A Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD7503 in Healthy Participants

Study Overview
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Brief Summary
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This study will evaluate safety, tolerability and pharmacokinetics (PK) of AZD7503, following subcutaneous (SC) administration of single ascending doses of AZD7503 in healthy participants.

Detailed Description
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This is a Phase I, First-in-Human, study in healthy males and females (non-childbearing potential) participants. In this study up to four dose levels of AZD7503 are planned to be evaluated. The planned doses of AZD7503 are dose 1, dose 2, dose 3, and dose 4. Eligible participants will be randomised to receive either AZD7503 or placebo. The study will include four single dose cohorts with an option to include two cohorts based on emerging data from planned cohorts in the study and two additional cohorts of Japanese participants and one cohort of Chinese participants will also be included. Dosing for each ascending dose cohort will be proceeded with sentinel dosing strategy. Here, sentinel sub-cohort will be included, such that 1 participant will be randomised to receive placebo and 1 participant will be randomised to receive AZD7503. The safety data from the sentinel participants up to 24 hours post-dose will be reviewed by the Principal Investigator (PI) before the remaining participants in the cohort are dosed The study will comprise: A Screening Period of maximum 28 days; A Treatment Period during which participants will be resident at the Study Centre from the day before study medication administration (Day -1) until at least 72 hours after study medication administration; discharged from the Study Centre on Day 4; Follow-up Visits on 1,2,4,6 and 8 weeks; and A Final Follow-up Visit 10 weeks after the last study medication dose. Each participant will be involved in the study for approximately 14 weeks.

Official Title
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A Phase I Randomised Single-blind Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD7503 Following Single Ascending Dose Administration to Healthy Participants

Conditions
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Safety, Tolerability, Pharmacokinetics, Healthy Participants

