A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients

• ClinicalTrials.gov Identifier: NCT04483947
• Recruitment Status: Recruiting
• First Posted: July 23, 2020
• Last Update Posted: May 11, 2023
• Sponsor: AstraZeneca
• Collaborator: Parexel
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

This study is intended to investigate the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD2693, following subcutaneous (SC) administration of multiple ascending doses in participants with Non-alcoholic Steatohepatitis (NASH) with fibrosis Stage 0 to 3 and who are carriers of the patatin-like phospholipase domain-containing 3 (PNPLA3) 148M risk alleles.

Condition or disease	Intervention/treatment	Phase
Non-alcoholic Steatohepatitis (NASH)	Drug: AZD2693; Other: Placebo	Phase 1

Detailed Description:

This study is a double blind, randomised, placebo-controlled, multi-centre study in participants with NASH and fibrosis stage between F0 (no fibrosis) and F3 (bridging fibrosis), and who are carriers of the PNPLA3 148M risk alleles.

The study will comprise of:

• An optional Pre-Screening Visit may be completed to determine PNPLA3 genotype and collect minimal baseline data and participants who are carriers of the PNPLA3 148M risk allele(s) will continue the study and enter the Screening Period.
• A Screening Period with a maximum of 60 days.
• For participants in all Cohorts, the dosing period will be 8 weeks during which participants will be resident of the study site for Dose 1 and Dose 3. Dose 1 will have participants reside at the study site from the day prior to study intervention administration (Day -1) until at least 2 days after study intervention administration with discharge on Day 3. Dose 2 will be administered at the study site on Day 29 with no overnight stay. Dose 3 will have participants reside at the study site from the day prior to study intervention administration (Day 56) until at least 2 days after study intervention administration with discharge on Day 59.
• Each participant will be followed for approximately 15 weeks post last dose.

The study will be performed at up to 30 study sites in the United States (US) and up to 5 study sites in Mexico. Approximately 80 participants comprising of male and female participants of non-childbearing potential may be enrolled into the first 4 cohorts of this study in order to achieve a target of 56 to 64 evaluable participants.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: The study will be blinded for all study site personal including the principal investigator during the clinical conduct of a given cohort. Investigators will remain blinded to each participant's assigned study intervention throughout the course of the study.
• Primary Purpose: Treatment
• Official Title: A Phase 1, Double Blind, Randomised, Placebo-Controlled, Multi-centre, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD2693 in Patients With Non-alcoholic Steatohepatitis (NASH) With Fibrosis Stage 0-3 and Carriers of the PNPLA3 148M Risk Alleles
• Actual Study Start Date: November 6, 2020
• Estimated Primary Completion Date: November 1, 2023
• Estimated Study Completion Date: November 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; 15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo	Drug: AZD2693; Subcutaneous administration of AZD2693 multiple ascending doses in participants with NASH and who are carriers of the PNPLA3 148M risk allele(s).; Other: Placebo; Participants randomised to placebo will receive the corresponding dose volume of solution as participants receiving AZD2693 within the same cohort
Experimental: Cohort 2; 15 participants will receive AZD2693 dose 2 and 5 participants will receive placebo	Drug: AZD2693; Subcutaneous administration of AZD2693 multiple ascending doses in participants with NASH and who are carriers of the PNPLA3 148M risk allele(s).; Other: Placebo; Participants randomised to placebo will receive the corresponding dose volume of solution as participants receiving AZD2693 within the same cohort
Experimental: Cohort 3; 15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo	Drug: AZD2693; Subcutaneous administration of AZD2693 multiple ascending doses in participants with NASH and who are carriers of the PNPLA3 148M risk allele(s).; Other: Placebo; Participants randomised to placebo will receive the corresponding dose volume of solution as participants receiving AZD2693 within the same cohort
Experimental: Cohort 4; 15 participants will receive AZD2693 dose 3 and 5 participants will receive placebo	Drug: AZD2693; Subcutaneous administration of AZD2693 multiple ascending doses in participants with NASH and who are carriers of the PNPLA3 148M risk allele(s).; Other: Placebo; Participants randomised to placebo will receive the corresponding dose volume of solution as participants receiving AZD2693 within the same cohort

Outcome Measures

Primary Outcome Measures :

1. Number of participants with adverse events [ Time Frame: Up to 32 weeks (From Screening to Final Visit) ]

Secondary Outcome Measures :

1. Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC) [ Time Frame: Baseline (Day 1), Week 8, Week 12 ]
2. Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC) [ Time Frame: Baseline (Day 1), Week 8, Week 12 ]
3. Absolute change from baseline in Alanine Aminotransferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
4. Percent change from baseline in Alanine Aminotransferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
5. Absolute change from baseline in Aspartate Aminotransferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
6. Percent change from baseline in Aspartate Aminotransferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
7. Absolute change from baseline in Gamma Glutamyl Transferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
8. Percent change from baseline in Gamma Glutamyl Transferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
9. Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
10. Percent change from baseline in ELF score [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
11. Absolute change from baseline in plasma pharmacodynamic biomarker [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
12. Percent change from baseline in plasma pharmacodynamic biomarker [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
13. Absolute change from baseline in disease-specific biomarkers [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
14. Percentage change from baseline in disease-specific biomarkers [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
15. Absolute change from baseline β-Hydroxybutyrate and lipid profile [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
16. Percent change from baseline β-Hydroxybutyrate and lipid profile [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
17. Maximum observed plasma drug concentration (Cmax) [ Time Frame: Day 1 to Day 162 ]
18. Time to reach maximum observed plasma concentration (tmax) [ Time Frame: Day 1 to Day 162 ]
19. Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz) [ Time Frame: Day 1 to Day 162 ]
20. Apparent terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic concentration-time curve, estimated as (ln2)/λz (t½λz) [ Time Frame: Day 1 to Day 162 ]
21. Area under the plasma concentration-time curve from time zero to 48 hours after dosing (AUC(0-48h)) [ Time Frame: Day 1 to Day 162 ]
22. Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast) [ Time Frame: Day 1 to Day 162 ]
23. Area under the concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC) [ Time Frame: Day 1 to Day 162 ]
24. Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F) [ Time Frame: Day 1 to Day 162 ]
25. Mean residence time (MRT) [ Time Frame: Day 1 to Day 162 ]
26. Time delay between drug administration and the first observed concentration in plasma (tlag) [ Time Frame: Day 1 to Day 162 ]
27. Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz (Vz/F) [ Time Frame: Day 1 to Day 162 ]
28. Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D) [ Time Frame: Day 1 to Day 162 ]
29. Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D) [ Time Frame: Day 1 to Day 162 ]
30. Observed maximum plasma concentration divided by the dose administered (Cmax/D) [ Time Frame: Day 1 to Day 162 ]
31. Time of the last quantifiable concentration (tlast) [ Time Frame: Day 1 to Day 162 ]
32. Maximum observed plasma drug concentration at steady state (Cssmax) [ Time Frame: Day 1 to Day 162 ]
33. Minimum observed drug concentration at steady state (Cssmin) [ Time Frame: Day 1 to Day 162 ]
34. Time to reach maximum observed plasma concentration at steady state (tssmax) [ Time Frame: Day 1 to Day 162 ]
35. Area under the concentration-time curve in the dose interval (AUCss) [ Time Frame: Day 1 to Day 162 ]
36. Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F) [ Time Frame: Day 1 to Day 162 ]
37. Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUCss/D) [ Time Frame: Day 1 to Day 162 ]
38. Observed maximum plasma concentration divided by the dose administered (Cssmax/D) [ Time Frame: Day 1 to Day 162 ]
39. Accumulation ratio based on Cmax (RacCmax) [ Time Frame: Day 1 to Day 162 ]
40. Accumulation ratio based on AUC (RacAUC) [ Time Frame: Day 1 to Day 162 ]
41. Temporal change parameter in systemic exposure (TCP) [ Time Frame: Day 1 to Day 162 ]
42. Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2)) [ Time Frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose ]
43. Cumulative amount of analyte excreted from time zero through the last sampling interval (Ae(0-last)) [ Time Frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose ]
44. Fraction of dose excreted unchanged into the urine from time t1 to t2 (fe(t1-t2)) [ Time Frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose ]
45. Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point (fe(0-last)) [ Time Frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose ]
46. Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC (CLR) [ Time Frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose ]
47. Change from placebo to Week 10 in PNPLA3 messenger ribonucleic acid (mRNA) and protein expression (Cohort 4 only) [ Time Frame: Week 10 ]
48. Change from baseline to Week 10 in PNPLA3 mRNA and protein expression (Cohort 4 only) [ Time Frame: Baseline, Week 10 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

For Cohorts 1 to 3:

• An MRI-PDFF ≥7% and one of the following:

  • Previous liver biopsy: Acceptable if taken in the previous 3 years for fibrosis stages F0 to F2, or within the previous 1 year for stage F3; or
  • Previous imaging results taken in the previous 2 years: An MRE between 2.55 kPa and 3.63 kPa, or a vibration-controlled transient elastography (VCTE) between 7.1 kPa and 11.9 kPa;
• Participants who are homozygous for rs738409 (PNPLA3 148M). Cohort 2 will enroll participants who are heterozygous for PNPLA3 148M.

For Cohort 4:

• An MRI-PDFF ≥ 7% and participant's consent for a liver biopsy.

