Clinical trial NCT04492709: A Study to Assess the Effect of Multiple Doses of AZD5718 on Pharmacokinetics of Oral Midazolam in Healthy Subjects
Official title: A Fixed Sequence, Open-Label Study to Assess the Effect of Multiple Doses of AZD5718 on the Pharmacokinetics of Oral Midazolam (a CYP450 3A Probe) in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cardiovascular Disease
Keywords: AZD5718, CYP3A4 substrate, Drug-drug Interaction, Fixed sequence, Midazolam, Open-label, Pharmacokinetics
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2020-07-30
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Fixed sequence
Primary purpose: OTHER

Brief summary: In clinical practice, AZD5718 will be co-administered with CYP3A substrates. Therefore, it is important to determine the impact of AZD5718 on the pharmacokinetics (PK) of CYP3A4 substrates. The primary objective of this study is to evaluate the effect of AZD5718 on the PK of midazolam, a known sensitive CYP3A4 substrate.

Detailed description: This is a Phase 1, fixed sequence, open-label study in healthy subjects, performed at a single study center. This study will consist of 3 treatment periods to assess the PK of midazolam when administered alone and in combination with multiple doses of AZD5718.

The study will comprise:

* A screening period of maximum 28 days;
* Three treatment periods during which subjects will be resident from the day before first dosing (Day -1) until at least 24 hours after last dosing (Day 7); discharged on the morning of Day 8, and;
* A final Follow-up Visit within 5 to 7 days after the last administration of investigational medicinal product (IMP).

Eligibility criteria: Inclusion Criteria:

* Provision of signed and dated, written informed consent prior to any study specific procedures.
* Healthy male and female subjects aged 18 to 55 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
* Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling one of the following criteria:

  1. Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone levels in the postmenopausal range.
  2. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
* Male subject must adhere to the contraception methods details.
* Have a body mass index between 18.5 and 30 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive.

Exclusion Criteria:

* History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study.
* History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
* History or presence of acute pulmonary insufficiency, marked neuromuscular respiratory weakness, obsessional states, phobic states, sleep apnea syndrome, or unstable myasthenia gravis.
* Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
* Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, at screening and/or on admission to the Clinical Unit, as judged by the Investigator, including:

  1. Alanine aminotransferase \> 1.5 x upper limit of normal (ULN);
  2. Aspartate aminotransferase \> 1.5 x ULN;
  3. Bilirubin (total) \> 1.5 x ULN; and
  4. Gamma glutamyl transpeptidase \> 1.5 x ULN.
* Any clinically significant abnormal findings in vital signs (blood pressure and pulse; supine) at screening and/or admission to the Clinical Unit, as judged by the Investigator.
* Any clinically significant abnormalities on 12-lead electrocardiogram at screening, as judged by the Investigator.
* Any positive result on screening for serum hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus antibody.
* Known or suspected Gilbert syndrome.
* Known or suspected history of drug abuse in the last 2 years, as judged by the Investigator.
* Has received another new chemical or biological entity within 3 months of the first administration of IMP 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.
* Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.
* History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator. History of hypersensitivity to drugs with a similar chemical structure or class to AZD5718 or known hypersensitivity to benzodiazepines or to any formulation excipients.
* Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening.
* Positive screen for drugs of abuse or cotinine at screening or on admission to the study unit, or positive screen for alcohol on screening or on admission to the study unit.
* Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
* Use of any prescribed (other than hormone-replacement therapy for females) or non-prescribed 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 the first administration of IMP or longer if the medication has a long half-life.
* Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate) as judged by the Investigator. Excessive intake of caffeine defined as the regular consumption of more than 600 mg of caffeine per day or would likely be unable to refrain from the use of caffeine-containing beverages during confinement at the investigational site.
* Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the Investigator. Excessive intake of alcohol defined as the regular consumption of more than 24 g of alcohol per day for men or 12 g of alcohol per day for women.
* Involvement of any AstraZeneca, Parexel, or study site employee or their close relatives.
* Subjects who have previously received AZD5718.
* Subjects with history of lactose intolerance.
* Judgment by the Investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., 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.
* Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
* Subjects who cannot communicate reliably with the Investigator.

Primary outcomes:
measure: Maximum observed plasma peak concentration (Cmax) of midazolam
timeFrame: Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours (h) post-dose
measure: Area under plasma concentration-time curve from time zero to infinity (AUCinf) of midazolam
timeFrame: Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 h post-dose
measure: Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of midazolam
timeFrame: Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 h post-dose
measure: Time to reach maximum observed plasma concentration (tmax) of midazolam
timeFrame: Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 h post-dose
measure: Half-life (t1/2) of midazolam
timeFrame: Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 h post-dose
measure: Plasma concentrations of AZD5718
timeFrame: Day 2-Day 7: at trough and Day 7: 4 h post-dose
Secondary outcomes:
measure: Number of subjects with adverse events (AEs) and serious AEs
timeFrame: AE: From Day 1 to post-treatment follow-up visit (Day 13); SAE: From screening to post-treatment follow-up visit (Day 13)
measure: Number of subjects with abnormal 12-lead electrocardiogram (ECG)
timeFrame: At screening and post-treatment follow-up visit (Day 13)
measure: Number of subjects with abnormal physical examination
timeFrame: At screening, Day -1, Day 1, Day 4, Day 7, Day 8, and post-treatment follow-up visit (Day 13)
measure: Number of subjects with abnormal blood pressure (BP)
timeFrame: For approximately 6 weeks (from screening to post-treatment follow-up)
measure: Number of subjects with abnormal pulse rate
timeFrame: For approximately 6 weeks (from screening to post-treatment follow-up)
measure: Number of subjects with abnormal oxygen saturation levels
timeFrame: On Day 1 and Day 7: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8 and 12 h post-dose
measure: Number of subjects with abnormal hematology parameters
timeFrame: At screening, Day -1, Day 1 (pre-dose), Day 2 and Day 4 (pre-dose), Day 7 (pre-dose), Day 8, and post-treatment follow-up visit (Day 13)
measure: Number of subjects with abnormal clinical chemistry parameters
timeFrame: At screening, Day -1, Day 1 (pre-dose), Day 2 and Day 4 (pre-dose), Day 7 (pre-dose), Day 8, and post-treatment follow-up visit (Day 13)
measure: Number of subjects with abnormal urine analysis parameters
timeFrame: At screening, Day -1, Day 1 (pre-dose), Day 2 and Day 4 (pre-dose), Day 7 (pre-dose), Day 8, and post-treatment follow-up visit (Day 13)
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Parexel Early Phase Clinical Unit London
name: Dr. Pablo Forte Soto, MD, MSc, PhD
role: PRINCIPAL_INVESTIGATOR
References: