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Non-alcoholic Steatohepatitis (NASH)Phase 1NCT04483947

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

A Phase 1 study testing AZD2693 in people with Non-alcoholic Steatohepatitis (NASH), run by AstraZeneca at 16 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Non-alcoholic Steatohepatitis (NASH)
What is being tested?
AZD2693
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
74 participants
Where
16 sitesUnited States
Study dates
6 Nov 2020to 18 Dec 2023
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
Show all 11Show fewer
  • 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).

Who cannot join

  • 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.

Trial locations and contacts

16 sites in 1 country.

16 sites in 1 country

United States16 sites

  • Research Site

    Arlington, Texas, 76012

  • Research Site

    Chula Vista, California, 91911

  • Research Site

    Columbus, Ohio, 43213

  • Research Site

    Dallas, Texas, 75203

  • Research Site

    Doral, Florida, 33166

  • Research Site

    Hershey, Pennsylvania, 17033

  • Research Site

    Hialeah, Florida, 33014

  • Research Site

    Hialeah, Florida, 33016

  • Research Site

    Indianapolis, Indiana, 46202

  • Research Site

    La Mesa, California, 91942

  • Research Site

    Miami Lakes, Florida, 33014

  • Research Site

    Montclair, California, 91763

  • Research Site

    Morehead City, North Carolina, 28557

  • Research Site

    San Antonio, Texas, 78215

  • Research Site

    San Antonio, Texas, 78229

  • Research Site

    San Diego, California, 92103

Other trials in United States

About this study

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

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.

Read the 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.

Being tested
AZD2693, Placebo
Keywords
Pharmacokinetics, Pharmacodynamics, Obese, PNPLA3 148M Risk Alleles, Multiple Ascending Dose
Medical subject headings
Non-alcoholic Fatty Liver Disease, Obesity

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AZD2693Drug

    Subcutaneous administration of AZD2693 multiple ascending doses in participants with NASH and who are carriers of the PNPLA3 148M risk allele(s).

  • PlaceboOther

    Participants randomised to placebo will receive the corresponding dose volume of solution as participants receiving AZD2693 within the same cohort

Study groups in NCT04483947
Study groupRoleWhat they receive
Cohort 1Experimental15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo
Receives: Drug: AZD2693; Other: Placebo
Cohort 2Experimental15 participants will receive AZD2693 dose 2 and 5 participants will receive placebo
Receives: Drug: AZD2693; Other: Placebo
Cohort 3Experimental15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo
Receives: Drug: AZD2693; Other: Placebo
Cohort 4Experimental15 participants will receive AZD2693 dose 3 and 5 participants will receive placebo
Receives: Drug: AZD2693; Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of participants with adverse events

    Measured: Up to 32 weeks (From Screening to Final Visit)

Secondary outcomes (48)

  1. Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC)

    Measured: Baseline (Day 1), Week 8, Week 12

  2. Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC)

    Measured: Baseline (Day 1), Week 8, Week 12

  3. Absolute change from baseline in Alanine Aminotransferase

    Measured: Up to 32 weeks (From Pre-Screening to Final Visit)

  4. Percent change from baseline in Alanine Aminotransferase

    Measured: Up to 32 weeks (From Pre-Screening to Final Visit)

  5. Absolute change from baseline in Aspartate Aminotransferase

    Measured: Up to 32 weeks (From Pre-Screening to Final Visit)

  6. Percent change from baseline in Aspartate Aminotransferase

    Measured: Up to 32 weeks (From Pre-Screening to Final Visit)

  7. Absolute change from baseline in Gamma Glutamyl Transferase

    Measured: Up to 32 weeks (From Pre-Screening to Final Visit)

  8. Percent change from baseline in Gamma Glutamyl Transferase

    Measured: Up to 32 weeks (From Pre-Screening to Final Visit)

  9. Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score

    Measured: Up to 32 weeks (From Pre-Screening to Final Visit)

  10. Percent change from baseline in ELF score

    Measured: Up to 32 weeks (From Pre-Screening to Final Visit)

