Assess the Safety, Tolerability and Pharmacokinetics of AZD5055 Following Single and Multiple Ascending Doses in Healthy Participants
Study Details
Study Description
Brief Summary
This is a phase I, First-in-Human study in healthy participants, performed at a single study center, consisting of 2 parts: Part 1 is a single ascending dose (SAD) study and Part 2 is a multiple ascending dose (MAD) study.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
Part 1: This is a double-blind, randomized, placebo-controlled study consisting of 2 parts. Part 1: SAD and Part 2: MAD. Part 1 consist of two parts: 1a and 1b.
Part 1a will be a sequential SAD design. Each cohort (1, 2, 3, 4 and 5) participants will be randomized to receive AZD5055 or placebo. There will a screening period of a maximum of 6 weeks.
Part 1b will evaluate the effect of a high-fat meal on the safety, tolerability, and PK of a single oral dose of AZD5055. In Part 1b, there will a screening period of a maximum of 6 weeks (as in Part 1a) only for participants who have not previously participated in a Part 1a cohort. A washout period of at least 4 days after IMP administration in Part 1a.
For Part 1: Depending on the evaluation of data from the preceding cohorts, up to 2 additional cohorts/dose levels may be added at the discretion of the Safety Review Committee (SRC). For Part 2: Depending on the evaluation of data from the preceding cohorts, up to 1 additional cohort may be added or expanded at the discretion of the SRC.
Part 2: This will be a 14-day, MAD design. Participants will be naïve, ie, will not have participated in Part 1 of this study. Three different dose levels of AZD5055 are planned to be investigated in 3 cohorts. In each cohort (1, 2 and 3) subjects will be randomized to receive AZD5055 or placebo.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part 1a - fasted state Healthy participants will be randomized to a single dose of AZD5055 or placebo. |
Drug: AZD5055
Healthy participants will receive AZD5055
Drug: Placebo
Healthy participants will receive placebo
|
| Experimental: Part 1b - fed state Healthy participants will be randomized to a single dose of AZD5055 or placebo. |
Drug: AZD5055
Healthy participants will receive AZD5055
Drug: Placebo
Healthy participants will receive placebo
|
| Experimental: Part 2 Healthy participants will be randomized to repeated dosing with AZD5055 or placebo |
Drug: AZD5055
Healthy participants will receive AZD5055
Drug: Placebo
Healthy participants will receive placebo
|
Outcome Measures
Primary Outcome Measures
- Part 1a and 1b: Number of participants with adverse events (AEs) [Until Follow-up (7 days post dose) (approximately up to 53 days)]
To investigate the safety and tolerability of AZD5055 by assessment of AEs (non-serious and serious) following administration of single ascending doses (SAD)
- Part 2: Number of participants with AEs [Until follow-up (45 days post-last dose) (approximately up to 89 days)]
To investigate the safety and tolerability of AZD5055 by assessment of AEs (non-serious and serious) following administration of multiple ascending doses (MAD)
Secondary Outcome Measures
- Part 1a and 1b: Maximum observed plasma (peak) drug concentration (Cmax) [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Maximum observed plasma (peak) drug concentration (Cmax) [Day 1 and Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of multiple ascending doses to healthy participants
- Part 1a and 1b: Area under plasma concentration time curve from zero to infinity (AUCinf) [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf) [Day 1: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of multiple ascending doses to healthy participants
- Part 1a and 1b: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) [Day 1: profile pre-dose to 48 h after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) [Day 1: profile pre-dose to 24 hours after dose. Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Time to reach maximum observed concentration (tmax) [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Time to reach maximum observed concentration (tmax) [Day 1: profile pre-dose to 24 hours . Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Partial area under the plasma concentration-time curve from 0 to time 12 hours post dose [AUC(0-12)] [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Partial area under the plasma concentration-time curve from 0 to time 12 hours post dose [AUC(0-12)] [Day 1: profile pre-dose to 24 hours after dose. Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Partial area under the plasma concentration-time curve from 0 to time 24 hours post dose [AUC(0-24)] [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Partial area under the plasma concentration-time curve from 0 to time 24 hours post dose [AUC(0-24)] [Day 1: profile pre-dose to 24 hours after dose. Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) [Day 1: profile pre-dose to 24 hours after dose. Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Mean residence time of the unchanged drug in the systemic circulation (MRTinf) [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Mean residence time of the unchanged drug in the systemic circulation (MRTinf) [Day 1: profile pre-dose to 24 hours after dose . Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) [Day 1: profile pre-dose to 24 hours after dose. Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Apparent volume of distribution following extravascular administration based on terminal phase (Vz/F) [Day 1: profile pre-dose to 48 hours after dose.]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Apparent volume of distribution following extravascular administration based on terminal phase (Vz/F) [Day 1: profile pre-dose to 24 hours after dose . Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] [Day 1 and Day 14]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)] [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)] [Day 1 and Day 14]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 1a and 1b: Renal clearance of drug from plasma (CLR) [Day 1: profile pre-dose to 48 hours after dose]
To characterize the PK of AZD5055 and the effect of a high-fat meal on the PK of AZD5055 following oral administration of SAD to healthy participants
- Part 2: Renal clearance of drug from plasma (CLR) [Day 1 and Day 14]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 2: Accumulation ratio (Rac) [Day 1: profile pre-dose to 24 hours after dose. Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
- Part 2: Temporal change parameter in systemic exposure (TCP) [Day 1: profile pre-dose to 24 hours after dose. Day 14: profile pre-dose to 24 hours after dose]
To characterize the PK of AZD5055 following oral administration of MAD to healthy participants
Eligibility Criteria
Criteria
Inclusion Criteria
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Healthy male and female (of non-childbearing potential) subjects aged 18 to 45 years, inclusive, with suitable veins for cannulation or repeated venipuncture.
