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A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD0780 in Healthy Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05384262
Recruitment Status : Recruiting
First Posted : May 20, 2022
Last Update Posted : May 15, 2023
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Study Description
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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
Dyslipidemia Drug: AZD0780 Drug: Placebo 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.

  • Part A:

    • A Screening Period of maximum 28 days.
    • Admission to study center (Day -1 or Day -2).
    • A Treatment Period (Day 1 to Day 3) with a single dose of AZD0780 or placebo on Day 1. Subjects will be discharged on Day 3.
    • A Follow-up Visit within 5 to 7 days after the Investigational Medicinal Product (IMP) dose for all cohorts.

    • An additional Follow-up Visit within 9 to 11 days after the IMP dose from Cohort 3 onwards.

      (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 9 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:

  • 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).
  • 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 9 days dosing (subjects will receive a single dose of IMP on Day 1 followed by daily dosing on Days 8 to 15 [there is no dose on Days 2 to 7]). The second cohort of 8 Japanese subjects will receive a higher dose level of AZD0780 or placebo.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This study will be a randomized, single-blind (study center staff including the Principal Investigator [PI] to remain blinded during the dosing phase of each cohort), placebo-controlled, Single Ascending Dose (SAD)/MAD, parallel type of design in healthy male and/or female subjects, performed at multiple study centers.

56 subjects have been planned for Part A and 76 subjects for Part B to receive AZD0780, or placebo.

(i) Part A1 - Up to 5 dose cohorts of AZD0780 are planned to be investigated. (ii) Part A2 - The subjects from a chosen cohort in Part A1 will return to the study center no sooner than 9 days after the first dose administration of IMP and will receive AZD0780 or placebo after breakfast.

The subjects will stay at the study center until 48 hours post-dose in both the parts.

• Part B:

  • Global Multiple Ascending Dose (MAD) cohort - Up to 3 dose cohorts are planned to be investigated.
  • Japanese Single and Multiple Ascending Dose (JSMAD) cohort - Two cohorts are planned.
Masking: Single (Participant)
Masking Description: This study will be a randomized, single-blind (study center staff including the PI to remain blinded during the dosing phase of each cohort), placebo-controlled, SAD/MAD, sequential group design study in healthy male and/or female subjects, performed at multiple study centers.
Primary Purpose: Treatment
Official Title: A Phase I, Randomized, Single-Blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD0780 Following Single and Multiple Ascending Dose Administration to Healthy Subjects With or Without Elevated LDL-C Levels
Actual Study Start Date : May 18, 2022
Estimated Primary Completion Date : September 18, 2023
Estimated Study Completion Date : September 18, 2023
Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Cohort 1: Part A1 - 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 ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single ascending dose.
Active Comparator: Cohort 2: Part A1 - 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 ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single ascending dose.
Active Comparator: Cohort 3: Part A1 - 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 ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single ascending dose.
Active Comparator: Cohort 4: Part A1 - 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 ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single 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 ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single ascending dose.
Active Comparator: Cohort 6: Part B - AZD0780 dose 6/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 multiple ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a multiple ascending dose.
Active Comparator: Cohort 7: Part B - 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 multiple ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a multiple ascending dose.
Active Comparator: Cohort 8: Part B - 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 multiple ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a multiple ascending dose.
Active Comparator: Cohort 9: Part B - AZD0780 dose 9/placebo tablet
A total of 6 subjects will receive single and multiple ascending doses of AZD0780 and 2 will receive placebo.
 Drug: AZD0780
Subjects will receive AZD0780 orally as a single and multiple ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single and multiple ascending dose.
Active Comparator: Cohort 10: Part B - AZD0780 dose 10/placebo tablet
A total of 6 subjects will receive single and multiple ascending doses of AZD0780 and 2 will receive placebo.
 Drug: AZD0780
Subjects will receive AZD0780 orally as a single and multiple ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single and multiple ascending dose.
Active Comparator: Cohort 11: Part A2 - AZD0780 dose 11/placebo tablet
A total of 5 subjects will receive single ascending doses of AZD0780 and placebo.
 Drug: AZD0780
Subjects will receive AZD0780 orally as a single ascending dose.

Drug: Placebo
Subjects will receive placebo matching the AZD0780 dose orally as a single ascending dose.


Outcome Measures
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Primary Outcome Measures :
  1. Number of subjects with Adverse Events [ Time Frame: From Screening (≤ 28 days) until Follow-up Visit (5 to 7 days post-dose for all cohorts, and 9 to 11 days post-dose for subjects from Cohort 3 onwards) ]
    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 :
  1. Area under plasma concentration time curve from zero to infinity (AUCinf) [ Time Frame: Part A and Part B: Day 1 ]
    The single dose and steady state AUCinf of AZD0780 following oral administration of AZD0780 will be assessed.

  2. Area under plasma concentration time curve from zero to t hours post-dose (AUC[0-t]) [ Time Frame: 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.

  3. Area under the plasma concentration-curve across the dosing interval (AUCτ) [ Time Frame: Part B: Day 1, and Day 8 ]
    The single dose and steady state AUCτ of AZD0780 following oral administration of AZD0780 will be assessed.

  4. Maximum observed plasma (peak) drug concentration [Cmax] [ Time Frame: 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.

  5. Amount of unchanged drug excreted into urine from zero to the last quantifiable concentration by interval and cumulatively (Ae[0-last]) [ Time Frame: 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.

  6. Percentage of dose excreted unchanged in urine from zero to the last quantifiable concentration, by interval and cumulatively (fe[0-last]) [ Time Frame: 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.

  7. Renal clearance of drug from plasma (CLR) [ Time Frame: 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.

  8. LDL-C [ Time Frame: 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.

  9. Proprotein convertase subtilisin/kexin type 9 (PCSK9) [ Time Frame: 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
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Provision of signed and dated, written informed consent prior to any study specific procedures (including the Pre Screening Visit for Part B).
  • Healthy male and female subjects (of nonchildbearing potential), aged 18 to 50 years inclusive, with suitable veins for cannulation or repeated venipuncture.

  • 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 by fulfilling one of the following criteria:

    1. Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH levels in the postmenopausal range.
    2. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
  • Have a BMI between 18 and 35 kg/m2 inclusive and weigh at least 50 kg and no more than 120 kg inclusive at the Screening Visit and on admission to the study center.

  • For Japanese subjects (Part B) and Chinese subjects (Part A):

    1. 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.
    2. 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.
  • For Part B (MAD), at the Screening Visit subjects must have LDL-C ≥ 70 mg/dL but ≤ 190 mg/dL (or ≥ 1.8 mmol/L but ≤ 4.9 mmol/L for London EPCU [Early Phase Clinical Unit]), and triglycerides < 400 mg/dL (or < 10.3 mmol/L for London EPCU).

Exclusion Criteria:

  • History of any clinically important disease or disorder.
  • 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.
  • Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first vaccination within 30 days prior to randomization.
  • SARS-CoV-2 second vaccination within 10 days of screening.
  • Confirmed Coronavirus disease 2019 (COVID-19) infection during screening and admission, by Polymerase Chain Reaction (PCR) test (in the London EPCU, COVID-19 infection before or during Screening and/or admission will be confirmed by a COVID-19 test. Subjects will undergo COVID-19 testing prior to ICF signing and any subject testing positive will not be screened for the study).
  • Any clinically important abnormalities in clinical chemistry, coagulation, hematology, or urinalysis results.
  • Any positive result on Screening for serum hepatitis B surface antigen, hepatitis C antibody, and Human immunodeficiency virus (HIV).
  • Abnormal vital signs after 10 minutes supine rest at the Screening Visit and on admission to the study center.
  • 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.
  • Known or suspected history of drug abuse.
  • Current smokers or those who have smoked or used nicotine products within the previous 3 months.
  • History of alcohol abuse or excessive intake of alcohol.
  • Positive screen for drugs of abuse, cotinine (nicotine), or alcohol at Screening and/or admission to the study center.
  • 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.
  • Excessive intake of caffeine-containing drinks or food.
  • Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
  • 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.
  • Plasma donation within one month of the Screening Visit or any blood donation/blood loss during the 3 months prior to the Screening Visit.
  • Has received another new chemical entity within 30 days or 5 half-lives of the first administration of IMP in this study.
  • Subjects who have previously received AZD0780 within 60 days of the first administration of IMP in this study.
  • Involvement of any Astra Zeneca or study center employee or their close relatives.
  • 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.
  • Subjects who are vegans or have medical dietary restrictions.
  • Subjects who cannot communicate reliably with the investigator.
  • Vulnerable subjects.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05384262


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

Locations
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United States, California
Research Site Recruiting
Glendale, California, United States, 91206
United States, Maryland
Research Site Recruiting
Brooklyn, Maryland, United States, 21225
United Kingdom
Research Site Recruiting
Harrow, United Kingdom, HA1 3UJ
Sponsors and Collaborators
AstraZeneca
Parexel
More Information
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT05384262    
Other Study ID Numbers: D7960C00001
2022-002221-10 ( EudraCT Number )
First Posted: May 20, 2022    Key Record Dates
Last Update Posted: May 15, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request 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 de-identified 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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Elevated LDL-C
Hypercholesterolemia
Additional relevant MeSH terms:
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Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases