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
- K75 NULL
- Registration Number
- PER-016-23
- Lead Sponsor
- AstraZeneca AB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- In enrollment
- Sex
- All
- Target Recruitment
- 1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1Participant must be 18 to 75 years of age (inclusive) at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2Participants who consent to give blood and buccal swab samples for genetic testing and diagnostic test development for PNPLA3 rs738409 148M who are carriers for the PNPLA3 rs738409 148M risk allele, (specifically the PNPLA3 substitution rs738409 (NG 008631.1:g.10109C > G, NM 025225.3:c.444C > G, NP 079501.2:p.I148M), further referenced as PNPLA3 I148M risk allele), ie, who have either homozygous or heterozygous G/G or G/C genotypes. The genotyping samples must be provided during Visit 1, unless already obtained during the Screening Study in Participants at risk for or with confirmed NASH.”
3Participants who accept to have one liver biopsy performed during the screening period (if no biopsy within 6 months before randomisation is available) and one at 54 weeks (Visit 22). Participants who have had a liver biopsy more than 3 months before randomisation should have stable weight (< 5% difference) within 6 months prior to screening.
4Participants 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 based on central pathologist evaluation:
(a)Definitive NASH with NAS = 4 with = 1 in each component (ie, steatosis, lobular inflammation, and ballooning).
(b)Presence of fibrosis stage F2 or F3 according to the NASH CRN fibrosis staging system.
5If participants (with or without diabetes) are on GLP1 RA, SGLT2i or pioglitazone, the medication must be stable (no change in dose) for 6 months before screening visit.
6For participants with T2DM, HbA1c = 9.5% (inclusive) at screening visit, and is considered clinically stable disease (stable doses of antidiabetic medication) for 3 months prior to screening visit (Visit 2).
7No evidence of COVID-19 signs or symptoms (fever, cough, sore throat or other symptoms) and testing to be performed according to site-specific and local guidance.
Sex
8Male or female
Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
(a)Male participants:
oContraception is not required.
(b)Female participants of non-childbearing potential:
oContraception is not required.
oWomen not of childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause. The following age-specific requirements apply:
?Women < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle-stimulating hormone levels in the postmenopausal range.
?Women = 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
(c)Female participants of childbearing potential:
oWomen of childbearing potential must use one highly
5.2Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1Any clinically significant illness, medical/surgical procedure, or significant trauma within 4 weeks of the first administration of study intervention (Visit 3).
2History of liver transplant or current placement on a liver transplant list.
3Liver 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) including positive results for HBsAg or hepatitis C antibody and has not received curative treatment within the last 3 years. HCV RNA PCR reflex test to be performed in participants with a positive Hepatitis C antibody titre at screening.
4History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy, or variceal bleeding.
5Historical persistent or pre-existing renal disease marked by eGFR < 40 mL/min/1.73 m2 (as defined by Kidney Disease Improving Global Outcomes guidelines).
6CV event of acute myocardial infarction/coronary artery bypass graft surgery/percutaneous coronary intervention, unstable angina, or stroke in the period 6 months before the screening visit.
7High-degree AV block II-III, clinically significant sinus node dysfunction not treated with pacemaker and heart rate of = 45 beats per minute on screening ECG (Visit 2).
8Ventricular or atrial arrhythmias requiring treatment. Participants with permanent atrial fibrillation and optimally regulated ventricular rate who are not on medication with an anticoagulant are eligible.
9Severe congestive heart failure (New York Heart Association Class IV).
10History of malignancy within the last 5 years, excluding successful treatment of basal cell skin carcinoma or in situ carcinoma of cervix.
11History of > 5% weight loss in the 6 months prior to screening visit, plans to initiate a weight loss diet or plans to undergo bariatric surgery.
12Recent (within 3 months of screening visit) use of drugs approved for weight loss (eg, orlistat, bupropion/naltrexone, phentermine, lorcaserin).
13Recent (within 6 months of screening visit) use of drugs under investigation for treatment of NASH (see Section 6.5.1 for details).
14Recent (within 6 months of screening visit) use of drugs associated with development of NAFLD (see Section 6.5.1 for details).
15Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, or symptoms of increased risk of bleeding (frequent bleeding gums or nosebleeds).
16History of major bleeding or high-risk of bleeding diathesis.
17Previous bone marrow transplant.
18History of type I diabetes.
19Participants with a significant COVID-19 illness within 6 months of enrolment:
?Participant’s 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 hospitalisation and/or oxygen supplementation therapy.
Prior/Concomitant Therapy
20High dose vitamin E (> 400 IU), unless on a stable dose for at least 6 months prior to the baseline biopsy and not initiated after the biopsy was taken.
21Use of anabolic st
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Primary endpoint will be analysed using a Cochran-Mantel-Haenszel test with stratification by T2DM presence and F2/F3 fibrosis stages based on the FAS population.<br> NAME OF THE RESULT: •Proportion of participants achieving NASH resolution without worsening of fibrosis based on histology after Week 52<br> PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE<br> PRIMARY RESULT: During the study development.
- Secondary Outcome Measures
Name Time Method