A Phase IIa, Randomized, Double-blind, Placebo-controlled Study to Evaluate Safety, Tolerability, and Pharmacodynamics of AZD4831 in Participants with Non-cirrhotic Non-alcoholic Steatohepatitis (NASH) with Fibrosis

Trial ID: 2022-500594-13-00
Protocol: D6581C00001
Sponsor: AstraZeneca AB

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Diseases & Conditions

Metabolic dysfunction-associated steatohepatitis Non-alcoholic steatohepatitis

Objectives

The primary objective of this study is to evaluate the **safety** and **tolerability** of AZD4831, as well as its **pharmacodynamics**, in participants with non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis. This is clinically relevant as NASH is a progressive liver disease that can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. Understanding the safety and pharmacodynamics of AZD4831 could provide insights into potential therapeutic options for managing NASH with fibrosis.

Secondary objectives include:

Assessing the effect of AZD4831 on circulating biomarkers of **fibrosis** compared with placebo, which could help in understanding the drug's impact on disease progression.
Evaluating the **pharmacokinetics** (PK) of AZD4831, which is essential for determining the drug's absorption, distribution, metabolism, and excretion in the body.

Participants

The clinical trial involves a total of **46 participants** diagnosed with **Non-Alcoholic Steatohepatitis (NASH)**, a progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD). The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on histologically confirmed NASH, with fibrosis stages F1, F2, or F3, and a NASH CRN NAFLD Activity Score (NAS) of at least 4. The trial does not include a vulnerable population. Participants may have Type 2 Diabetes Mellitus (T2DM) with a Hemoglobin A1c of 9.5% or less, managed by stable medication. Lifestyle considerations include a stable weight, defined as a change of 5% or less, for at least three months prior to randomization. The trial population is not restricted by gender, and both male and female participants are included, with specific contraceptive requirements for women of childbearing potential. The study does not involve pregnant or lactating women. Participants are required to provide informed consent, including consent for optional genetic research.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety, tolerability, and pharmacodynamics of AZD4831 in participants with non-cirrhotic **Non-Alcoholic Steatohepatitis (NASH)** with fibrosis. The trial is set to span approximately 12 weeks, with the estimated recruitment start date being October 31, 2022, and an estimated end date of July 1, 2024. Participants will be randomly assigned to receive either AZD4831 or a placebo, administered orally in the form of a film-coated tablet. The primary objective is to assess the safety and tolerability of AZD4831, with secondary endpoints including changes in plasma concentration and pharmacokinetic modeling.

The sequence of study visits begins with an inclusion (screening) visit, where participants are assessed for eligibility based on criteria such as age, histologically confirmed NASH, and stable weight. Following successful screening, participants will undergo randomization and commence the treatment phase. Throughout the trial, participants will attend regular follow-up visits to monitor safety parameters, including changes in ALT levels and other relevant biomarkers. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the overall impact of the treatment.

Participant involvement is expected to last for the duration of the 12-week treatment period. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial is conducted in accordance with ethical guidelines, ensuring that participants provide informed consent and are aware of the study's requirements and restrictions. The trial aims to contribute valuable data on the potential therapeutic benefits of AZD4831 in managing NASH with fibrosis.

Treatment

The clinical trial involves the administration of **AZD4831**, an experimental medication, to evaluate its safety, tolerability, and pharmacodynamics in participants with non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis. **AZD4831** is a small molecule, chemically derived, and is provided in the form of a film-coated tablet. The active substance in this medication is **AZD4831**, and it is manufactured by AstraZeneca AB. The medication is administered orally with a maximum daily dose of 5 mg and a total maximum dose of 420 mg over a treatment period of up to 12 weeks. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a placebo is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the **AZD4831** film-coated tablet in appearance but does not contain the active substance. The placebo is also administered orally, following the same dosing schedule as the experimental medication. The use of a placebo allows for the assessment of the true effects of **AZD4831** by providing a baseline for comparison. Participants are randomly assigned to receive either the experimental medication or the placebo, and neither the participants nor the investigators are aware of the group assignments to maintain the study's integrity.