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Female subjects must have a negative pregnancy test.
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Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg.
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Male subjects and their women of childbearing potential partners must be willing to use highly effective contraception measures and must refrain from donating sperm or fathering a child from the first day of dosing until 15 days after the last dose of Investigational medicinal product.
Exclusion Criteria
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History of any clinically important disease or disorder, or a major medical/surgical procedure or significant trauma within 4 weeks of the first dose of IMP.
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Untreated tuberculosis (TB) or a positive result for the interferon gamma release assay (ie, QuantiFERON TB Gold).
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A positive result for serum hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody, at the Screening Visit.
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Ongoing acquired or inherited immunodeficiency disorders, including but not limited to HIV or common variable immunodeficiency, or the subject is taking immune replacement therapy.
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Individuals with chronic infections (eg, urinary tract infection) or who are at increased risk of infection (eg, surgery, trauma, severe dental disease, or significant infection) within 30 days of screening.
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History of severe COVID-19 infection requiring hospitalization within the last 12 months prior to Screening, or clinical history compatible with Long COVID 19 (symptoms beyond 12 weeks of acute infection).
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Confirmed COVID-19 infection during Screening and/or admission by reverse transcription polymerase chain reaction (RT-PCR) test.
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History of cancer within the last 10 years (20 years for breast cancer) except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured. Any history of lymphoma is not allowed.
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History of osteoporosis, osteomalacia, Paget's disease of the bone, thyrotoxicosis, rheumatoid arthritis, Cushing's disease, or a pathological fracture.
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History of a traumatic fracture within 6 months of the Screening visit.
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A Bone density scans (DEXA scan) bone mineral density value with T-score < -1 for post-menopausal women and Z score < -1.5 for male participants and premenopausal women of non-childbearing potential subjects (MAD cohorts only).
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Has received live or live attenuated vaccine in the 30 days prior to dosing, the first dose of COVID-19 vaccine within 30 days prior to randomization, or a COVID 19 vaccine second or booster vaccination within 10 days of screening.
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Ongoing acute gastrointestinal (GI) disease, a history of chronic GI disease, ongoing acute hepatic disease, or a history of chronic hepatic disease, chronic renal disease, pancreatic disease, diabetes mellitus, or any condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
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History of Gilbert's syndrome.
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History of muscle disease or rhabdomyolysis.
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Any laboratory values with the deviations at the Screening Visit and/or Day -1 from the reference range.
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Any clinically important abnormalities in clinical chemistry, hematology, or urinalysis.
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Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12 lead ECG that may interfere with the interpretation of QTc interval changes, including abnormal ST wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy.
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Known or suspected history of drug abuse.
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Current smokers who smoke > 5 cigarettes/e-cigarette/pipes per week or use of any tobacco in any other form.
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History of alcohol abuse or excessive intake of alcohol within 6 months prior to screening.
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Positive screen for drugs of abuse or alcohol at screening or admission.
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History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity.
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Plasma donation within 1 month of Screening or any blood donation/loss > 500 mL within 3 months of Screening.
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Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), HRT (for females), herbal remedies, mega dose vitamins and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half life.
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Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
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Excessive intake of high caffeine-containing drinks or food (eg, coffee, tea, energy drinks).
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Has received another new chemical entity (defined as a compound that has not been approved for marketing) within 3 months of the first administration of IMP in this study.
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Subjects who are vegans or have medical dietary restrictions.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Brooklyn | Maryland | United States | 21225 |
Sponsors and Collaborators
- AstraZeneca
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D8960C00001