A Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4041 in Healthy Volunteers

A Phase I Randomized, Double-blind Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of AZD4041 Following Single Ascending Dose Administration to Healthy Volunteers

This is a Phase I, first-in-human (FIH), single-center, randomized, double-blind, placebo controlled, single ascending dose, sequential group study in healthy vasectomized male and female subjects of non-childbearing potential, aged 18 to 65 years.

Study Overview

• Status: Completed
• Conditions: Smoking Cessation
• Intervention / Treatment: Drug: AZD4041; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Nevada
    • Las Vegas, Nevada, United States, 89113
      • Research Site
  • Texas
    • Austin, Texas, United States, 78744
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria

1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form and in this clinical study protocol.
2. Provision of signed and dated, written Informed Consent Form prior to any mandatory study specific procedures, sampling, and analyses.
3. Subjects must be ≥18 and less than or equal to 65 years of age at the time of signing the Informed Consent Form.
4. Individuals who are healthy as determined by medical evaluation, including medical history, physical examination, laboratory tests, and cardiac monitoring.
5. Individuals who weigh ≥50 kg and who have a body mass index (BMI) between 18.0 and 30.0 kg/m2, inclusive.
6. Either male or female.
7. Female subjects must have a negative pregnancy test result at screening and check-in and, on admission to the unit, must not be lactating.

8. Female subjects must be of non-childbearing potential, as confirmed at screening by fulfilling one of the following criteria:

   1. Post-menopausal women must have had ≥12 months of spontaneous amenorrhea with a follicle stimulating hormone (FSH) concentration consistently ≥40 mIU/mL and must have a negative pregnancy test result at screening and check-in.
   2. Surgically sterile women, defined as those who have had a hysterectomy, bilateral ovariectomy (oophorectomy), bilateral salpingectomy, or bilateral tubal ligation. Women who are surgically sterile must provide documentation of the procedure by an operative report or relevant medical records, or by ultrasound, and must have a negative pregnancy test result at screening and check-in.
9. Male subjects must be vasectomized.

Exclusion criteria

1. History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
2. History of any significant psychiatric disorder according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (American Psychiatric Association 2013) which, in the opinion of the Investigator, could be detrimental to subject safety or could compromise study data interpretation.
3. Male subjects with a history of oligospermia or azoospermia or any other disorder of the reproductive system.
4. Subjects who are undergoing treatment or evaluation for infertility.
5. History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
6. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of administration of Investigational Product.
7. Any clinically important abnormalities noted at the screening assessments in clinical chemistry, hematology, or urinalysis results as judged by the Investigator.
8. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus antibodies.

