A study to evaluate AZD2693 in participants who are carriers of the PNPLA3 148M Risk Allele with non-cirrhotic non-alcoholic steatohepatitis with fibrosis

Phase 2

Recruiting

• Conditions: Inflammatory liver disease, unspecified,

• Registration Number: CTRI/2023/07/055524
• Lead Sponsor: AstraZeneca AB

Brief Summary

This is a Phase 2b, 52-week randomised, double-blind, placebo-controlled, multi-centre, multinational trial comparing once monthly SC administration of AZD2693 in participants with non-cirrhotic NASH (F2-F3) carrying the PNPLA3 rs738409 148M risk allele, in male and female participants 18 to 70 years of age (inclusive).The study will be conducted in approximately 200 centers in 23 countries, The study includes a screening period of up to 10 weeks (inclusive of 2-week early genotyping assessment) followed by randomization, 52-week treatment period and about 12-week safety follow-up period. The study will randomize approximately 232 participants.

This Phase 2b study is planned to evaluate 2 different doses with corresponding injection volumes of placebo.

The randomization ratio of homozygous participants receiving AZD2693 or placebo will be 2:1. The randomisation ratio of heterozygous participants receiving AZD2693 or placebo will be 1:1.

Detailed Description

Not available

Study Timeline

• Study Start: 2023-03-08
• Last Update Posted: 2024-10-07

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 232

Inclusion Criteria

• Age. 1 Participant must be 18 to 75 years of age (inclusive) at the time of signing the informed consent. Type of Participant and Disease Characteristics 2 Participants 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. 3. Participants 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. 4. 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 based on central pathologist evaluation: (a) Definitive NASH with NAS ≥ 4 with ≥ 1 in each component (ie, steatosis, lobular inflammation, and ballooning). (a) Presence of fibrosis stage F2 or F3 according to the NASH CRN fibrosis staging system. 5. If 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. 6. For 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). 7. No 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 8. Male or female Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. (a) Male participants:.
• Contraception is not required. (b) Female participants of non-childbearing potential:.
• Contraception is not required. Women not of childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral alpingectomy), 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:.
• Women of childbearing potential must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly (see below). Women of childbearing potential who are sexually active with a non-sterilised male partner must agree to use one highly effective method of birth control, as defined below, from enrolment throughout the study and until at least 12 weeks after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only and lactational amenorrhoea method are not acceptable methods of contraception. Female condom and male condom should not be used together. In all women of childbearing potential, a urine pregnancy test should be performed at any time during the trial (in addition to scheduled testing) if a menstrual period is missed, or as required by local law. A urine pregnancy test will be performed after the serum pregnancy test at screening and must be negative. In addition, a serum pregnancy test must be administered by the end of the exposure period (at the follow-up appointment).
• Highly effective birth control methods include: sexual abstinence (of note, unacceptable methods of contraception include periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of exposure to IP, and withdrawal), a vasectomised partner, Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo-Proveraâ„¢ injections, oral contraceptives, and Evra Patchâ„¢, Xulaneâ„¢, or NuvaRing®. Women of childbearing potential must agree to use one highly effective methods of birth control, as defined above, from enrolment throughout the study and to within 12 weeks after last dose of study intervention. Informed Consent 9. Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 10. Participants who consent only to the main study may fully participate in the main study without participating in the optional component. However, to participate in the optional component of the study, the participant must: (a) Provide signed and dated, written informed consent prior to collection of samples for future biomarker research. (b) Provide signed and dated, written informed consent prior to collection of samples for genetic research (Optional Genomics Initiative, see Appendix D).

Exclusion Criteria

• Medical Conditions 1.Any clinically significant illness, medical/surgical procedure, or significant trauma within 4 weeks of the first administration of study intervention (Visit 3) 2.History of liver transplant or current placement on a liver transplant list. 3.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; Wilsons 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. 4.History of cirrhosis and/or hepatic decompensation, including ascites, hepatic encephalopathy, or variceal bleeding. 5.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). 6.CV 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. 7.High-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). 8.Ventricular 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. 9.Severe congestive heart failure (New York Heart Association Class IV). 10.History of malignancy within the last 5 years, excluding successful treatment of basal cell skin carcinoma or in situ carcinoma of cervix. 11.History 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. 12.Recent (within 3 months of screening visit) use of drugs approved for weight loss (eg, orlistat, bupropion/naltrexone, phentermine, lorcaserin). 13.Recent (within 6 months of screening visit) use of drugs under investigation for treatment of NASH (see Section 6.5.1 for details). 14.Recent (within 6 months of screening visit) use of drugs associated with development of NAFLD (see Section 6.5.1 for details). 15.Blood 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). 16.History of major bleeding or high-risk of bleeding diathesis. 17.Previous bone marrow transplant. 18.History of type I diabetes 19.Participants 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 20.High 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. 21.Use of anabolic steroids and systemic treatment with glucocorticosteroids for more than 7 days within 3 months prior to the screening visit. 22.Non-leucocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection (Visit 1). 23.Use of warfarin, direct and indirect thrombin inhibitors, factor Xa inhibitors or any antiplatelet therapy other than low-dose aspirin (≤ 100 mg/day); for details see Table 5. Other Exclusions: 24.Any confirmed clinically significant abnormalities in clinical chemistry, haematology or urinalysis results as judged by the investigator at the screening visits. 25.Confirmed platelet count < LLN at the screening visita. 26.Any of the following confirmed at the screening visita: (a) ALT > 5.0 × ULN (b) TBL > 1.5 mg/dL (TBL > 1.5 mg/dL is allowed if conjugated bilirubin is < 1.5 × ULN) (c) INR > 1.3 (d) ALP > 1.5 × ULN (unless the ALP elevation is from a non-hepatic origin as determined by a bone-specific ALP). 27. A difference in baseline serum ALT of > 50% based on 2 repeat measurements whilst establishing baseline ALT levels (a third sample could be obtained, refer to Section 8.2.5.1). 28. Any abnormal vital signs after 10 minutes supine rest, as defined in the list below, at the screening visit and/or Day –1. Out-of-range tests may be repeated once for each visit at the discretion of the investigator; participants with BP above the values defined in the list below may be rescreened after treatment has been established for hypertension. (a) Systolic BP < 95 mmHg or > 160 mmHg (b) Diastolic BP < 50 mmHg or > 90 mmHg BP medication should be optimised according to national guidelines and per investigator judgement. 29. Any clinically significant abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator at the screening visit and/or on Day −1. Out-of-range test may be repeated once at the discretion of the investigator. (a)Prolonged QT interval corrected for HR using Fridericia’s formula (QTcF) > 70 ms. (b)Family history of long QT syndrome. (c) PR (PQ) interval prolongation (> 220 ms), intermittent second- or third-degree AV block (regardless of Wenckebach block), or AV dissociation. (d) Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay with ECG interval measured from the onset of the QRS complex to the J point (QRS) ≥ 120 ms or if there is evidence of eg, ventricular hypertrophy or pre-excitation. 30. Known or suspected history of drug abuse (up to 2 years prior to the screening visit), as judged by the investigator; see SoA in Section 1.3 for details. 31. Positive screen for drugs of abuse at the screening visit; see SoA in Section 1.3 for details. 32. History or suspected excessive alcohol consumption defined as an average weekly intake of > 21 drinks/week for males or > 14 drinks/week for females. One drink is equivalent to 14 g alcohol. The participant should not have alcohol dependence (assessed by Alcohol Use Disorders Identification Test questionnaire, see Appendix K). 33. History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD2693. 34. Plasma donation within 1 month of the screening visit or any blood donation/blood loss > 500 mL during the 3 months prior to the screening visit. 35. Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship or committed to an institution by governmental or juridical order. 36. Involvement of any AstraZeneca study site employee or their close relatives. 37. Judgement 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. 38. Participants who cannot communicate reliably with the investigator or designee. 39. For women only.
• currently pregnant (confirmed with positive pregnancy test) or breastfeeding.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To assess the effect of AZD2693 versus placebo on histological resolution of NASH in participants with non-cirrhotic NASH with fibrosis (and homozygous for the PNPLA3 rs738409 148M risk allele)	Proportion of participants achieving NASH resolution a without worsening of fibrosis b based on histology after Week 52

Secondary Outcome Measures

Name	Time	Method
To assess the effects of AZD2693 versus placebo on histological fibrosis improvement in participants homozygous for the PNPLA3 rs738409 148M risk allele.
To assess the effect of AZD2693 versus placebo on ≥ 2-point improvement in NAS in participants homozygous for the PNPLA3 rs738409 148M risk allele	Proportion of participants with ≥ 2-point improvement from baseline in NAS based on biopsy after Week 52
To assess the effect of AZD2693 versus placebo on improvement in fibrosis by at least one stage in participants homozygous for the PNPLA3 rs738409 148M risk allele	Proportion of participants with improvement in fibrosis by at least one stage based on biopsy after Week 52
Safety- To assess safety & tolerability of AZD2693 compared with placebo in participants with noncirrhotic NASH with fibrosis who are carriers d of PNPLA3 rs738409 148M risk allele

Trial Locations

Locations (13)

AIIMS New Delhi; 🇮🇳 Delhi, DELHI, India

Fortis Hospital, Mohali; 🇮🇳 Chandigarh, CHANDIGARH, India

Gujarat Hospital -Gastro and Vascular Centre; 🇮🇳 Surat, GUJARAT, India

IPGME AND R RESEARCH, KOLKATA; 🇮🇳 Kolkata, WEST BENGAL, India

King George’s Medical University; 🇮🇳 Lucknow, UTTAR PRADESH, India

KLES Dr Prabhakar Kore Hospital and Medical Research Centre; 🇮🇳 Belgaum, KARNATAKA, India

Kumudini Devi Diabetes Research Center, Ramdev Rao Hospital; 🇮🇳 Hyderabad, TELANGANA, India

Medanta-The Medicity; 🇮🇳 Gurgaon, HARYANA, India

Midas Multispeciality Hospital Pvt.Ltd.; 🇮🇳 Nagpur, MAHARASHTRA, India

Post Graduate Institute of Medical Education and Research (PGIMER) Nehru Hospital Extension Block; 🇮🇳 Chandigarh, CHANDIGARH, India

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AIIMS New Delhi

🇮🇳Delhi, DELHI, India

Dr Shalimar

Principal investigator

9868397211

drshalimar@yahoo.com