo<br>Participants in this arm will receive placebo | Other: Placebo<br>* Sodium chloride 0.9% solution SC once per month<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving NASH resolution without worsening of fibrosis based on histology after 52 weeks treatment | To assess the effect of AZD2693 versus placebo on histological resolution of NASH in participants with non-cirrhotic NASH with fibrosis and PNPLA3 risk allele carriers after 52 weeks | after 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with at least one stage of liver fibrosis improvement with no worsening of NASH based on biopsy after 52 weeks treatment | To assess the effects of AZD2693 versus placebo on histological fibrosis improvement | after 52 weeks | 
| Proportion of participants with ≥ 2-point improvement from baseline in NAS based on biopsy after 52 weeks treatment | To assess the effect of AZD2693 versus placebo on ≥ 2-point improvement in NAS | after 52 weeks | 
| Proportion of participants with improvement in fibrosis by at least one stage based on biopsy after 52 weeks treatment | To assess the effect of AZD2693 versus placebo on improvement in fibrosis by at least one stage | after 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonalcoholic Steatohepatitis, NASH, fatty liver disease, Non alcoholic fatty liver, liver fibrosis, PNPLA3 148M Risk Allele, Non Cirrhotic