9. Abnormal vital signs, after 10 minutes supine rest, defined as any of the following:

   1. Systolic BP <90 mmHg or ≥140 mmHg.
   2. Diastolic BP <50 mmHg or ≥90 mmHg.
   3. HR <45 or >85 beats per minute.
10. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG which, in the Investigator's opinion, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology.
11. ECG interval measured from the onset of the QRS complex to the end of the T wave (QT) interval corrected for HR using Fridericia's formula (QTcF) >450 ms or family history of long QT syndrome.
12. ECG interval measured from the onset of the P wave to the onset of the QRS complex (PR[PQ]) interval shortening <120 ms (PR >110 ms but <120 ms is acceptable if there is no evidence of ventricular pre-excitation).
13. PR(PQ) interval prolongation (>240 ms), persistent or intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.
14. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with ECG interval measured from the onset of the QRS complex to the J point (QRS) >110 ms. Subjects with QRS >110 ms but <115 ms are acceptable if there is no evidence of, eg, ventricular hypertrophy or pre-excitation.
15. Known or suspected history of drug abuse as judged by the Investigator.
16. Current smokers or those who have smoked or used nicotine products within the previous 3 months.
17. History of alcohol abuse or excessive intake of alcohol defined as an average weekly intake of >21 units or an average daily intake of >3 units for men or an average weekly intake of >14 units or an average daily intake of >2 units for women. One unit is equivalent to a half pint (250 mL) of beer, 1 measure (25 mL) of spirits, or 1 glass (125 mL) of wine. If a subject is currently diagnosed with abuse of or dependence on alcohol, the subject will not be allowed to enroll in the study, unless the alcohol abuse/dependence is in full (complete, not partial), sustained (>1 year) remission.
18. Positive screen for drugs of abuse at screening or admission to the unit or positive screen for alcohol at screening to the unit prior to administration of IP.
19. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD4041.
20. Plasma donation within 1 month of screening or any blood donation/blood loss >500 mL during the 3 months prior to screening.
21. Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as judged by the Investigator.
22. Use of drugs with enzyme inducing properties, such as St John's wort, within 3 weeks prior to administration of IP.
23. Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to administration of IP or longer if the medication has a long half life.
24. Use of any prescribed or nonprescribed oral and topical inhibitors/inducers of CYP3A4 (including shampoo).
25. Use of hormone replacement therapy.
26. Subjects who have previously received AZD4041.
27. Has received another new chemical entity (defined as a compound that has not been approved for marketing) within 3 months of administration of IP in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit, whichever is the longest. Note: subjects consented and screened, but not randomized in this study or a previous Phase I study, are not excluded.
28. Involvement of any AstraZeneca or study site employee or their close relatives.
29. Judgement by the Investigator that the subject should not participate in the study if they have any ongoing or recent (ie, during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.
30. Subjects who are vegans or have medical dietary restrictions.
31. Subjects who cannot communicate reliably with the Investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Administration by Oral syringe
Experimental: AZD4041	Drug: AZD4041; Administration by Oral syringe

