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

NCT05384262 | Completed Phase 1 FDA Drug

• 2 other identifiers: D7960C000012022-002221-10
• Study Type: interventional
• Target: 183
• Locations: 2 countries
• Sites: 3

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 141 subjects for Part B. Additional subjects may be included for the optional cohorts depending upon emerging data.

Conditions

Dyslipidemia

Keywords

Elevated LDL-C; Hypercholesterolemia

Outcome Measures

Primary Outcomes (1)

• Number of subjects with Adverse Events

  The safety and tolerability of AZD0780 following oral administration of single ascending doses (Part A) and multiple ascending doses (Part B) will be assessed.

  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)

Secondary Outcomes (9)

• Area under plasma concentration time curve from zero to infinity (AUCinf)

  SAD cohorts: Day 1-3 until 5-7 days (cohort 1 & 2) & 9-11 days (cohort 3 onwards) post-dose; JSMAD cohorts: Day 1-3,5,8,10,13,15,16 until 7-10 days post-dose; MAD Cohorts: Day 1 to 3,5,8,9,12,15,18,22,25,29 until Days 36, 43 [± 1day]

• Area under plasma concentration time curve from zero to t hours post-dose (AUC[0-t])

  SAD cohorts: Day 1-3 until 5-7 days (cohort 1 & 2) & 9-11 days (cohort 3 onwards) post-dose; JSMAD cohorts: Day 1-3,5,8,10,13,15,16 until 7-10 days post-dose; MAD Cohorts: Day 1 to 3,5,8,9,12,15,18,22,25,29 until Days 36, 43 [± 1day]

• Area under the plasma concentration-curve across the dosing interval (AUCτ)

  SAD cohorts: Day 1-3 until 5-7 days (cohort 1 & 2) & 9-11 days (cohort 3 onwards) post-dose; JSMAD cohorts: Day 1-3,5,8,10,13,15,16 until 7-10 days post-dose; MAD Cohorts: Day 1 to 3,5,8,9,12,15,18,22,25,29 until Days 36, 43 [± 1day]

• Maximum observed plasma (peak) drug concentration [Cmax]

  SAD cohorts: Day 1-3 until 5-7 days (cohort 1 & 2) & 9-11 days (cohort 3 onwards) post-dose; JSMAD cohorts: Day 1-3,5,8,10,13,15,16 until 7-10 days post-dose; MAD Cohorts: Day 1 to 3,5,8,9,12,15,18,22,25,29 until Days 36, 43 [± 1day]

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

  SAD cohorts (Parts A1 & A2): Day 1 to Day 3; JSMAD cohorts (Part B): Day 1 & 15; Global MAD Cohorts Day 1 & 10; Rosuvastatin Global MAD Cohorts (Part B): Day 1 & 8

Study Arms (14)

Cohort 1: Part A1 - AZD0780 dose 1/placebo tablet

ACTIVE COMPARATOR

A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo.

Drug: AZD0780; Drug: Placebo

Cohort 2: Part A1 - AZD0780 dose 2/placebo tablet

ACTIVE COMPARATOR

A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo.

Drug: AZD0780; Drug: Placebo

Cohort 3: Part A1 - AZD0780 dose 3/placebo tablet

ACTIVE COMPARATOR

A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo.

Drug: AZD0780; Drug: Placebo

Cohort 4: Part A1 - AZD0780 dose 4/placebo tablet

ACTIVE COMPARATOR

A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo.

Drug: AZD0780; Drug: Placebo

Cohort 5: Part A1 - AZD0780 dose 5/placebo tablet

ACTIVE COMPARATOR

A total of 6 subjects will receive single ascending doses of AZD0780 and 2 will receive placebo.

Drug: AZD0780; Drug: Placebo

Cohort 6: Part B - AZD0780 dose 6/placebo tablet

ACTIVE COMPARATOR

A total of 20 subjects will be assigned as 3:1::AZD0780:Placebo to receive multiple ascending doses.

Drug: AZD0780; Drug: Placebo

Cohort 7: Part B - AZD0780 dose 7/placebo tablet

ACTIVE COMPARATOR

A total of 20 subjects will be assigned as 3:1::AZD0780:Placebo to receive multiple ascending doses.

