Metabolic DisordersPhase 1NCT04142424
A Study to Understand the Safety, Tolerability, and Activity of Drug in Body Over a Period of Time of AZD2693, in Subjects of Non-Childbearing Potential in Overweight But Otherwise Healthy Subjects, and Healthy Chinese and Japanese Subjects
A Phase 1 study testing AZD2693 in people with Metabolic Disorders and Non-alcoholic Steatohepatitis, run by AstraZeneca at 1 site in United States.
Trial summary
This Phase 1, first-in-human (FiH), single-ascending-dose (SAD) study, will assess the safety and tolerability and characterize the pharmacokinetics (PK) of AZD2693, following subcutaneous (SC) SAD administration of AZD2693 in male and female subjects of non-childbearing potential in overweight but otherwise healthy… Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Metabolic Disorders, Non-alcoholic Steatohepatitis
- 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
- 73 participants
- Where
- 1 siteUnited States
- Study dates
- 28 Oct 2019to 12 Nov 2021
- 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 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit, must not be lactating and must be of non-child-bearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria: A. Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone levels in the postmenopausal range B. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
- Have a body mass index between 25 and 32 kg/m^2 for healthy subjects, or between 18 and 32 kg/m^2 for healthy Japanese and Chinese subjects, and weigh at least 60 kg (or 50 kg for healthy Japanese and Chinese subjects)
- Willing to participate in mandatory retrospective genotyping analysis for PNPLA3 1148M and the provision of blood and buccal swab samples for this analysis
- Willing and able to comply with all required study procedures
- Applicable to Japanese and Chinese subjects only:
- A Japanese subject is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan
- A Chinese subject is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China
Who cannot join
- History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study
- History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs
- Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP
- Any clinically significant cardiovascular event within the last 6 months prior to the Screening Visit
- Any laboratory values with the following deviations at Screening or Day -1:
- Alanine aminotransferase > upper limit of normal (ULN)
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- Aspartate aminotransferase > ULN
- Creatinine > ULN
- White blood cell count < lower limit of normal (LLN)
- Hemoglobin < LLN
- Platelet count < LLN
- Activated partial thrombin time > ULN and prothrombin time > ULN
- Estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m^2 calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and applying the standard correction factor for African Americans to the CKD-EPI by multiplying the GFR estimate by 1.159; (eGFR < 60 mL/min/1.73m^2 for healthy Japanese and Chinese subjects) and confirmed
- Urinary albumin-to-creatinine ratio > 3 mg/μmol (30 mg/g)
- Any other clinically important abnormalities in clinical chemistry, hematology or urinalysis results, than those described under previous exclusion criterion above, as judged by the Investigator at Screening or Day -1
- Any positive result on Screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus
- Abnormal vital signs, after 10 minutes supine rest, defined as any of the following at Screening or Day -1:
- Systolic BP < 90 mmHg or > 140 mmHg
- Diastolic blood pressure (BP) < 50 mmHg or > 90 mmHg
- HR < 45 or > 90 bpm
- Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12-lead ECG as considered by the Investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy at Screening or Day -1:
- Prolonged QTcF > 450 ms
- Shortened QTcF < 340 ms
- Family history of long QT syndrome
- PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation)
- PR (PQ) interval prolongation intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation
- Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay with QRS > 110 ms Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of e.g. ventricular hypertrophy or pre-excitation
- Known or suspected history of drug abuse as judged by the Investigator
- Smokers with > 10 cigarettes/day and unable to comply with the nicotine restrictions during the study
- History of alcohol abuse or excessive intake of alcohol. Definition of excessive intake: an average weekly intake of >21 drinks/week for men or >14 drinks/week for women. One drink is equivalent to (14 g alcohol)