Intervention / Treatment
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* Drug: AZD7503
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy non smoking male and/or female (of non childbearing potential) participants with suitable veins for cannulation or repeated venipuncture. Females must have a negative pregnancy test at screening and on admission to the study centre, must not be lactating and must be of non childbearing potential. Body mass index (BMI) between 18 and 30 kg/m^2, inclusive, and weigh at least 60 kg for healthy participants or between 18 and 32 kg/m^2, inclusive, and weigh at least 50 kg for Japanese and Chinese participants. For Japanese and Chinese participants: A Japanese participant is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes first-, second-and third-generation Japanese whose parents or grandparents are living in a country other than Japan. A Chinese participant is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes first-, second-and third-generation Chinese whose parents or grandparents are living in a country other than China. Willing to participate in retrospective genotyping analysis for HSD17B13. Exclusion Criteria: History of any clinically important disease or disorder. History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of administration of study intervention. Any laboratory values with the following deviations at screening and/or Day 1: Alanine aminotransferase > Upper Limit of Normal (ULN) Aspartate aminotransferase > ULN Total bilirubin > ULN Creatinine > ULN White blood cell count < Lower Limit of Normal (LLN) Hemoglobin < LLN Estimated glomerular filtration rate < 60 mL/min/1.73 m^2 Platelets >ULN and/or <LLN. Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results other than those described above, including participants with platelet or bleeding disorders, known platelet dysfunction disorders. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody or Human Immunodeficiency Virus. Confirmed coronavirus disease 2019 (COVID-19) infection during screening and/or admission by polymerase chain reaction (PCR) test. Abnormal vital signs, after 5 minutes supine rest Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12 lead ECG. Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the previous 3 months. History of alcohol abuse or excessive intake of alcohol History of Drug abuse or positive screen for drug of abuse or cotinine (nicotine) or alcohol. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7503. Excessive intake of caffeine containing drinks or food (eg, coffee, tea, chocolate) Use of any prescribed or non prescribed medication during the 2 weeks prior to the administration of study intervention or longer if the medication has a long half-life. Plasma donation within one month of screening or any blood donation/blood loss more than 500 mL during the 3 months prior to screening. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days (or 5 half lives, whichever is longer) of the administration of study intervention in this study. Any ongoing or recent (ie, during the screening period) minor medical complaints. Previous bone marrow transplant. Non leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: AZD7503 dose 1<br>Randomised healthy participants will receive a single dose 1 of AZD7503. | Drug: AZD7503<br>* Randomised participants will receive a single ascending dose of AZD7503 by SC injection (dose 1, dose 2, dose 3, dose 4, dose X and dose Y).<br>|
| Experimental: Cohort 2: AZD7503 dose 2<br>Randomised healthy participants will receive a single dose 2 of AZD7503. | Drug: AZD7503<br>* Randomised participants will receive a single ascending dose of AZD7503 by SC injection (dose 1, dose 2, dose 3, dose 4, dose X and dose Y).<br>|
| Experimental: Cohort 3: AZD7503 dose 3<br>Randomised healthy participants will receive a single dose 3 of AZD7503. | Drug: AZD7503<br>* Randomised participants will receive a single ascending dose of AZD7503 by SC injection (dose 1, dose 2, dose 3, dose 4, dose X and dose Y).<br>|
| Experimental: Cohort 4: AZD7503 dose 4<br>Randomised healthy participants will receive a single dose 4 of AZD7503. | Drug: AZD7503<br>* Randomised participants will receive a single ascending dose of AZD7503 by SC injection (dose 1, dose 2, dose 3, dose 4, dose X and dose Y).<br>|
| Experimental: Cohort 5 : AZD7503 dose X<br>Randomised healthy participants will receive a single dose X of AZD7503. | Drug: AZD7503<br>* Randomised participants will receive a single ascending dose of AZD7503 by SC injection (dose 1, dose 2, dose 3, dose 4, dose X and dose Y).<br>|
| Experimental: Cohort 6: AZD7503 dose Y<br>Randomised healthy participants will receive a single dose Y of AZD7503. | Drug: AZD7503<br>* Randomised participants will receive a single ascending dose of AZD7503 by SC injection (dose 1, dose 2, dose 3, dose 4, dose X and dose Y).<br>|
| Placebo Comparator: Pooled Placebo for AZD7503 (Cohorts 1 to 6)<br>Randomised healthy participants will receive placebo. | Drug: Placebo<br>* Randomised participants will receive placebo by SC injection<br>|
| Experimental: Japanese Cohort 1: AZD7503 dose 3<br>Randomised healthy Japanese participants will receive a single dose 3 of AZD7503. | Drug: AZD7503<br>* Randomised participants will receive a single ascending dose of AZD7503 by SC injection (dose 1, dose 2, dose 3, dose 4, dose X and dose Y).<br>|
| Experimental: Japanese Cohort 2: AZD7503 dose 4<br>Randomised healthy Japanese participants will receive a single dose 4 of AZD7503. | Drug: AZD7503<br>* Randomised participants will receive a single ascending dose of AZD7503 by SC injection (dose 1, dose 2, dose 3, dose 4, dose X and dose Y).<br>|
| Placebo Comparator: Placebo (Japanese Cohorts)<br>Randomised healthy Japanese participants will receive placebo. | Drug: Placebo<br>* Randomised participants will receive placebo by SC injection<br>|
| Experimental: Chinese Cohort: AZD7503 dose 4<br>Randomised healthy Chinese participants will receive a single dose 4 of AZD7503. | Drug: AZD7503<br>* Randomised participants will receive a single ascending dose of AZD7503 by SC injection (dose 1, dose 2, dose 3, dose 4, dose X and dose Y).<br>|
| Placebo Comparator: Placebo (Chinese Cohort)<br>Randomised healthy Chinese participants will receive placebo. | Drug: Placebo<br>* Randomised participants will receive placebo by SC injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events (AEs) | To assess adverse events as a variable of safety and tolerability of AZD7503 following SC single dose administration. | Up to Final Follow-up (FU) Visit (Week 10) or Early Termination (ET) (assessed up to 14 Weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under plasma concentration time-curve from zero to infinity (AUCinf) of AZD7503 | To characterise the PK (AUCinf) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of AZD7503 | To characterise the PK (AUClast) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Maximum observed plasma (peak) drug concentration (Cmax) of AZD7503 | To characterise the PK (Cmax) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Time to reach peak or maximum observed concentration or response following drug administration (tmax) of AZD7503 | To characterise the PK (tmax) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Time of last observed (quantifiable) concentration (tlast) of AZD7503 | To characterise the PK (tlast) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Partial area under the plasma concentration-time curve from time 0 to time 48 hours post dose [AUC(0-48)] of AZD7503 | To characterise the PK [AUC(0-48)] of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Half-life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t½λz) of AZD7503 | To characterise the PK (t½λz) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Mean residence time of the unchanged drug in the systemic circulation (MRTinf) of AZD7503 | To characterise the PK (MRTinf) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of AZD7503 | To characterise the PK (CL/F) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Apparent volume of distribution at steady state following extravascular administration (Vz/F) of AZD7503 | To characterise the PK (Vz/F) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 and final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 
| Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] of AZD7503 | To characterise the PK [Ae(t1-t2)] of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 | 
| Percentage of dose excreted unchanged in urine from time t1 to t2 [Fe(t1-t2)] of AZD7503 | To characterise the PK [Fe(t1-t2)] of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 | 
| Renal clearance of drug from plasma (CLR) of AZD7503 | To characterise the PK (CLR) of AZD7503 following SC administration of single ascending doses of AZD7503. | (Pre-dose and Post-dose) Days 1 to 4 | 
| Number of participants with positive anti-drug antibodies (ADA) of AZD7503 | To explore the formation of ADAs. | Day -1 to final FU visit (Week 10 post last dose) or ET (assessed up to 14 Weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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First-in-Human, Placebo-controlled, AZD7503, Single Ascending Dose, Sentinel Dosing