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events	Number of participants experiencing any adverse event	6 weeks
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	Number of participants experiencing any treatment emergent adverse events	6 weeks
Number of Participants With Treatment-Related TEAEs	Number of participants experiencing any treatment-related TEAEs	6 weeks
Number of Participants With Moderate TEAEs	Number of participants experiencing any moderate TEAEs	6 weeks
Number of Participants With Treatment-Related Moderate TEAEs	Number of participants experiencing any treatment-related moderate TEAEs	6 weeks
Number of Participants With Severe TEAEs	Number of participants experiencing any severe TEAEs	6 weeks
Number of Participants With Treatment-Related Severe TEAEs	Number of participants experiencing any treatment-related severe TEAEs	6 weeks
Number of Participants With Serious Adverse Events (SAEs)	Number of participants experiencing any serious adverse events (SAEs)	6 weeks
Number of Participants With Treatment-Related SAEs	Number of participants experiencing any treatment-related serious adverse events (SAEs)	6 weeks
Number of Participants With TEAEs Leading to Early Discontinuation	Number of participants with treatment-emergent adverse events leading to early discontinuation	6 weeks
Number of Participant Deaths	Number of participants who died	6 weeks
Number of Participants With Abnormal Vital Signs	Number of participants with treatment-related abnormal vital signs considered clinically significant or reported as a treatment-emergent adverse event by the investigator.	6 weeks
Number of Participants With Abnormal Vital Signs (Blood Pressure)	Number of participants with treatment-related abnormal blood pressure considered clinically significant or reported as a treatment-emergent adverse event by the investigator	6 weeks
Number of Participants With Abnormal Vital Signs (Heart Rate)	Number of participants with treatment-related abnormal heart rate considered clinically significant or reported as a treatment-emergent adverse event by the investigator	6 weeks
Pulse Rate at Baseline and Day 1 2 Hours Post.	Measured by standing pulse rate at baseline and 2 hours post	Baseline and Day 1
Number of Participants With Abnormal Safety Laboratory Tests (Hematology)	Number of participants with treatment-related abnormal hematology values considered clinically significant or reported as a treatment-emergent adverse event by the investigator	6 weeks
Number of Participants With Abnormal Safety Laboratory Tests (Serum Chemistry)	Number of participants with treatment-related abnormal serum chemistry values considered clinically significant or reported as a treatment-emergent adverse event by the investigator	6 weeks
Number of Participants With Abnormal Safety Laboratory Tests (Urinalysis)	Number of participants with treatment-related abnormal urinalysis values considered clinically significant or reported as a treatment-emergent adverse event by the investigator	6 weeks
Number of Participants With Abnormal 12-lead ECGs	Number of participants with abnormal 12-lead electrocardiograms (ECGs), considered clinically significant or reported as a treatment-emergent adverse event by the investigator	4 days
Heart Rate at Baseline and Times Post Dose	Measured by digital electrocardiograms (ECGs)	Thru Day 4
Aggregate P-R Interval at Baseline and Time Post Dose	PR interval is the time from the beginning of atrial depolarization to the onset of ventricular depolarization. Measured by digital electrocardiograms (ECGs)	Thru Day 4
Aggregate QRS Complex at Baseline and Times Post Dose	QRS complex represents the electrical impulse as it spreads through the ventricles and indicates ventricular depolarization. Measured by digital electrocardiograms (ECGs)	Thru Day 4
Aggregate QT Interval at Baseline and Times Post Dose	The QT interval is measured from the beginning of the QRS complex to the end of the T wave and primarily represents the return of stimulated ventricles to their resting state (ventricular repolarization). Measured by digital electrocardiograms (ECGs)	Thru Day 4
Aggregate QTcF Interval and Times Post Dose	The QTcF if the QT interval corrected for heart rate using Fridercia's formula. Measured by digital electrocardiograms (ECGs)	Thru Day 4
Aggregate RR Interval at Baseline and Times Post Dose	The RR interval the time elapsed between two successive R waves of the QRS signal on the electrocardiogram. Measured by digital electrocardiograms (ECGs)	Thru Day 4
Number of Participants With Abnormal Testosterone Test Results	Number of participants with abnormal testosterone levels test results, considered clinically significant or reported as a treatment-emergent adverse event by the investigator	Thru Day 4
Number of Participants With Abnormal Luteinizing Hormone Test Results	Number of participants with abnormal luteinizing hormone (LH) levels test results, considered clinically significant or reported as a treatment-emergent adverse event by the investigator	Thru Day 4
Number of Participants With Abnormal Follicle Stimulating Hormone Test Results	Number of participants with abnormal follicle stimulating hormone (FSH) levels test results, considered clinically significant or reported as a treatment-emergent adverse event by the investigator	Thru Day 4
Number of Participants With Abnormal Inhibin B Test Results	Number of participants with abnormal Inhibin B levels test results, considered clinically significant or reported as a treatment-emergent adverse event by the investigator	Thru Day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of AZD4041	Maximum (peak) plasma concentration of AZD4041	Thru Day 4
Tmax of AZD4041	Time to reach maximum (peak) plasma concentration of AZD4041	Thru Day 4
AUC0-t	Area under the curve of AZD4041 from time 0 to time t (AUC from zero to the last measurable concentration)	Thru Day 4
AUC0-inf	Extrapolation of the area under the curve of AZD4041 from zero to infinity	Thru Day 4
t1/2λz	Terminal half-life of AZD4041	Thru Day 4
CL/F (Volume/Time)	Apparent total clearance of the AZD4041 from plasma	Thru Day 4
Vss/F (Plasma)	Apparent volume of distribution of AZD4041 at steady state	Thru Day 4

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: National Institutes of Health (NIH); Eolas Therapeutics INC.
• Investigators: Principal Investigator: Rebecca N. Wood-Horrall, MD, PPD; Principal Investigator: Darin Brimhall, DO, FACP, PPD

Publications and helpful links

Helpful Links

• CSR Synopsis

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2019
• Primary Completion (Actual): January 2, 2022
• Study Completion (Actual): January 2, 2022

Study Registration Dates

• First Submitted: August 6, 2019
• First Submitted That Met QC Criteria: August 30, 2019
• First Posted (Actual): September 3, 2019

Study Record Updates

• Last Update Posted (Actual): July 17, 2024
• Last Update Submitted That Met QC Criteria: June 20, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Healthy Volunteers; Tolerability
• Other Study ID Numbers: D7460C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymised individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• 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 refer 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 sponsor 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: Yes
• Studies a U.S. FDA-regulated device product: No