- Positive screen for drugs of abuse at Screening or admission to the Clinical Unit or positive screen for alcohol on admission to the Clinical Unit prior to the first administration of the IMP
- History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD2693
- Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate, Red Bull®-like drinks) as judged by the Investigator
- Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega-dose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life
- Plasma donation within one month of the Screening Visit or any blood donation/blood loss > 500 mL during the 3 months prior to the Screening Visit
- Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days of last follow-up to first administration of IMP or, if known, 5 half-lives from last dose to first administration of IMP, whichever is the longest
- 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)
- Involvement of any AstraZeneca or Clinical Unit employee or their close relatives
- Judgment by the Investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., 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
- Subjects who are vegans or have medical dietary restrictions, or who are not willing to comply with the dietary requirements in the study as judged by the Investigator
- Subjects who cannot communicate reliably with the Investigator
- Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order
- Previous bone marrow transplant
- Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genotyping sample collection
- Males who are unwilling to use an acceptable method of birth control
- Subjects with a significant Coronavirus disease (COVID-19) illness within 6 months of enrollment:
- a Subjects with diagnosis of COVID-19 pneumonia based on radiological assessment b Subjects with diagnosis of COVID-19 with significant findings from pulmonary imaging tests c Subjects with diagnosis of COVID-19 requiring hospitalization and/or oxygen supplementation therapy
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD2693 Following Single Ascending Dose Administration in Male and Female Subjects of Non-childbearing Potential in Overweight But Otherwise Healthy Subjects, and Healthy Chinese and Japanese Subjects
This Phase 1, first-in-human (FiH), single-ascending-dose (SAD) study, will assess the safety and tolerability and characterize the pharmacokinetics (PK) of AZD2693, following subcutaneous (SC) SAD administration of AZD2693 in male and female subjects of non-childbearing potential in overweight but otherwise healthy subjects, and healthy Chinese and Japanese subjects.
Read the detailed description
This is a single center study, and approximately 64 overweight/mildly obese but otherwise healthy male and female subjects, and up to 16 healthy Japanese subjects and 8 healthy Chinese (all of non-childbearing potential) will be enrolled into this study.
Study will consist of following planned cohorts:
Eligible healthy subjects will be divided in 6 cohorts, each consisting of 8 subjects, within each cohort, 6 subjects will receive AZD2693 at dose level 1 and 2 subjects will receive placebo. Dosing for each ascending dose cohort will proceed with 2 subjects in a sentinel cohort, such that 1 subject will be randomized to receive placebo and 1 subject will be randomized to receive AZD2693.
Eligible healthy Japanese and Chinese subjects will be divided as two cohorts of Japanese subjects, and one cohort of Chinese subjects. Each cohort will consist of 8 subjects. Within each cohort, 6 subjects will receive AZD2693 and 2 subjects will receive placebo.
Depending on emerging data, up to 2 additional cohorts may be added to test additional dose levels based on Sponsor's decision.
Full study will comprise of following periods:
- Screening period of maximum 28 days.
- A Dosing Session during which subjects will be resident at the Clinical Unit from the day before investigational medicinal product (IMP) administration (Day -1) until at least 3 days after IMP administration with discharge on Day 4.
- A Follow-Up Period of 16 weeks that will consist of 9 Follow-Up Visits, for which the subjects will return to the Clinical Unit at 1, 2, 4, 6, 8, 10, 12, 14, and 16 weeks post dose.
- Conditions
- Metabolic Disorders, Non-alcoholic Steatohepatitis
- Being tested
- AZD2693, Placebo
- Keywords
- Single-ascending-dose, First-in-human, Chinese, Japanese, Dyslipidemia, Type II diabetes mellitus, Non-alcoholic fatty liver disease
- Medical subject headings
- Metabolic Diseases, Non-alcoholic Fatty Liver Disease, Dyslipidemias, Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD2693Drug
Subjects will receive SC injection of AZD2693 as per the arms they are randomized.
