Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of AZD3366 in Healthy Subjects, Japanese and Chinese Subjects

NCT04588727 | Completed Phase 1 FDA Drug

• 1 other identifier: D2911C00001
• Study Type: interventional
• Target: 103
• Locations: 1 country
• Sites: 1

Brief Summary

Part A of this study is a Phase 1, First-in-human (FiH), randomized, single-blind, placebo controlled study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AZD3366 following single intravenous (IV) ascending doses. Part B of this study is a randomized, single-blind, parallel group placebo-controlled study to assess the safety, tolerability and PD of a single IV administration of AZD3366 with concomitant loading doses followed by repeated maintenance dosing of ticagrelor and acetylsalicylic acid (ASA).

Conditions

Cardiovascular Disease

Keywords

Pharmacokinetics; Cardiovascular disease; Acute myocardial infarction; Acute ischemic stroke; First in Human; Healthy subjects; Healthy Japanese subjects; Healthy Chinese subjects

Outcome Measures

Primary Outcomes (1)

• Number of subjects with adverse events and serious adverse events in both Part A and Part B

  Adverse events will be assessed to investigate the safety and tolerability of intravenous administration of AZD3366 in healthy subjects, healthy Japanese subjects and healthy Chinese subjects.

  From screening (Day -21) to follow-up (Day 60 for Part A and Day 50 for Part B)

Secondary Outcomes (26)

• Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) to characterize the PK of AZD3366 in Part A

  Pre-dose, and post-dose (Day 1 to Day 60)

• Terminal half life (t½λz), estimated as (ln2)/λz to characterize the PK of AZD3366 in Part A

  Pre-dose, and post-dose (Day 1 to Day 60)

• Total body clearance of drug from plasma after intravascular administration (CL) to characterize the PK of AZD3366 in Part A

  Pre-dose, and post-dose (Day 1 to Day 60)

• Volume of distribution at steady state from a systemic dose (Vss) to characterize the PK of AZD3366 in Part A

  Pre-dose, and post-dose (Day 1 to Day 60)

• Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast) to characterize the PK of AZD3366 in Part A

  Pre-dose, and post-dose (Day 1 to Day 60)

Study Arms (10)

AZD3366 Dose 1 Part A

EXPERIMENTAL

Randomized healthy subjects will receive Dose 1 of AZD3366.

Drug: AZD3366

AZD3366 Dose 2 Part A

EXPERIMENTAL

Randomized healthy subjects will receive Dose 2 of AZD3366.

Drug: AZD3366

AZD3366 Dose 3 Part A

EXPERIMENTAL

Randomized healthy subjects will receive Dose 3 of AZD3366.

Drug: AZD3366

AZD3366 Dose 4 Part A

EXPERIMENTAL

Randomized healthy subjects will receive Dose 4 of AZD3366.

Drug: AZD3366

AZD3366 Dose 5 Part A

EXPERIMENTAL

Randomized healthy subjects and healthy Japanese subjects will receive Dose 5 of AZD3366.

Drug: AZD3366

AZD3366 Dose 6 Part A

EXPERIMENTAL

Randomized healthy subjects and healthy Japanese subjects will receive Dose 6 of AZD3366.

Drug: AZD3366

AZD3366 Dose 7 Part A

EXPERIMENTAL

Randomized healthy subjects, healthy Japanese subjects, and healthy Chinese subjects will receive Dose 7 of AZD3366.

Drug: AZD3366

Placebo Part A

PLACEBO COMPARATOR

Randomized healthy subjects, healthy Japanese subjects, and healthy Chinese subjects will receive Placebo matched to AZD3366.

Drug: Placebo

AZD3366 Dose X Part B

EXPERIMENTAL

Randomized healthy subjects will receive Dose X of AZD3366 in conjunction with concomitant administration of ticagrelor and ASA.

Drug: AZD3366; Drug: Ticagrelor; Drug: acetylsalicylic acid (ASA)

Placebo Dose X Part B

PLACEBO COMPARATOR

Randomized healthy subjects will receive Dose X of placebo in conjunction with concomitant administration of ticagrelor and ASA.

Drug: Placebo; Drug: Ticagrelor; Drug: acetylsalicylic acid (ASA)

Interventions

AZD3366 DRUG

In Part A, subjects will be randomized to receive intravenous infusion AZD3366 dose 1-7, single ascending dose (SAD). In Part A, Dose 2-7 may be adjusted based on PK data from previous cohort\[s\]. In Part B, subjects will be randomized to receive intravenous infusion AZD3366 dose X (a dose resulting in predicted therapeutic exposure).