• Participants with suspected or confirmed Non-alcoholic fatty liver disease (NAFLD) or NASH are eligible for the Screening liver biopsy if they meet main protocol inclusion/exclusion criteria AND have any of the following:

Alanine aminotransferase > Upper Limit of Normal (ULN) but < 3 × ULN, OR Imaging demonstrating hepatic steatosis including attenuation parameter (CAP) > 290dB/m, OR A Magnetic resonance elastography (MRE) between 2.55 kPa and 3.63 kPa, or a vibration-controlled transient elastography (VCTE) between 7.1 kPa and 11.9 kPa.

• Histologic evidence of NAFLD or NASH with a NASH Activity Score (NAS) ≥ 3 (independent of subcategory scoring) following Screening liver biopsy.
• Participants who are homozygous for rs738409 (PNPLA3 148M).

Exclusion Criteria:

• History of liver transplant, or current placement on a liver transplant list (this may be checked at the optional Pre-Screening Visit).
• History or presence of hepatic disease (with the exception of hepatic steatosis, NASH) or evidence of other known forms of known chronic liver disease such as alcoholic liver disease, hepatitis B, primary biliary cirrhosis, primary sclerotic cirrhosis, autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (this may be checked at the optional Pre-Screening Visit).
• Histological or imaging (MRE or VCTE) evidence of cirrhosis.

• Participants with history or pre-existing renal disease, as defined below:

  - estimated glomerular filtration rate < 60 mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula)

• Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gums or nose bleeds).
• History of major bleed or high-risk of bleeding diathesis.

Contacts and Locations

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

Locations

United States, Arizona

Research Site; Withdrawn

Chandler, Arizona, United States, 85224

Research Site; Withdrawn

Scottsdale, Arizona, United States, 85258

United States, California

Research Site; Withdrawn

Anaheim, California, United States, 92801

Research Site; Recruiting

Chula Vista, California, United States, 91911

Research Site; Withdrawn

Coronado, California, United States, 92118

Research Site; Completed

La Mesa, California, United States, 91942

Research Site; Recruiting

Montclair, California, United States, 91763

Research Site; Recruiting

San Diego, California, United States, 92103

United States, District of Columbia

Research Site; Withdrawn

Washington, District of Columbia, United States, 20007

United States, Florida

Research Site; Recruiting

Doral, Florida, United States, 33166

Research Site; Completed

Hialeah, Florida, United States, 33014

Research Site; Recruiting

Hialeah, Florida, United States, 33016

Research Site; Recruiting

Miami Lakes, Florida, United States, 33014

United States, Indiana

Research Site; Recruiting

Indianapolis, Indiana, United States, 46202

United States, Massachusetts

Research Site; Withdrawn

Boston, Massachusetts, United States, 02118

United States, New York

Research Site; Withdrawn

Manhasset, New York, United States, 11030

United States, North Carolina

Research Site; Withdrawn

Durham, North Carolina, United States, 27710

Research Site; Recruiting

Morehead City, North Carolina, United States, 28557

United States, Ohio

Research Site; Completed

Columbus, Ohio, United States, 43213

United States, Pennsylvania

Research Site; Recruiting

Hershey, Pennsylvania, United States, 17033

United States, Texas

Research Site; Completed

Arlington, Texas, United States, 76012

Research Site; Recruiting

Dallas, Texas, United States, 75203

Research Site; Recruiting

San Antonio, Texas, United States, 78215

Research Site; Completed

San Antonio, Texas, United States, 78229

Research Site; Recruiting

San Antonio, Texas, United States, 78229

Mexico

Research Site; Withdrawn

Ciudad de México, Mexico, 06700

Research Site; Not yet recruiting

Ciudad de México, Mexico, 06700

Research Site; Withdrawn

D.F, Mexico, 14000

Research Site; Not yet recruiting

Mexico D.F., Mexico, 014080

Sponsors and Collaborators

AstraZeneca

Parexel

Investigators

• Principal Investigator: Rohit Loomba, MD, MHSc; Director, NAFLD Research Center Director of Hepatology, Professor of Medicine Vice Chief, Division of Gastroenterology University of California at San Diego ACTRI Building, 1W202 9500 Gilman Drive La Jolla, CA, 92037-0887

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04483947
• Other Study ID Numbers: D7830C00002
• First Posted: July 23, 2020
• Last Update Posted: May 11, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

Keywords provided by AstraZeneca:

Pharmacokinetics; Pharmacodynamics; Obese; PNPLA3 148M Risk Alleles; Multiple Ascending Dose

Additional relevant MeSH terms:

Fatty Liver; Non-alcoholic Fatty Liver Disease; Liver Diseases; Digestive System Diseases