Efficacy

The efficacy of AZD4831 in the treatment of non-cirrhotic Non-alcoholic Steatohepatitis (NASH) with fibrosis will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the change from baseline in **alanine aminotransferase (ALT)** levels compared to placebo at Week 12. Secondary endpoints include the change from baseline in ProC3 levels over placebo to Week 12. Additionally, the plasma concentration of AZD4831 will be measured at various timepoints and dose levels. If pharmacokinetic (PK) data allow, a population PK model may be developed and potentially coupled with separate pharmacodynamic (PD) models. The derived PK parameters and modeling results will be documented in a separate PK and population PK/PD report.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant must be ≥ 18 to ≤ 75 years of age at the time of signing the informed consent.
Participants with histologically confirmed NASH as diagnosed by liver biopsy within 12 months of provision of written informed consent fulfilling all of the following histological criteria and in accordance with the NASH CRN NAFLD Activity Score (NAS). (a) NAS ≥4 with a score of at least 1 in each of the 3 histological components (ie, steatosis, lobular inflammation, and ballooning) (b) Presence of fibrosis stage F1, F2, or F3 Participants without a historical biopsy that meets the above histological criteria should be willing to undergo a liver biopsy at screening, result of which subsequently fulfills the criteria.
Hemoglobin A1c ≤ 9.5% (inclusive) at Visit 1 if T2DM present, managed by a stable medication (ie, no major dose adjustments in prior 3 months to randomization).
One increased serum ALT measurement (ALT > ULN) at screening, and historical local serum ALT level (> ULN [41 U/L for men and 31 U/L for women] but < 300 U/L) on ≥ 1 occasion in the 6 months prior to screening
Participants with or without diabetes. If participants are on GLP-1 receptor agonists, SGLT2 inhibitors, or pioglitazone, the medication has to be stable for at least 6 months prior to randomization.
Stable weight for at least 3 months prior to randomization. Stable weight is defined as ≤ 5% change.
Male and/or female. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. (a) Criterion not applicable to this CSP version. (b) Criterion not applicable to this CSP version. (c) Female participants:  Female participants must not be pregnant or lactating.  Females of childbearing potential who are sexually active with a non-sterilized male partner must agree to use an acceptable method of birth control, from enrolment throughout the study and until at least 4 weeks after last dose of study intervention. Acceptable methods of contraception include birth control pills, injections, implants or patches, intrauterine devices, and tubal ligation/occlusion. The following are not acceptable methods of contraception: periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea. Female condom and male condom should not be used together.
Capable of giving signed informed consent as described in Appendix D 3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol (including use of sample for genetic testing where allowed).
Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative.