AZD3366 Dose 1 Part A; AZD3366 Dose 2 Part A; AZD3366 Dose 3 Part A; AZD3366 Dose 4 Part A; AZD3366 Dose 5 Part A; AZD3366 Dose 6 Part A; AZD3366 Dose 7 Part A; AZD3366 Dose X Part B

Placebo DRUG

In Part A and Part B, subjects will be randomized to receive intravenous infusion of placebo (0.9% sodium chloride solution).

Placebo Dose X Part B; Placebo Part A

Ticagrelor DRUG

In Part B, subjects will receive oral ticagrelor tablets.

Also known as: Brilinta

AZD3366 Dose X Part B; Placebo Dose X Part B

acetylsalicylic acid (ASA) DRUG

In Part B, subjects will receive oral ASA chewable tablets.

Also known as: Chewable aspirin

AZD3366 Dose X Part B; Placebo Dose X Part B

Eligibility Criteria

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

You may qualify if:

• Healthy men and women of non-childbearing potential
• Females must have a negative pregnancy test at Screening and on admission to the study center, must not be lactating, and must be of non-childbearing potential, confirmed at Screening, by fulfilling one of the below criteria:
• Postmenopausal defined as amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments and Follicle stimulating hormone levels in the postmenopausal range.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not bilateral tubal ligation.
• Subjects described as healthy subjects are defined as not having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent \[for example, Cambodia, China, India, Indonesia, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam\] except for subjects enrolled into the Japanese (subject for whom both parents and all grandparents are Japanese; born in Japan and not lived outside Japan for more than 10 years) and Chinese (a subject for whom both parents and all grandparents are Chinese and not lived outside of China for more than 10 years) cohorts.
• Body mass index: 18 and 30 kg/m\^2, and weigh minimum 50 kg and not \>100 kg.

You may not qualify if:

• Subjects having history of the following are excluded:
• Any clinically important disease or disorder which, may put the subject at risk, or influence the results or the subject's ability to participate in the study.
• History or presence of gastrointestinal, hepatic or renal disease or other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
• Hemophilia, von Willebrand´s disease, lupus anticoagulant or other diseases/syndromes that can either alter or increase the propensity of bleeding.
• Any clinically significant non-traumatic bleed or clinically significant enhanced bleeding.
• Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
• 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 AZD3366 or to ASA or ticagrelor.
• Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results, coagulation parameters, including but not limited to the list below:
• Alanine aminotransferase \> upper limit of normal (ULN)
• Aspartate aminotransferase \> ULN
• Creatinine \> ULN
• White blood cell count \< lower limit of normal (LLN)
• Hemoglobin \< LLN
• Platelet count \< 150,000/µL
• Total bilirubin 1.2 x \> ULN

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Glendale, California, 91206, United States

Location

Related Publications (1)

• Kardassis D, Egnell AC, Astrand M, Daniels SJ, Whatling C, Fjellstrom O, Gabrielsen A. Safety, Tolerability, and Pharmacodynamics of AZD3366 (Optimized Human CD39L3 Apyrase) Alone and in Combination With Ticagrelor and Acetylsalicylic Acid: A Phase 1, Randomized, Placebo-Controlled Study. J Am Heart Assoc. 2024 Jun 4;13(11):e033985. doi: 10.1161/JAHA.123.033985. Epub 2024 May 28.

  PMID: 38804212 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; Ischemic Stroke

Interventions

Ticagrelor; Aspirin

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• David Han

  PAREXEL Early Phase Clinical Unit Los Angeles 1560 Chevy Chase Drive, Suite 140 Glendale, CA 91206 United States of America

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Staff will remain blinded. For this single-blind study (in which the study center staff have remained blinded during the dosing phase of the study), the randomization code will be available at the SRC meeting and the data will be reviewed unblinded. The pharmacokineticist will remain unblinded during the study conduct, unless otherwise required based on study findings. The following personnel will have access to the randomization list: 1. The AstraZeneca personnel carrying out the labeling and packaging of subject specific treatments 2. The pharmacy personnel preparing study drug at the site 3. The personnel performing the bioanalyses of the plasma/urine samples. The randomization list should be kept in a secure location until the end of the study. In the event of a medical emergency, the treatment received may be revealed by personnel authorized by the principal investigator (PI), after discussing with AstraZeneca.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2020
• First Posted: October 19, 2020
• Study Start: October 15, 2020
• Primary Completion: January 19, 2022
• Study Completion: January 19, 2022
• Last Updated: December 18, 2023

Record last verified: 2023-12

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 re-refer 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 (1)