A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD0780 in Healthy Subjects
Study Details
Study Description
Brief Summary
This study will assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AZD0780 following single and multiple dose administration to healthy subjects with or without elevated Low-Density Lipoprotein-Cholesterol (LDL-C) levels.
This study will consist of two parts (Parts A and B).
56 subjects have been planned for Part A and 76 subjects for Part B. Additional subjects may be included for the optional cohorts depending upon emerging data.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is a Phase I, First In Human (FIH), randomized, single-blind, placebo-controlled, study in healthy male and/or female subjects of non-childbearing potential including healthy subjects of Chinese and Japanese ethnicity performed at multiple centers (up to 4 study centers).
56 subjects have been planned for Part A and 76 subjects for Part B.
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Part A:
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A Screening Period of maximum 28 days.
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Admission to study center (Day -1 or Day -2).
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A Treatment Period (Day 1 to Day 3) with a single dose of AZD0780 or placebo on Day
- Subjects will be discharged on Day 3.
- A Follow-up Visit within 5 to 7 days after the Investigational Medicinal Product (IMP) dose.
(i) Part A1 - Up to 5 dose cohorts of AZD0780 are planned to be investigated. Depending on the findings, up to 4 additional dose cohorts may be added. Within each cohort, 6 subjects will be randomized to receive AZD0780, and 2 subjects randomized to receive placebo. Dosing for each ascending dose cohort will proceed with 2 subjects in a sentinel sub-cohort such that one subject will be randomized to receive AZD0780, and one subject will be randomized to receive placebo.
(ii) Part A2 - The subjects from a chosen cohort in Part A1 will return to the study center no sooner than 5 days after the first dose administration of IMP and will receive AZD0780 or placebo after intake of a high-calorie, high-fat breakfast, to assess the effect of food on the PK of AZD0780..
The subjects will stay at the study center until 48 hours post-dose in both the parts.
• Part B:
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Global Multiple Ascending Dose (MAD) cohort - Up to 3 dose cohorts are planned to be investigated. In each cohort, 20 subjects will participate and receive either AZD0780 or placebo, randomized 3:1 for 28 days dosing. Depending on the findings, 3 additional dose levels may be added in up to 3 additional cohorts (up to 20 subjects per cohort).
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Japanese Single and Multiple Ascending Dose (JSMAD) cohort - Two cohorts are planned. One cohort of 8 Japanese subjects will receive a medium dose level of AZD0780 or placebo randomized 3:1 for 7 days dosing (subjects will receive a single dose of IMP on Day 1 followed by daily dosing on Days 3 to 8 [there is no dose on Day 2]). The second cohort of 8 Japanese subjects will receive a higher dose level of AZD0780 or placebo.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Cohort 1: AZD0780 dose 1/placebo tablet A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
| Active Comparator: Cohort 2: AZD0780 dose 2/placebo tablet A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
| Active Comparator: Cohort 3: AZD0780 dose 3/placebo tablet A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
| Active Comparator: Cohort 4: AZD0780 dose 4/placebo tablet A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
| Active Comparator: Cohort 5: AZD0780 dose 5/placebo tablet A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
| Active Comparator: Cohort 6: AZD0780 dose 6/placebo tablet A total of 5 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
| Active Comparator: Cohort 7: AZD0780 dose 7/placebo tablet A total of 20 subjects will be assigned as 3:1::AZD0780:Placebo to receive multiple ascending doses. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
| Active Comparator: Cohort 8: AZD0780 dose 8/placebo tablet A total of 20 subjects will be assigned as 3:1::AZD0780:Placebo to receive multiple ascending doses. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
| Active Comparator: Cohort 9: AZD0780 dose 3/placebo tablet A total of 8 subjects will be assigned in a ratio of 3:1::AZD0780:Placebo to receive single and multiple ascending doses. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
| Active Comparator: Cohort 10: AZD0780 dose 10/placebo tablet A total of 8 subjects will be assigned in a ratio of 3:1::AZD0780:Placebo to receive single and multiple ascending doses. |
Drug: AZD0780
Subjects will receive AZD0780 orally as a single or multiple ascending dose.
Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single or multiple ascending dose.
|
Outcome Measures
Primary Outcome Measures
- Number of subjects with Adverse Events [From Screening (≤ 28 days) until Follow-up Visit (5 to 7 days post-dose)]
The safety and tolerability of AZD0780 following oral administration of single ascending doses (Part A) and multiple ascending doses (Part B) will be assessed.
Secondary Outcome Measures
- Area under plasma concentration time curve from zero to infinity (AUCinf) [Part A and Part B: Day 1]
The single dose and steady-state AUCinf of AZD0780 following oral administration of AZD0780 will be assessed.
- Area under plasma concentration time curve from zero to t hours post-dose (AUC[0-t]) [Part A and Part B: Day 1]
The single dose and steady-state AUC(0-t) of AZD0780 following oral administration of AZD0780 will be assessed.