  11. Absolute change from baseline in plasma pharmacodynamic biomarker

    Measured: Days 1, 8, 29, 36, 50, 64, and 78

  12. Percent change from baseline in plasma pharmacodynamic biomarker

    Measured: Days 1, 8, 29, 36, 50, 64, and 78

  13. Absolute change from baseline in disease-specific biomarkers

    Measured: Days 1, 8, 29, 36, 50, 64, and 78

  14. Percentage change from baseline in disease-specific biomarkers

    Measured: Days 1, 8, 29, 36, 50, 64, and 78

  15. Absolute change from baseline β-Hydroxybutyrate and lipid profile

    Measured: Days 1, 8, 29, 36, 50, 64, and 78

  16. Percent change from baseline β-Hydroxybutyrate and lipid profile

    Measured: Days 1, 8, 29, 36, 50, 64, and 78

  17. Maximum observed plasma drug concentration (Cmax)

    Measured: Day 1 to Day 162

  18. Time to reach maximum observed plasma concentration (tmax)

    Measured: 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)

    Measured: 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)

    Measured: Day 1 to Day 162

  21. Area under the plasma concentration-time curve from time zero to 48 hours after dosing (AUC(0-48h))

    Measured: Day 1 to Day 162

  22. Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)

    Measured: 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)

    Measured: Day 1 to Day 162

  24. Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F)

    Measured: Day 1 to Day 162

  25. Mean residence time (MRT)

    Measured: Day 1 to Day 162

  26. Time delay between drug administration and the first observed concentration in plasma (tlag)

    Measured: 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)

    Measured: 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)

    Measured: 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)

    Measured: Day 1 to Day 162

  30. Observed maximum plasma concentration divided by the dose administered (Cmax/D)

    Measured: Day 1 to Day 162

  31. Time of the last quantifiable concentration (tlast)

    Measured: Day 1 to Day 162

  32. Maximum observed plasma drug concentration at steady state (Cssmax)

    Measured: Day 1 to Day 162

  33. Minimum observed drug concentration at steady state (Cssmin)

    Measured: Day 1 to Day 162

  34. Time to reach maximum observed plasma concentration at steady state (tssmax)

    Measured: Day 1 to Day 162

  35. Area under the concentration-time curve in the dose interval (AUCss)

    Measured: Day 1 to Day 162

  36. Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F)

    Measured: 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)

    Measured: Day 1 to Day 162

  38. Observed maximum plasma concentration divided by the dose administered (Cssmax/D)

    Measured: Day 1 to Day 162

  39. Accumulation ratio based on Cmax (RacCmax)

    Measured: Day 1 to Day 162

  40. Accumulation ratio based on AUC (RacAUC)

    Measured: Day 1 to Day 162

  41. Temporal change parameter in systemic exposure (TCP)

    Measured: Day 1 to Day 162

  42. Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2))

    Measured: 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))

    Measured: 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))

    Measured: 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))

    Measured: 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)

    Measured: 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)

    Measured: Week 10

  48. Change from baseline to Week 10 in PNPLA3 mRNA and protein expression (Cohort 4 only)

    Measured: Baseline, Week 10

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Jul 2020
  2. Study start6 Nov 2020
  3. Primary completion18 Dec 2023
  4. Study completion18 Dec 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Sequential
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
74 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04483947
Sponsor's protocol ID
D7830C00002
Status last verified
Jan 2024
First submitted
6 Jul 2020
Last updated
17 Jan 2024
Results posted
No
FDA-regulated drug
Yes
FDA-regulated device
Yes
Individual data sharing
Yes: 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.

Publications

  • Armisen J, Rauschecker M, Sarv J, Liljeblad M, Wernevik L, Niazi M, Knochel J, Eklund O, Sandell T, Sherwood J, Bergenholm L, Hallen S, Wang S, Kamble P, Bhat M, Maxvall I, Wang Y, Lee RG, Bhanot S, Guo S, Romeo S, Lawitz E, Fjellstrom O, Linden D, Blau JE, Loomba R. AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials. J Hepatol. 2025 Jul;83(1):31-42. doi: 10.1016/j.jhep.2024.12.046. Epub 2025 Jan 9.

    PubMed 39798707

  • Lai M, Lai JC, Allegretti AS, Patidar KR, Cullaro G. Investigating the Association between Steatotic Liver Disease and CKD in a Nationally Representative Sample. Kidney360. 2024 Dec 1;5(12):1844-1852. doi: 10.34067/KID.0000000569. Epub 2024 Sep 5.

    PubMed 39235870

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing AZD2693 in people with Non-alcoholic Steatohepatitis (NASH), run by AstraZeneca at 16 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 16 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of participants with adverse events (time frame: Up to 32 weeks (From Screening to Final Visit)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04483947, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jan 2024.

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