PlaceboDrug
Subjects will receive SC injection of placebo matched to AZD2693, as per the arms they are randomized.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 healthy subjects: AZD2693 Dose 1 | Experimental | Subjects will receive a subcutaneous (SC) injection of single dose 1 of AZD2693 or placebo matched to AZD2693 on Day 1. Receives: Drug: AZD2693; Drug: Placebo |
| Cohort 2 healthy subjects: AZD2693 Dose 2 | Experimental | Subjects will receive a SC injection of single dose 2 of AZD2693 or placebo matched to AZD2693 on Day 1. Receives: Drug: AZD2693; Drug: Placebo |
| Cohort 3 healthy subjects: AZD2693 Dose 3 | Experimental | Subjects will receive a SC injection of single dose 3 of AZD2693 or placebo matched to AZD2693 on Day 1. Receives: Drug: AZD2693; Drug: Placebo |
| Cohort 4 healthy subjects: AZD2693 Dose 4 | Experimental | Subjects will receive a SC injection of single dose 4 of AZD2693 or placebo matched to AZD2693 on Day 1. Receives: Drug: AZD2693; Drug: Placebo |
| Cohort 5 healthy subjects: AZD2693 Dose 5 | Experimental | Subjects will receive a SC injection of single dose 5 of AZD2693 or placebo matched to AZD2693 on Day 1. Receives: Drug: AZD2693; Drug: Placebo |
| Cohort 6 healthy subjects: AZD2693 Dose 6 | Experimental | Subjects will receive a SC injection of single dose 6 of AZD2693 or placebo matched to AZD2693 on Day 1. Receives: Drug: AZD2693; Drug: Placebo |
| Cohort 7 healthy Japanese subjects: AZD2693 Dose 7 | Experimental | Subjects will receive a SC injection of single dose 7 of AZD2693 or placebo matched to AZD2693 on Day 1. Receives: Drug: AZD2693; Drug: Placebo |
| Cohort 8 healthy Japanese subjects: AZD2693 Dose 8 | Experimental | Subjects will receive a SC injection of single dose 8 of AZD2693 or placebo matched to AZD2693 on Day 1. Receives: Drug: AZD2693; Drug: Placebo |
| Cohort 9 healthy Chinese subjects: AZD2693 Dose 9 | Experimental | Subjects will receive a SC injection of single dose 9 of AZD2693 or placebo matched to AZD2693 on Day 1. Receives: Drug: AZD2693; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of subjects experiencing adverse events and serious adverse events
To investigate the safety and tolerability of SC administration of SAD of AZD2693
Measured: From baseline (Day 1) until Day 112 (Week 16, Final follow-up)
Secondary outcomes (20)
Area under the concentration-time curve from time zero extrapolated to infinity (AUC)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25 hours [h], 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-time curve from time zero to 48 hours after dosing [AUC(0-48h)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Maximum observed plasma drug concentration (Cmax) of AZD2693
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Observed maximum plasma concentration divided by the dose administered (Cmax/D)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Time to reach maximum observed concentration following drug administration (tmax)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Apparent terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic concentration-time curve, estimated as (ln2)/λz (t½λz)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693.
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing CL/F by λz (Vz/F)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Mean residence time (MRT)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Time delay between drug administration and the first observed concentration in plasma (tlag)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Time of the last quantifiable concentration (tlast)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point [fe(0-last)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Cumulative amount of analyte excreted into the urine from time zero through the last sampling interval [Ae(0-last)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
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]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Fraction of dose excreted unchanged into the urine from time t1 to t2 [fe(t1-t2)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Measured: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Oct 2019
- Study start28 Oct 2019
- Primary completion12 Nov 2021
- Study completion12 Nov 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metabolic DisordersStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Parallel groups
- Model description
- Subjects in this study will be categorized as follows: 1. Overweight/mildly obese, but otherwise healthy subjects: There will be 6 cohorts, with 8 subjects in each cohort. 2. Japanese and Chinese subjects: There will be 2 cohorts for Japanese subjects, and one cohort for Chinese subjects, with 8 subjects in each cohort.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 73 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Parexel
- Responsible party
- Sponsor
- Investigators
- David Han, MD, Principal investigator, Parexel Early Clinical Unit - Los Angeles
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04142424
- Sponsor's protocol ID
- D7830C00001
- Status last verified
- Nov 2021
- First submitted
- 22 Oct 2019
- Last updated
- 26 Nov 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- 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
Study at a glance
From the registry record, last updated by the sponsor on 26 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD2693 Following Single Ascending Dose Administration in Male and Female Subjects of Non-childbearing Potential in Overweight But Otherwise Healthy Subjects, and Healthy Chinese and Japanese Subjects
- ClinicalTrials.gov ID
- NCT04142424
- Acronym / sponsor ID
- D7830C00001
- Conditions
- Metabolic Disorders, Non-alcoholic Steatohepatitis
- Keywords
- Single-ascending-dose, First-in-human, Chinese, Japanese, Dyslipidemia, Type II diabetes mellitus, Non-alcoholic fatty liver disease
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 73 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Collaborators
- Parexel
- Study start
- 28 Oct 2019 (actual)
- Primary completion
- 12 Nov 2021 (actual)
- Study completion
- 12 Nov 2021 (actual)
- First posted
- 29 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This Phase 1, first-in-human (FiH), single-ascending-dose (SAD) study, will assess the safety and tolerability and characterize the pharmacokinetics (PK) of AZD2693, following subcutaneous (SC) SAD administration of AZD2693 in male and female subjects of non-childbearing potential in overweight but otherwise healthy subjects, and healthy Chinese and Japanese subjects.
Detailed description
This is a single center study, and approximately 64 overweight/mildly obese but otherwise healthy male and female subjects, and up to 16 healthy Japanese subjects and 8 healthy Chinese (all of non-childbearing potential) will be enrolled into this study.
Study will consist of following planned cohorts:
Eligible healthy subjects will be divided in 6 cohorts, each consisting of 8 subjects, within each cohort, 6 subjects will receive AZD2693 at dose level 1 and 2 subjects will receive placebo. Dosing for each ascending dose cohort will proceed with 2 subjects in a sentinel cohort, such that 1 subject will be randomized to receive placebo and 1 subject will be randomized to receive AZD2693.
Eligible healthy Japanese and Chinese subjects will be divided as two cohorts of Japanese subjects, and one cohort of Chinese subjects. Each cohort will consist of 8 subjects. Within each cohort, 6 subjects will receive AZD2693 and 2 subjects will receive placebo.
Depending on emerging data, up to 2 additional cohorts may be added to test additional dose levels based on Sponsor's decision.
Full study will comprise of following periods:
- Screening period of maximum 28 days.
- A Dosing Session during which subjects will be resident at the Clinical Unit from the day before investigational medicinal product (IMP) administration (Day -1) until at least 3 days after IMP administration with discharge on Day 4.
- A Follow-Up Period of 16 weeks that will consist of 9 Follow-Up Visits, for which the subjects will return to the Clinical Unit at 1, 2, 4, 6, 8, 10, 12, 14, and 16 weeks post dose.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 9
- Model description
- Subjects in this study will be categorized as follows: 1. Overweight/mildly obese, but otherwise healthy subjects: There will be 6 cohorts, with 8 subjects in each cohort. 2. Japanese and Chinese subjects: There will be 2 cohorts for Japanese subjects, and one cohort for Chinese subjects, with 8 subjects in each cohort.
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 healthy subjects: AZD2693 Dose 1 | Experimental | Drug: AZD2693, Drug: PlaceboSubjects will receive a subcutaneous (SC) injection of single dose 1 of AZD2693 or placebo matched to AZD2693 on Day 1. |
| Cohort 2 healthy subjects: AZD2693 Dose 2 | Experimental | Drug: AZD2693, Drug: PlaceboSubjects will receive a SC injection of single dose 2 of AZD2693 or placebo matched to AZD2693 on Day 1. |
| Cohort 3 healthy subjects: AZD2693 Dose 3 | Experimental | Drug: AZD2693, Drug: PlaceboSubjects will receive a SC injection of single dose 3 of AZD2693 or placebo matched to AZD2693 on Day 1. |
| Cohort 4 healthy subjects: AZD2693 Dose 4 | Experimental | Drug: AZD2693, Drug: PlaceboSubjects will receive a SC injection of single dose 4 of AZD2693 or placebo matched to AZD2693 on Day 1. |
| Cohort 5 healthy subjects: AZD2693 Dose 5 | Experimental | Drug: AZD2693, Drug: PlaceboSubjects will receive a SC injection of single dose 5 of AZD2693 or placebo matched to AZD2693 on Day 1. |
| Cohort 6 healthy subjects: AZD2693 Dose 6 | Experimental | Drug: AZD2693, Drug: PlaceboSubjects will receive a SC injection of single dose 6 of AZD2693 or placebo matched to AZD2693 on Day 1. |
| Cohort 7 healthy Japanese subjects: AZD2693 Dose 7 | Experimental | Drug: AZD2693, Drug: PlaceboSubjects will receive a SC injection of single dose 7 of AZD2693 or placebo matched to AZD2693 on Day 1. |
| Cohort 8 healthy Japanese subjects: AZD2693 Dose 8 | Experimental | Drug: AZD2693, Drug: PlaceboSubjects will receive a SC injection of single dose 8 of AZD2693 or placebo matched to AZD2693 on Day 1. |
| Cohort 9 healthy Chinese subjects: AZD2693 Dose 9 | Experimental | Drug: AZD2693, Drug: PlaceboSubjects will receive a SC injection of single dose 9 of AZD2693 or placebo matched to AZD2693 on Day 1. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit, must not be lactating and must be of non-child-bearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria: A. Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone levels in the postmenopausal range B. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
- Have a body mass index between 25 and 32 kg/m^2 for healthy subjects, or between 18 and 32 kg/m^2 for healthy Japanese and Chinese subjects, and weigh at least 60 kg (or 50 kg for healthy Japanese and Chinese subjects)
- Willing to participate in mandatory retrospective genotyping analysis for PNPLA3 1148M and the provision of blood and buccal swab samples for this analysis
- Willing and able to comply with all required study procedures
- A Japanese subject is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan
Key exclusion criteria (47 listed)
- History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study
- History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs
- Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP
- Any clinically significant cardiovascular event within the last 6 months prior to the Screening Visit
- Any laboratory values with the following deviations at Screening or Day -1:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AZD2693Subjects will receive SC injection of AZD2693 as per the arms they are randomized. | Drug | Cohort 1 healthy subjects: AZD2693 Dose 1, Cohort 2 healthy subjects: AZD2693 Dose 2, Cohort 3 healthy subjects: AZD2693 Dose 3, Cohort 4 healthy subjects: AZD2693 Dose 4, Cohort 5 healthy subjects: AZD2693 Dose 5, Cohort 6 healthy subjects: AZD2693 Dose 6, Cohort 7 healthy Japanese subjects: AZD2693 Dose 7, Cohort 8 healthy Japanese subjects: AZD2693 Dose 8, Cohort 9 healthy Chinese subjects: AZD2693 Dose 9 |
| PlaceboSubjects will receive SC injection of placebo matched to AZD2693, as per the arms they are randomized. | Drug | Cohort 1 healthy subjects: AZD2693 Dose 1, Cohort 2 healthy subjects: AZD2693 Dose 2, Cohort 3 healthy subjects: AZD2693 Dose 3, Cohort 4 healthy subjects: AZD2693 Dose 4, Cohort 5 healthy subjects: AZD2693 Dose 5, Cohort 6 healthy subjects: AZD2693 Dose 6, Cohort 7 healthy Japanese subjects: AZD2693 Dose 7, Cohort 8 healthy Japanese subjects: AZD2693 Dose 8, Cohort 9 healthy Chinese subjects: AZD2693 Dose 9 |
Primary outcome
Number of subjects experiencing adverse events and serious adverse events
Time frame: From baseline (Day 1) until Day 112 (Week 16, Final follow-up)
To investigate the safety and tolerability of SC administration of SAD of AZD2693
20 secondary outcomes
Area under the concentration-time curve from time zero extrapolated to infinity (AUC)
Time frame: At Day 1 pre-dose, 0.25 hours [h], 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-time curve from time zero to 48 hours after dosing [AUC(0-48h)]
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
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: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Maximum observed plasma drug concentration (Cmax) of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Observed maximum plasma concentration divided by the dose administered (Cmax/D)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Time to reach maximum observed concentration following drug administration (tmax)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
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: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing CL/F by λz (Vz/F)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Mean residence time (MRT)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Time delay between drug administration and the first observed concentration in plasma (tlag)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Time of the last quantifiable concentration (tlast)
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point [fe(0-last)]
Time frame: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Cumulative amount of analyte excreted into the urine from time zero through the last sampling interval [Ae(0-last)]
Time frame: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
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: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)]
Time frame: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Fraction of dose excreted unchanged into the urine from time t1 to t2 [fe(t1-t2)]
Time frame: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Nov 2021.
- Derived from this study: PubMed 39798707Armisen 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.
- Individual participant dataSharing planned: 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Han, MD principal investigator
Parexel Early Clinical Unit - Los Angeles
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing AZD2693 in people with Metabolic Disorders and Non-alcoholic Steatohepatitis, run by AstraZeneca at 1 site 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 7 inclusion and 47 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 26 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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 subjects experiencing adverse events and serious adverse events (time frame: From baseline (Day 1) until Day 112 (Week 16, Final follow-up)). 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 NCT04142424, which also lists 1 linked publication.
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 26 Nov 2021.