- Area under the plasma concentration-curve across the dosing interval (AUCτ) [Part B: Day 1, and Day 8]
The single dose and steady-state AUCτ of AZD0780 following oral administration of AZD0780 will be assessed.
- Maximum observed plasma (peak) drug concentration [Cmax] [Part A: Day 1 to Day 3 Part B: Day 1 to Day 3, Day 8 to Day 10]
The single dose and steady-state Cmax of AZD0780 following oral administration of AZD0780 will be assessed.
- Amount of unchanged drug excreted into urine from zero to the last quantifiable concentration by interval and cumulatively (Ae[0-last]) [Part A: Day 1 to Day 3; Part B: Day 1, and Day 8]
The single dose and steady-state Ae[0-last] of AZD0780 following oral administration of AZD0780 will be assessed.
- Percentage of dose excreted unchanged in urine from zero to the last quantifiable concentration, by interval and cumulatively (fe[0-last]) [Part A: Day 1 to Day 3; Part B: Day 1, and Day 8]
The single dose and steady-state fe[0-last] of AZD0780 following oral administration of AZD0780 will be assessed.
- Renal clearance of drug from plasma (CLR) [Part A: Day 1 to Day 3; Part B: Day 1, and Day 8]
The single dose and steady-state CLR of AZD0780 following oral administration of AZD0780 will be assessed.
- LDL-C [Part A: Day 1 to Day 3; Part B: Days 1-3, 5, 8, 12, 15, 18, 22, 25, and 29 (Main cohort), Days 1-3, 5, 8-10 (JSMAD cohort)]
The pharmacodynamics (PD) of AZD0780 by assessment of LDL-C following oral administration of single ascending doses (Part A) and multiple ascending doses (Part B) will be assessed.
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) [Main cohorts: Days 1, 8, 15, 22, and 29; JSMAD cohort: Days 1, 3, 5, and 8-10]
The PD of AZD0780 by assessment of total PCSK9 (and compound stabilized PCSK9 for Part A) following oral administration of single ascending doses (Part A) will be assessed.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Females must have a negative pregnancy test at the Screening Visit and on admission to the study center, must not be lactating, and must be of non-childbearing potential confirmed at the Screening Visit.
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For Japanese subjects (Part B) and Chinese subjects (Part A): (i) A subject will be considered Japanese if both parents and all grandparents are Japanese, the subject was born in Japan, and the subject has not lived outside Japan for more than 10 years.
(ii) A subject will be considered Chinese if both parents and all grandparents are Chinese, the subject was born in China, and the subject has not lived outside China for more than 10 years.
Exclusion Criteria:
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History of any clinically important disease or disorder.
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History or presence of gastrointestinal, hepatic or, renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
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Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first vaccination within 30 days prior to randomization.
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SARS-CoV-2 second vaccination within 10 days of screening.
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Confirmed Coronavirus disease 2019 (COVID-19) infection during screening and admission, by Polymerase Chain Reaction (PCR) test.
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Any clinically important abnormalities in clinical chemistry, hematology, or urinalysis results.
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Any positive result on Screening for serum hepatitis B surface antigen, hepatitis C antibody, and Human immunodeficiency virus (HIV).
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Abnormal vital signs after 10 minutes supine rest at the Screening Visit and on admission to the study center.
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Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12-lead ECG that may interfere with the interpretation of ECG interval measured from the onset of the QRS complex to the end of the T wave (QT) corrected for heart rate (QTc) interval changes including abnormal ST-T-wave morphology at the Screening Visit and/or on admission to the study center.
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Known or suspected history of drug abuse.
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Current smokers or those who have smoked or used nicotine products within the previous 3 months.
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History of alcohol abuse or excessive intake of alcohol.
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Positive screen for drugs of abuse or cotinine at Screening or admission to the study center or positive screen for alcohol on admission to the study center prior to the first administration of the IMP.
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History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD0780.
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Excessive intake of caffeine-containing drinks or food.
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Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
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Use of any prescribed or nonprescribed medication including antacids, analgesics, herbal remedies, mega-dose vitamins, and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life.
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Plasma donation within one month of the Screening Visit or any blood donation/blood loss during the 3 months prior to the Screening Visit.
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Has received another new chemical entity within 30 days or 5 half-lives of the first administration of IMP in this study.
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Subjects who have previously received AZD0780.
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Involvement of any Astra Zeneca or study center employee or their close relatives.
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Any ongoing or recent minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.
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Subjects who are vegans or have medical dietary restrictions.
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Subjects who cannot communicate reliably with the investigator.
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Vulnerable subjects.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Glendale | California | United States | 91206 |
| 2 | Research Site | Brooklyn | Maryland | United States | 21225 |
Sponsors and Collaborators
- AstraZeneca
- Parexel
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D7960C00001