A Phase IIa Study to assess Safety, Tolerability, and Pharmacodynamics of AZD4831 in Adult Participants with Non-cirrhotic NASH with Fibrosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astrazeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18], Phenomena and Processes [G] - Metabolism [G03], Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

14 Dec 2022 → 4 Apr 2024

Decision date (initial)

2022-10-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2022-500594-13-00

ClinicalTrials.gov

NCT05638737

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety

The primary objective of this study is to evaluate safety and tolerability of AZD4831 and pharmacodynamics in participants with non-cirrhotic NASH with fibrosis.

Secondary objectives 2

1. To assess the effect of AZD4831 on circulating biomarkers of fibrosis compare with placebo
2. To assess the PK of AZD4831

Conditions and MedDRA coding

"Non-Alcoholic Steatohepatatis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD)with a prevalence of approximately 2% to 3% of the general population. Non-alcoholic steatohepatitis can lead to cirrhosis and its complications, hepatocellular carcinoma, and end stage liver disease. Non-alcoholic steatohepatitis is defined histologically as a multicomponent condition composed of hepatic steatosis, inflammation, and hepatocyte ballooning in varying proportions. NASH differs from steatosis alone by the presence of hepatic cell inflammation and injury in response to lipotoxic intermediates that are accumulated and metabolized in the steatotic liver. NASH is closely associated with metabolic risk factors including obesity, T2DM, and dyslipidemia. Pathophysiologically, NASH is frequently associated with a hyperinsulinemic or insulin resistant state, leading to adipose tissue dysfunction and increased hepatic de novo lipogenesis."

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Participant must be ≥ 18 to ≤ 75 years of age at the time of signing the informed consent.
2. 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.
3. 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).
4. 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
5. 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.
6. Stable weight for at least 3 months prior to randomization. Stable weight is defined as ≤ 5% change.
7. 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.
8. 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).
9. 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.

Exclusion criteria 36

1. 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.
2. Any positive results for HIV infection or positive results for hepatitis B surface antigen or hepatitis B core antibody or hepatitis C antibody test.
3. 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).
4. History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy, or variceal bleeding.
5. Prior or planned liver transplantation.
6. 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.
7. 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.
8. Severe congestive heart failure (New York Heart Association Class IV).
9. 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.
10. 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.
11. 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.
12. History or ongoing drug allergies or hypersensitivity reactions to drugs (including but not limited to rash, angioedema, acute urticaria).
13. Participants with hyperthyroidism, uncontrolled hypothyroidism, or any clinically significant thyroid disease as judged by the investigator. Patients with TSH ≥ ULN should be excluded.
14. 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.
15. Participants with a positive SARS-CoV-2 infection test at screening (Visit 1), if clinically indicated, based on investigator discretion.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. Participants planning to make significant lifestyle changes to their diet or exercise regimen during the conduct of the study.
22. Criterion not applicable to this CSP version.
23. High dose vitamin E (> 400 IU) unless on a stable dose within 6 months of screening.
24. 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.
25. Participation in a clinical study testing anti-obesity medications within 12 months of screening.
26. 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).
27. Recent (within 6 months of screening) use of obeticholic acid or other therapy under investigation for NASH (Table 5).
28. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients.
29. 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.
30. 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.
31. Heart rate > 110 bpm or < 50 bpm at randomization.
32. 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.
33. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
34. Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
35. 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.
36. Previous randomization in the present study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline and over placebo to Week 12: ALT

Secondary endpoints 2

1. Change from baseline and over placebo to Week 12: ProC3
2. Plasma concentration of AZD4831 will be summarized by timepoints and dose level. If PK data permit, a population PK model may be developed and potentially coupled with separate PD models; the derived PK parameters and the modelling will be provided in a separate PK and population PK/PD report.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astrazeneca AB

Sponsor organisation

Astrazeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

6 EU/EEA countries · 27 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications