Assess the Safety, Tolerability and Pharmacokinetics of AZD5055 Following Single and Multiple Ascending Doses in Healthy Participants

Study Overview
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Brief Summary
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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.

Detailed Description
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Part 1: This is a double-blind, randomized, placebo-controlled study consisting of 2 parts. Part 1: SAD and Part 2: MAD. Part 1 will be a double-blind, randomized, placebo-controlled study, with a sequential SAD design. Three dose levels of AZD5055 are planned to be investigated in 3 cohorts. Depending on evaluation of data from the preceding cohorts, 2 additional cohorts/dose levels may be added at the discretion of the SRC. Part 1 will comprise of: A Screening Period of a maximum of 6 weeks. A Treatment Period during which subjects will be resident at the Clinical Unit from 1 day before IMP administration (Day 1) until at least 72 hours after IMP administration (Day 4). Subjects will receive a single oral dose of AZD5055 or placebo on Day 1. A Follow up Visit within 6 ± 1 day after the IMP dose. Part 2 will be a double-blind, randomized, placebo-controlled study with a MAD design. Subjects will receive AZD5055 on Day 1 and Day 3 to Day 16, with no dosing on Day 2. Subjects will be naïve, ie, will not have participated in Part 1 of this study. Three dose levels of AZD5055 are planned to be investigated in 3 cohorts. Depending on evaluation of data of the preceding cohorts, up to 2 additional dose levels/cohorts may be added or expanded at the discretion of the SRC. Part 2 will comprise of: A Screening Period of a maximum of 6 weeks. A treatment period with a dosing frequency (QD or BID) that will be dependent on emerging PK data from Part 1: A) For cohorts with QD dosing regimens: • A Treatment Period during which subjects will be resident at the Clinical Unit from 1 day before IMP administration (Day -1) until at least 72 hours after the last dose given on Day 16 (Day 19). Subjects will be dosed for a total of 15 days, receiving a single QD morning dose of AZD5055 or placebo on Day 1 and on Days 3 through Day 16. B) For cohorts with BID dosing regimens: A Treatment Period during which subjects will be resident at the Clinical Unit from 1 day before IMP administration (Day -1) until at least 72 hours after the last dose given on Day 16 (Day 19). Subjects will be dosed for a total of 15 days, receiving a single morning dose of AZD5055 or placebo on Day 1 and Day 16, and repeated BID dosing on Day 3 through Day 15, 12 hours (± 30 minutes) apart. A Follow-up Visit within 6 ± 1 day after the last IMP dose, and an additional Follow up Visit within 29 ± 2 days after the last IMP dose.

Official Title
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A Double-blind, Randomized, Placebo-controlled Study in Healthy Volunteers to Investigate the Safety, Tolerability and Pharmacokinetics of Oral AZD5055 Following Single and Multiple Ascending Doses

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: AZD5055
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Healthy male and female (of non-childbearing potential) subjects aged Part 1 (SAD): 18 - 55 years; Part 2 (MAD): 18 - 55 for male and 18 -49 for females, inclusive, with suitable veins for cannulation or repeated venipuncture. Female subjects must have a negative pregnancy test. Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg. 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 17 days after the last dose of Investigational medicinal product. Exclusion Criteria 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. Untreated tuberculosis (TB) or a positive result for the interferon gamma release assay (ie, QuantiFERON TB Gold). A positive result for serum hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody, at the Screening Visit. Ongoing acquired or inherited immunodeficiency disorders, including but not limited to HIV or common variable immunodeficiency, or the subject is taking immune replacement therapy. 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. 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). Confirmed COVID-19 infection during Screening and/or admission by reverse transcription polymerase chain reaction (RT-PCR) test. Subjects who previously had a positive test result during the screening visit or on Day-1 may be reconsidered for inclusion after they recover from the infection as confirmed by a negative retest before (re-)admission. 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. History of osteoporosis, osteomalacia, Paget's disease of the bone, thyrotoxicosis, rheumatoid arthritis, Cushing's disease, or a pathological fracture. History of a traumatic fracture within 6 months of the Screening visit. 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). 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. 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. History of Gilbert's syndrome. History of muscle disease or rhabdomyolysis. Any laboratory values with the deviations at the Screening Visit and/or Day -1 from the reference range. Any clinically important abnormalities in clinical chemistry, hematology, or urinalysis. 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. Known or suspected history of drug abuse. Current smokers who smoke > 5 cigarettes/e-cigarette/pipes per week or use of any tobacco in any other form. History of alcohol abuse or excessive intake of alcohol within 6 months prior to screening. Positive screen for drugs of abuse or alcohol at screening or admission. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity. Plasma donation within 1 month of Screening or any blood donation/loss > 500 mL within 3 months of Screening. 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. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP. Excessive intake of high caffeine-containing drinks or food (eg, coffee, tea, energy drinks). 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. Subjects who are vegans or have medical dietary restrictions.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 (single ascending doses [SAD])<br>Healthy participants will be randomized to a single dose of AZD5055 or placebo. | Drug: AZD5055<br>* Healthy participants will receive AZD5055<br>Drug: Placebo<br>* Healthy participants will receive placebo<br>|
| Experimental: Part 2 (multiple ascending doses [MAD])<br>Healthy participants will be randomized to repeated dosing with AZD5055 or placebo | Drug: AZD5055<br>* Healthy participants will receive AZD5055<br>Drug: Placebo<br>* Healthy participants will receive placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of participants with adverse events (AEs) | To investigate the safety and tolerability of AZD5055 by assessment of AEs (non-serious and serious) following administration of SAD | Until Follow-up (7 days post dose) (approximately up to 53 days) | 
| Part 2: Number of participants with AEs | To investigate the safety and tolerability of AZD5055 by assessment of AEs (non-serious and serious) following administration of MAD | Until follow-up (45 days post-last dose) (approximately up to 89 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximum observed plasma (peak) drug concentration (Cmax) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Maximum observed plasma (peak) drug concentration (Cmax) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 1: Area under plasma concentration time curve from zero to infinity (AUCinf) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose | 
| Part 1: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 1: Time to reach maximum observed concentration (tmax) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Time to reach maximum observed concentration (tmax) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 2: Area under plasma concentration-time curve in the dose interval (repeat dose only) (AUC[0-1τ]) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 1: Partial area under the plasma concentration-time curve from 0 to time 12 hours post dose [AUC(0-12)] | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Partial area under the plasma concentration-time curve from 0 to time 12 hours post dose [AUC(0-12)] | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 1: Partial area under the plasma concentration-time curve from 0 to time 24 hours post dose [AUC(0-24)] | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Partial area under the plasma concentration-time curve from 0 to time 24 hours post dose [AUC(0-24)] | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 1: Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 1: Mean residence time of the unchanged drug in the systemic circulation (MRTinf) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Mean residence time of the unchanged drug in the systemic circulation (MRTinf) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose | 
| Part 1: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 1: Apparent volume of distribution following extravascular administration based on terminal phase (Vz/F) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose. | 
| Part 2: Apparent volume of distribution following extravascular administration based on terminal phase (Vz/F) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 1: Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1-3 and Day 16-19 | 
| Part 1: Cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)] | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)] | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1-3 and Day 16-19 | 
| Part 1: Renal clearance of drug from plasma (CLR) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Renal clearance of drug from plasma (CLR) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1-3 and Day 16-19 | 
| Part 1: Accumulation ratio (Rac) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Accumulation ratio (Rac) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 
| Part 1: Temporal change parameter in systemic exposure (TCP) | To characterize the PK of AZD5055 following oral administration of SAD to healthy participants | Day 1: profile 0-72 hours after dose | 
| Part 2: Temporal change parameter in systemic exposure (TCP) | To characterize the PK of AZD5055 following oral administration of MAD to healthy participants | Day 1: profile 0-48 hours after dose, Day 16; profile 0-72 hours after dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD5055, Single ascending dose, Multiple ascending dose, Porcupine (PORCN) inhibitor, Healthy participants, Oral suspension