Drug: AZD0780; Drug: Placebo

Cohort 8: Part B - AZD0780 dose 8/placebo tablet

ACTIVE COMPARATOR

A total of 20 subjects will be assigned as 3:1::AZD0780:Placebo to receive multiple ascending doses.

Drug: AZD0780; Drug: Placebo

Cohort 9: Part B - AZD0780 dose 9/placebo tablet

ACTIVE COMPARATOR

A total of 6 subjects will receive single and multiple ascending doses of AZD0780 and 2 will receive placebo.

Drug: AZD0780; Drug: Placebo

Cohort 10: Part B - AZD0780 dose 10/placebo tablet

ACTIVE COMPARATOR

A total of 6 subjects will receive single and multiple ascending doses of AZD0780 and 2 will receive placebo.

Drug: AZD0780; Drug: Placebo

Cohort 11: Part A2 - AZD0780 dose 11/placebo tablet

ACTIVE COMPARATOR

A total of 5 subjects will receive single ascending doses of AZD0780 and placebo.

Drug: AZD0780; Drug: Placebo

Cohort 12: Part B - AZD0780 dose 1/rosuvastatin dose 12

ACTIVE COMPARATOR

A total of 20 subjects will receive single dose of AZD0780 and rosuvastatin.

Drug: AZD0780; Drug: Rosuvastatin

Cohort 13: Part B - placebo tablet/rosuvastatin dose 12

ACTIVE COMPARATOR

A total of 20 subjects will receive single dose of placebo and rosuvastatin.

Drug: Placebo; Drug: Rosuvastatin

Cohort 14: Part B - AZD0780 with placebo tablet/AZD0780 with rosuvastatin dose 12

ACTIVE COMPARATOR

A total of 20 subjects will receive AZD0780 in combination with rosuvastatin or 5 subjects will receive placebo in combination with rosuvastatin.

Drug: AZD0780; Drug: Placebo; Drug: Rosuvastatin

Interventions

AZD0780 DRUG

Subjects will receive AZD0780 orally as a single ascending dose.

Cohort 11: Part A2 - AZD0780 dose 11/placebo tablet; Cohort 1: Part A1 - AZD0780 dose 1/placebo tablet; Cohort 2: Part A1 - AZD0780 dose 2/placebo tablet; Cohort 3: Part A1 - AZD0780 dose 3/placebo tablet; Cohort 4: Part A1 - AZD0780 dose 4/placebo tablet; Cohort 5: Part A1 - AZD0780 dose 5/placebo tablet

Placebo DRUG

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

Cohort 11: Part A2 - AZD0780 dose 11/placebo tablet; Cohort 1: Part A1 - AZD0780 dose 1/placebo tablet; Cohort 2: Part A1 - AZD0780 dose 2/placebo tablet; Cohort 3: Part A1 - AZD0780 dose 3/placebo tablet; Cohort 4: Part A1 - AZD0780 dose 4/placebo tablet; Cohort 5: Part A1 - AZD0780 dose 5/placebo tablet

Rosuvastatin DRUG

Subjects will receive rosuvastatin orally.

Cohort 12: Part B - AZD0780 dose 1/rosuvastatin dose 12; Cohort 13: Part B - placebo tablet/rosuvastatin dose 12; Cohort 14: Part B - AZD0780 with placebo tablet/AZD0780 with rosuvastatin dose 12

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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 55 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:
• 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.
• 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):
• 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.
• 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).
• For Part B (rosuvastatin global MAD), at the Screening Visit subjects must have LDL-C ≥ 100 mg/dL but \< 190 mg/dL (≥ 2.6 mmol/L but ≤ 4.9 mmol/L for London EPCU).

You may not qualify if:

• 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.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (3)

Research Site

Glendale, California, 91206, United States

Location

Research Site

Brooklyn, Maryland, 21225, United States

Location

Research Site

Harrow, HA1 3UJ, United Kingdom

Location

MeSH Terms

Conditions

Dyslipidemias; Hypercholesterolemia

Interventions

Rosuvastatin Calcium

Condition Hierarchy (Ancestors)

Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperlipidemias

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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 design in healthy male and/or female subjects, performed at multiple study centers.

Study Record Dates

• First Submitted: May 17, 2022
• First Posted: May 20, 2022
• Study Start: May 18, 2022
• Primary Completion: June 14, 2024
• Study Completion: June 14, 2024
• Last Updated: July 19, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• 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.

Locations

US (2); GB (1)