Clinical trial NCT04076540: A Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4041 in Healthy Volunteers
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Smoking Cessation
Keywords: Safety
Tolerability
Pharmacokinetics
Healthy Volunteers
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: National Institutes of Health (NIH)
name: Eolas Therapeutics INC.
First posted: 2019-09-03
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Adverse Events
timeFrame: 6 weeks
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: 6 weeks
measure: Number of Participants With Treatment-Related TEAEs
timeFrame: 6 weeks
measure: Number of Participants With Moderate TEAEs
timeFrame: 6 weeks
measure: Number of Participants With Treatment-Related Moderate TEAEs
timeFrame: 6 weeks
measure: Number of Participants With Severe TEAEs
timeFrame: 6 weeks
measure: Number of Participants With Treatment-Related Severe TEAEs
timeFrame: 6 weeks
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: 6 weeks
measure: Number of Participants With Treatment-Related SAEs
timeFrame: 6 weeks
measure: Number of Participants With TEAEs Leading to Early Discontinuation
timeFrame: 6 weeks
measure: Number of Participant Deaths
timeFrame: 6 weeks
measure: Number of Participants With Abnormal Vital Signs
timeFrame: 6 weeks
measure: Number of Participants With Abnormal Vital Signs (Blood Pressure)
timeFrame: 6 weeks
measure: Number of Participants With Abnormal Vital Signs (Heart Rate)
timeFrame: 6 weeks
measure: Pulse Rate at Baseline and Day 1 2 Hours Post.
timeFrame: Baseline and Day 1
measure: Number of Participants With Abnormal Safety Laboratory Tests (Hematology)
timeFrame: 6 weeks
measure: Number of Participants With Abnormal Safety Laboratory Tests (Serum Chemistry)
timeFrame: 6 weeks
measure: Number of Participants With Abnormal Safety Laboratory Tests (Urinalysis)
timeFrame: 6 weeks
measure: Number of Participants With Abnormal 12-lead ECGs
timeFrame: 4 days
measure: Heart Rate at Baseline and Times Post Dose
timeFrame: Thru Day 4
measure: Aggregate P-R Interval at Baseline and Time Post Dose
timeFrame: Thru Day 4
measure: Aggregate QRS Complex at Baseline and Times Post Dose
timeFrame: Thru Day 4
measure: Aggregate QT Interval at Baseline and Times Post Dose
timeFrame: Thru Day 4
measure: Aggregate QTcF Interval and Times Post Dose
timeFrame: Thru Day 4
measure: Aggregate RR Interval at Baseline and Times Post Dose
timeFrame: Thru Day 4
measure: Number of Participants With Abnormal Testosterone Test Results
timeFrame: Thru Day 4
measure: Number of Participants With Abnormal Luteinizing Hormone Test Results
timeFrame: Thru Day 4
measure: Number of Participants With Abnormal Follicle Stimulating Hormone Test Results
timeFrame: Thru Day 4
measure: Number of Participants With Abnormal Inhibin B Test Results
timeFrame: Thru Day 4
Secondary outcomes:
measure: Cmax of AZD4041
timeFrame: Thru Day 4
measure: Tmax of AZD4041
timeFrame: Thru Day 4
measure: AUC0-t
timeFrame: Thru Day 4
measure: AUC0-inf
timeFrame: Thru Day 4
measure: t1/2λz
timeFrame: Thru Day 4
measure: CL/F (Volume/Time)
timeFrame: Thru Day 4
measure: Vss/F (Plasma)
timeFrame: Thru Day 4
Other outcomes:
Locations:
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: Austin
country: United States
facility: Research Site
state: Texas
Study officials:
affiliation: PPD Development, LP
name: Rebecca N. Wood-Horrall, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PPD Development, LP
name: Darin Brimhall, DO, FACP
role: PRINCIPAL_INVESTIGATOR
References: