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: July 28, 2022
• Sponsor: AstraZeneca
• Collaborator: Parexel
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: July 6, 2020
• First Posted Date: July 23, 2020
• Last Update Posted Date: July 28, 2022
• Actual Study Start Date: November 6, 2020
• Estimated Primary Completion Date: June 28, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 27, 2021)

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

Safety and tolerability will be evaluated in terms of number of participants with adverse events and/or abnormal values of vital signs and/or clinical laboratory and/or electrocardiogram and/or renal assessments and/or blood assessments.

Original Primary Outcome Measures (submitted: July 21, 2020)

Number of participants with adverse events [ Time Frame: Up to 36 weeks (From Screening to Final Visit) ]

Safety and tolerability will be evaluated in terms of number of subjects with adverse events and/or abnormal values of vital signs and/or clinical laboratory and/or electrocardiogram and/or renal assessments and/or blood assessments.

Current Secondary Outcome Measures (submitted: May 27, 2021)

• Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC) [ Time Frame: Baseline (Day 1), Week 8, Week 12 ]
  The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed.
• Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC) [ Time Frame: Baseline (Day 1), Week 8, Week 12 ]
  The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed.
• Absolute change from baseline in Alanine Aminotransferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.
• Percent change from baseline in Alanine Aminotransferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.
• Absolute change from baseline in Aspartate Aminotransferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.
• Percent change from baseline in Aspartate Aminotransferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.
• Absolute change from baseline in Gamma Glutamyl Transferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.
• Percent change from baseline in Gamma Glutamyl Transferase [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.
• Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
  The effect of AZD2693 on ELF score will be assessed.
• Percent change from baseline in ELF score [ Time Frame: Up to 32 weeks (From Pre-Screening to Final Visit) ]
  The effect of AZD2693 on ELF score will be assessed.
• Absolute change from baseline in plasma cholesteryl ester 16:1/16:0 ratio. [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
  The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.
• Percent change from baseline in plasma cholesteryl ester 16:1/16:0 ratio. [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
  The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.
• Absolute change from baseline in disease-specific biomarkers [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
  The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.
• Percentage change from baseline in disease-specific biomarkers [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
  The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.
• Absolute change from baseline β-Hydroxybutyrate and lipid profile [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
  To characterise effects of AZD2693 on lipid handling compared to placebo.
• Percent change from baseline β-Hydroxybutyrate and lipid profile [ Time Frame: Days 1, 8, 29, 36, 50, 64, and 78 ]
  To characterise effects of AZD2693 on lipid handling compared to placebo
• Maximum observed plasma drug concentration (Cmax) [ Time Frame: Day 1 to Day 162 ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations
• Time to reach maximum observed plasma concentration (tmax) [ Time Frame: Day 1 to Day 162 ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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 ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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 ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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 ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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 ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations
• 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 ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F) [ Time Frame: Day 1 to Day 162 ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Mean residence time (MRT) [ Time Frame: Day 1 to Day 162 ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations
• Time delay between drug administration and the first observed concentration in plasma (tlag) [ Time Frame: Day 1 to Day 162 ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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 ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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 ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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 ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Observed maximum plasma concentration divided by the dose administered (Cmax/D) [ Time Frame: Day 1 to Day 162 ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Time of the last quantifiable concentration (tlast) [ Time Frame: Day 1 to Day 162 ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Maximum observed plasma drug concentration at steady state (Cssmax) [ Time Frame: Day 1 to Day 162 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Minimum observed drug concentration at steady state (Cssmin) [ Time Frame: Day 1 to Day 162 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Time to reach maximum observed plasma concentration at steady state (tssmax) [ Time Frame: Day 1 to Day 162 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Area under the concentration-time curve in the dose interval (AUCss) [ Time Frame: Day 1 to Day 162 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F) [ Time Frame: Day 1 to Day 162 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Observed maximum plasma concentration divided by the dose administered (Cssmax/D) [ Time Frame: Day 1 to Day 162 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Accumulation ratio based on Cmax (RacCmax) [ Time Frame: Day 1 to Day 162 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Accumulation ratio based on AUC (RacAUC) [ Time Frame: Day 1 to Day 162 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Temporal change parameter in systemic exposure (TCP) [ Time Frame: Day 1 to Day 162 ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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 ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
• 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 ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
• 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 ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
• 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 ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
• 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 ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Original Secondary Outcome Measures (submitted: July 21, 2020)

• Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC) [ Time Frame: Baseline (Day 1), Week 8, Week 12 ]
  The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed. Samples will be taken under fasting conditions (10 h) in the morning at the same time (±1.5-2 h) during the day before lunch.
• Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC) [ Time Frame: Baseline (Day 1), Week 8, Week 12 ]
  The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed. Samples will be taken under fasting conditions (10 h) in the morning at the same time (±1.5-2 h) during the day before lunch.
• Absolute change from baseline in Alanine Aminotransferase [ Time Frame: Up to 36 weeks (From Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
• Percent change from baseline in Alanine Aminotransferase [ Time Frame: Up to 36 weeks (From Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
• Absolute change from baseline in Aspartate Aminotransferase [ Time Frame: Up to 36 weeks (From Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
• Percent change from baseline in Aspartate Aminotransferase [ Time Frame: Up to 36 weeks (From Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
• Absolute change from baseline in Gamma Glutamyl Transferase [ Time Frame: Up to 36 weeks (From Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
• Percent change from baseline in Gamma Glutamyl Transferase [ Time Frame: Up to 36 weeks (From Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.
• Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score [ Time Frame: Up to 36 weeks (From Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed. ELF score: <7.7: no or mild fibrosis, ≥7.7 to <9.8: moderate fibrosis, ≥9.8 to <11.3: severe fibrosis, and ≥11.3: cirrhosis. A negative change from baseline indicates decreased fibrosis.
• Percent change from baseline in ELF score [ Time Frame: Up to 36 weeks (From Screening to Final Visit) ]
  The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed. ELF score: <7.7: no or mild fibrosis, ≥7.7 to <9.8: moderate fibrosis, ≥9.8 to <11.3: severe fibrosis, and ≥11.3: cirrhosis. A negative change from baseline indicates decreased fibrosis.
• Absolute change from baseline in plasma cholesteryl ester 16:1/16:0 ratio. [ Time Frame: Days 1, 29, 50, and 78 ]
  The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.
• Percent change from baseline in plasma cholesteryl ester 16:1/16:0 ratio. [ Time Frame: Days 1, 29, 50, and 78 ]
  The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.
• Absolute change from baseline in disease-specific biomarkers [ Time Frame: Days 1, 29, 50, and 78 ]
  The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.
• Percentage change from baseline in disease-specific biomarkers [ Time Frame: Days 1, 29, 50, and 78 ]
  The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.
• Absolute change from baseline β-Hydroxybutyrate and lipid profile [ Time Frame: Days 1, 29, 50, and 78 ]
  To characterise effects of AZD2693 on lipid handling compared to placebo.
• Percent change from baseline β-Hydroxybutyrate and lipid profile [ Time Frame: Days 1, 29, 50, and 78 ]
  To characterise effects of AZD2693 on lipid handling compared to placebo
• Maximum observed plasma drug concentration (Cmax) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations
• Time to reach maximum observed plasma concentration (tmax) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Area under the plasma concentration-time curve from time zero to 48 hours after dosing (AUC(0-48h)) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations
• 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: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Mean residence time (MRT) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations
• Time delay between drug administration and the first observed concentration in plasma (tlag) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• 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: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Observed maximum plasma concentration divided by the dose administered (Cmax/D) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Time of the last quantifiable concentration (tlast) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Maximum observed plasma drug concentration at steady state (Cssmax) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Minimum observed drug concentration at steady state (Cssmin) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Time to reach maximum observed plasma concentration at steady state (tssmax) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Area under the concentration-time curve in the dose interval (AUCss) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUCss/D) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Observed maximum plasma concentration divided by the dose administered (Cssmax/D) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Accumulation ratio based on Cmax (RacCmax) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Accumulation ratio based on AUC (RacAUC) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Temporal change parameter in systemic exposure (TCP) [ Time Frame: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106. ]
  Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations
• Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2)) [ Time Frame: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose. ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
• Cumulative amount of analyte excreted from time zero through the last sampling interval (Ae(0-last)) [ Time Frame: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose. ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
• Fraction of dose excreted unchanged into the urine from time t1 to t2 (fe(t1-t2)) [ Time Frame: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose. ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
• Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point (fe(0-last)) [ Time Frame: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose. ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data
• 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: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose. ]
  Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients
• 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
• 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.

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. The Pre-Screening Visit is optional and sites may proceed with full screening if this is preferred.
• A Screening Period with a maximum of 60 days.
• An 8-week dosing period 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. All study interventions and PD assessments will be administered after a 10 hour fast.
• Each participant will be followed for 15 weeks post last dose (approximately 5× t½; t½ is estimated to approximately 22 days); however, the length of follow-up may be shortened or extended if the actual t½ is considerably shorter or longer than predicted.

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 60 participants comprised of male participants and female participants of non-childbearing potential will be randomized into the first 3 cohorts of this study in order to achieve 48 evaluable participants.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

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

• Condition: Non-alcoholic Steatohepatitis (NASH)

Intervention

• 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

Study Arms

• Experimental: Cohort 1
  15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo
  Interventions:

  • Drug: AZD2693
  • Other: Placebo
• Experimental: Cohort 2
  15 participants will receive AZD2693 dose 2 and 5 participants will receive placebo
  Interventions:

  • Drug: AZD2693
  • Other: Placebo
• Experimental: Cohort 3
  15 participants will receive AZD2693 dose 3 and 5 participants will receive placebo
  Interventions:

  • Drug: AZD2693
  • Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 27, 2022): 67
• Original Estimated Enrollment (submitted: July 21, 2020): 60
• Estimated Study Completion Date: June 28, 2023
• Estimated Primary Completion Date: June 28, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 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; or
  • Participant's consent for a liver biopsy or MRE/VCTE at screening, if previous biopsies or MRE/VCTE imaging data are not available.
• Participants who are homozygous for rs738409 (PNPLA3 148M). One cohort will enroll participants who are heterozygous for PNPLA3 148M.
• Body mass index (BMI) within the range 25 to 45 kg/m˄2 (inclusive).
• Male, or female of non-childbearing potential.
• Participants should agree to follow protocol defined contraceptive procedures.
• Provision of signed, written, and dated informed consent for mandatory Genetic PNPLA3 I148M determination genetic/biomarker, for inclusion or exclusion in the clinical study (this may be checked at the optional Pre-Screening Visit).

• Mandatory PNPLA3 Genetic Biomarker and Companion Diagnostic Development Samples (this may be checked at the optional Pre-Screening Visit):

  • The participant will be excluded from the study if consent for the PNPLA I148M Genetic Biomarker Samples is not given.
  • The mandatory consent will include assessment of PNPLA3 I148M status as well as additional genotyping of gene variants associated with PNPLA3 expression and/or variants in genes other than PNPLA3 known or suspected to be associated with NASH.
  • Provision of 3 blood samples (3 x 4 mL in ethylene-diamine-tetra-acetic acid [EDTA] tubes).
  • Provision of 3 buccal swabs.
• Provision of signed and dated written optional genetic research information informed consent prior to collection of samples for optional genetic research for the Genomic Initiative.

Exclusion Criteria:

• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
• 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).
• If a participant has a positive result at the screening visit for hepatitis C antibody, the investigator will document that the participant has hepatitis C RNA below the limit of detection and has not received curative treatment in the last 3 years.
• Histological or imaging (MRE or VCTE) evidence of cirrhosis.
• Any positive result at the Screening Visit for serum hepatitis B surface antigen and human immunodeficiency virus.

• 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) or
  • urinary albumin-to-creatinine ratio > 10 mg/μmol (100 mg/g).
• Clinically significant cardiovascular event within the last 6 months prior to the Screening Visit.
• Participants with a positive SARS-CoV-2 infection test at Screening Visit.

• Participants with a significant Coronavirus disease 2019 (COVID-19) illness within 6 months of enrolment:

  • Participants with a 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 hospitalization and/or oxygen supplementation therapy.
• Suspicion of or known Gilbert's syndrome.
• Weight loss of more than 5% within the last 6 months prior to randomization. Plans to initiate a weight loss diet or to undergo bariatric surgery.
• 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.
• Changes to any concomitant medication (initiation, dose change, or cessation) that may impact the study readouts (as judged by the investigator) within 1 month prior to the Screening Visit. This criterion does not apply to medication prescribed for occasional use.
• Use of anabolic steroids and systemic treatment with glucocorticosteroids within 3 months prior to the Screening Visit.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Mexico, United States

Administrative Information

• NCT Number: NCT04483947
• Other Study ID Numbers: D7830C00002
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• 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

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

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: 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

• PRS Account: AstraZeneca
• Verification Date: July 2022