Study to Assess the Effect of AZD4831 on the Pharmacokinetics (Drug Behavior in the Body) of Midazolam

A Fixed Sequence, Open-label Study to Assess the Effect of Multiple Doses of AZD4831 on the Pharmacokinetics of Oral Midazolam (a CYP450 3A Probe) in Healthy Subjects

The study is an open-label, fixed-sequence, cross-over study conducted at a single Clinical Unit to assess the pharmacokinetics (PK) of midazolam in healthy male and female (non-childbearing potential) subjects when administered alone and in combination with AZD4831 after multiple doses (once daily) of AZD4831 for 10 consecutive days.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: AZD4831; Drug: Midazolam

Detailed Description

The study will consist of 2 treatment periods and will comprise:

• A Screening period of maximum 28 days;
• Treatment Period 1 and Treatment Period 2:

Treatment Period 1: Midazolam only (Day 1). Treatment Period 2: AZD4831 only (Days 2 to 10, once daily dosing) and AZD4831 plus midazolam (Day 11).

- A final Follow-up Visit after the last administration of investigational medicinal product (IMP) (Day 20 [± 1 day]).

Each subject will be involved in the study for approximately 7 weeks.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Harrow, United Kingdom, HA1 3UJ
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male and/or female subjects with suitable veins for cannulation or repeated venepuncture.
• Males must be willing to use appropriate contraception methods.
• Females must not be lactating and must be of non-childbearing potential, confirmed at Screening.
• Have a body mass index between 18.5 and 30 kg/m^2 (inclusive) and weigh at least 50 kg and no more than 100 kg (inclusive) at Screening.

Exclusion Criteria:

• History of any clinically significant 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.
• A positive Corona Virus Disease 2019 test at Screening or admission to the Clinical Unit on Day -1.
• Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results.
• Any clinically significant abnormal findings in vital signs.
• clinically significant abnormalities on 12-lead electrocardiogram.
• Any positive result at the Screening Visit for Hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus antibody.
• Known or suspected history of drug abuse in the last 2 years.
• Current smokers or those who have smoked or used nicotine products within the 3 months prior to the Screening Visit.
• Known or suspected history of alcohol or drug abuse.
• Use of any prescribed or non-prescribed medication.
• Subjects with acute pulmonary insufficiency, marked neuromuscular respiratory weakness, obsessional states, phobic states, sleep apnoea syndrome, or unstable myasthenia gravis.
• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigatoror history of hypersensitivity to drugs with a similar chemical structure or class to AZD4831 or midazolam.
• History or ongoing allergy/hypersensitivity to drugs(including but not limited to rash, angioedema, acute urticaria).
• Subjects who, in the opinion of the Investigator, have any clinically significant skin condition.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment Arm; Subjects will receive midazolam on Day 1 and AZD4831 once daily from Days 2 to 10, and AZD4831 plus midazolam on Day 11.	Drug: AZD4831; Subjects will receive oral doses once daily from Days 2-11.; Drug: Midazolam; Subjects will receive oral single doses on Day 1 and Day 11.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under plasma concentration time curve from zero to infinity (AUCinf) of Midazolam	Effect of AZD4831 on AUCinf of Midazolam will be assessed.	Days 1, 2, 11, and 12
Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) of Midazolam	Effect of AZD4831 on AUClast of Midazolam will be assessed.	Days 1, 2, 11, and 12
Maximum observed plasma (peak) drug concentration (Cmax) of Midazolam	Effect of AZD4831 on Cmax of Midazolam will be assessed.	Days 1, 2, 11, and 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to reach peak or maximum observed concentration or response following drug administration (tmax) of Midazolam and AZD4831	tmax of Midazolam and AZD4831 will be assessed.	Midazolam:Days 1, 2, 11, and 12; AZD4831:Days 2-12
Half life associated with terminal slope (λz) of a semi logarithmic concentration timecurve (t½λz) of Midazolam and AZD4831	t½λz of Midazolam and AZD4831 will be assessed.	Midazolam:Days 1, 2, 11, and 12; AZD4831:Days 2-12
Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of Midazolam and AZD4831	CL/F of Midazolam and AZD4831 will be assessed.	Midazolam:Days 1, 2, 11, and 12; AZD4831:Days 2-12
Apparent volume of distribution based on terminal phase (Vz/F) of Midazolam	Vz/F of Midazolam will be assessed.	Days 1, 2, 11, and 12
Area under the plasma concentration-curve across the dosing interval (AUCtau) of AZD4831	AUCtau of AZD4831 will be assessed.	Days 2-12
Cmax of AZD4831	Cmax of AZD4831 will be assessed.	Days 2-12
Daily pre-dose plasma concentration (CpreD3 up to CpreD10) of AZD4831	Pre-dose plasma concentration of AZD4831 will be assessed.	Days 3-10
Plasma concentration 24 hours post the Day 10 dose (C24h) of AZD4831	Plasma concentration of AZD4831 will be assessed.	Day 11
Number of patients with adverse events (AE) and serious AEs (SAE)	Safety and tolerability of AZD4831 alone and in combination with midazolam will be assessed.	From Screening (Day -28 to Day -2) until Follow-up Visit (Day 20)

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 5, 2021
• Primary Completion (ACTUAL): November 29, 2021
• Study Completion (ACTUAL): November 29, 2021

Study Registration Dates

• First Submitted: September 14, 2021
• First Submitted That Met QC Criteria: September 14, 2021
• First Posted (ACTUAL): September 22, 2021

Study Record Updates

• Last Update Posted (ACTUAL): December 13, 2021
• Last Update Submitted That Met QC Criteria: December 10, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Cardiovascular Disease; Pharmacokinetics; Drug-drug interaction; Myeloperoxidase inhibitor; Fixed-sequence
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: D6580C00012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

• IPD Sharing 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.
• IPD Sharing 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No