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Exclusion Criteria

History of, or any existing condition that, in the opinion of the investigator, would interfere with evaluation of the study intervention, put the participant at risk, influence the participant’s ability to participate or affect the interpretation of the results of the study.
Any positive results for HIV infection or positive results for hepatitis B surface antigen or hepatitis B core antibody or hepatitis C antibody test.
Liver disease of other etiologies (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.
Prior or planned liver transplantation.
Clinically significant cardiovascular or cerebrovascular disease within the past 3 months, including but not limited to, myocardial infarction, acute coronary syndrome, unstable angina pectoris, transient ischemic attack, or stroke, or participants who have undergone percutaneous coronary intervention or a coronary artery bypass graft within the past 6 months or who are due to undergo these procedures at the time of screening.
Clinically significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery affecting the upper gastrointestinal tract (including bariatric surgery) that may affect gastric emptying or could affect the interpretation of the safety and tolerability data.
Severe congestive heart failure (New York Heart Association Class IV).
History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal) or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter or sinus node dysfunction with clinically significant pause or second to third degree AV-block untreated with pacemaker.
History of malignant neoplasms within 5 years prior to screening, except for adequately treated basal cell, squamous cell skin cancer, or in situ cervical cancer.
Prolonged QT interval (Fridericia-corrected QT interval > 470 ms) on ECG at screening (Visit 1), known congenital long QT syndrome, or family history of cardiac sudden death at age < 40 years.
History or ongoing drug allergies or hypersensitivity reactions to drugs (including but not limited to rash, angioedema, acute urticaria).
Participants with hyperthyroidism, uncontrolled hypothyroidism, or any clinically significant thyroid disease as judged by the investigator. Patients with TSH ≥ ULN should be excluded.
History of psychosis or bipolar disorder. History of major depressive disorder within the past year with the participant being clinically unstable, or any history of suicide attempt or history of suicidal ideation within the past year at the discretion of the investigator.
Participants with a positive SARS-CoV-2 infection test at screening (Visit 1), if clinically indicated, based on investigator discretion.
Participants with a significant COVID-19 illness within 6 months of enrollment: (a) Participants with a diagnosis of COVID-19 pneumonia based on radiological assessment. (b) Participants with diagnosis of COVID-19 with significant findings from pulmonary imaging tests. (c) Participants with a diagnosis of COVID-19 requiring hospitalization and/or oxygen supplementation therapy.
History of excessive alcohol consumption, defined as an average weekly intake of > 21 drinks/week (294 g/week) for males or > 14 drinks/week (196 g/week) for females. One drink is equivalent to 14 g alcohol.
Evidence of alcohol dependence as assessed by the AUDIT questionnaire at screening (Appendix B). Participants with an AUDIT questionnaire score to 13 or more in women and 15 or more in men will be excluded.
Positive screen for drugs of abuse at screening or admission to the study site prior to the administration of the study intervention. Note: participants who test positive for drugs (ie, opioids) that are prescribed for appropriate medical use are eligible to participate in the study.
Recent (within 3 months of randomization) use of drugs approved for weight loss (eg, orlistat, bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well as those drugs used off-label.
Participants planning to make significant lifestyle changes to their diet or exercise regimen during the conduct of the study.
Criterion not applicable to this CSP version.
High dose vitamin E (> 400 IU) unless on a stable dose within 6 months of screening.
Participation in another clinical study with an IP administered in the last 3 months or 5 half-lives of the therapy (whichever is longer) at the time of screening.
Participation in a clinical study testing anti-obesity medications within 12 months of screening.
Recent (within 6 months of screening) use of therapies associated with development of NAFLD (eg, systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or long-term use of tetracyclines) (Table 5).
Recent (within 6 months of screening) use of obeticholic acid or other therapy under investigation for NASH (Table 5).
Severe allergy/hypersensitivity to any of the proposed study treatments or excipients.
Abnormal laboratory values including any of the following: (a) AST or ALT > 5 × ULN. (b) ALP ≥ 1.5 × ULN, unless not of hepatic origin. (c) Impaired renal function defined as estimated glomerular filtration rate ≤ 30 mL/minute/1.73 m2 at screening (estimated according to chronic kidney disease epidemiology collaboration) (Inker et al 2021). (d) Albumin < 35 g/L. (e) International normalized ratio > 1.3. (f) TBL > ULN in the absence of known Gilbert’s disease. (g) Platelets < 150000/mm3. (h) MELD score ≥ 12. (i) Any other clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results as judged by the investigator.
Severely uncontrolled hypertension defined systolic BP ≥ 180 mmHg and/or diastolic BP ≥ 110 mmHg on the average of 2 supine measurements after being at rest for at least 10 minutes at screening or randomization.
Heart rate > 110 bpm or < 50 bpm at randomization.
Any clinically significant abnormalities in rhythm, conduction, or morphology of the resting ECG, as considered by the investigator at the screening visit (Visit 1) and/or on Week −1.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
Judgment by the investigator that the participant should not participate in the study if they have any ongoing or recent (ie, during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.
Previous randomization in the present study.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Not Recruiting	31 Oct 2022	9
Italy	Not Recruiting	31 Oct 2022	7
Norway	Not Recruiting	31 Oct 2022	10
Portugal	Not Recruiting	31 Oct 2022	4
Spain	Not Recruiting	31 Oct 2022	13
Sweden	Not Recruiting	31 Oct 2022	5