A First-in-human Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD2373 After Single Dose Administration in Healthy Male Subjects of African Ancestry.

Study Overview
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Brief Summary
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This is a Phase 1 study to assess the the safety, tolerability and pharmacokinetics (PK) of AZD2373, following subcutaneous (SC) administration of single ascending doses (SAD) of AZD2373 in healthy male subjects of African ancestry.

Detailed Description
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This study will be conducted as a single-centre, randomised, placebo-controlled, single-blind study to assess the effect of AZD2373 following ascending dose sequential group design administrations to healthy male subjects of African ancestry. The study will include 6 single dose cohorts with the option to include 2 additional cohorts based on emerging data from preceding cohorts in the study. Approximately 48 male subjects aged 18 to 55 years at the time of informed consent (inclusive) will be randomized with the aim to have 8 subjects participate in each cohort. Within each cohort, 6 subjects will receive AZD2373 and 2 subjects will receive placebo. Sentinel dosing will be applied for each cohort and will be divided into 2 groups: Group 1 (sentinel group): 1 active, 1 placebo; Group 2 (the rest of the cohort): 5 active, 1 placebo. The safety data of up to 72 hours post-dose in Group 1 will be reviewed by the Principal Investigator (PI) before the subjects in Group 2 are dosed. The study will comprise: A Screening Period of maximum 35 days; A Treatment Period during which subjects will be resident at the Clinical Unit from the day before investigational medicinal product (IMP) administration (Day -1) until at least 72 hours after IMP administration; discharged from the Clinical Unit on Day 4; Follow-up Visits on 1, 1.5, 2, 3, 4, 5, 6, and 8 weeks (Visits 3 to 10); and A Final Follow up Visit 10 weeks after the last IMP dose. The visit occurring at 5 weeks post dose (Visit 5) is optional. The expected duration for any subject participating in the study is approximately 10 weeks (excluding an up to 28-day Screening Period).

Official Title
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A Phase I, First-in-Human, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD2373 Following Single Ascending Dose Administrations to Healthy Male Subjects of African Ancestry

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: AZD2373 subcutaneous injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated, written informed consent prior to any study specific procedures. Healthy male subjects of West African ancestry aged 18 to 55 years (inclusive, at time of informed consent) with suitable veins for cannulation or repeated venipuncture. Have a body mass index (BMI) between 18 and 35 kg/m^2 (inclusive) and weigh at least 50 kg and no more than 120 kg (inclusive). Provision of signed, written and dated informed consent for study participation which includes mandatory genotyping (study objective). NOTE: If a subject would decline to participate in the mandatory genotyping component of the study, the subject will not be included in the study. Exclusion Criteria: Subjects with known ancestry outside of West Africa. 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. 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 prior to administration of IMP on Study Day 1. Any laboratory values with the following deviations: Alanine aminotransferase or aspartate aminotransferase greater than upper limit of normal and clinically significant as determined by the PI. White blood cell (WBC) count < 3.0 x 10^9/L. Hemoglobin (Hb) below lower limit normal . Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results, other than those described above, as judged by the PI.

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

Sexes Eligible for Study
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Male

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<br>On Day 1, randomized subjects will receive a subcutaneous (SC) injection of AZD2373 dose 1 (6 subjects) or matching placebo (2 subjects). | Drug: AZD2373 subcutaneous injection<br>* Randomised subjects will receive a single ascending dose of AZD2373 by SC injection (dose 1, dose 2, dose 3, dose 4, dose 5 and dose 6).<br>Drug: Placebo<br>* Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.<br>|
| Experimental: Cohort 2<br>On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 2 (6 subjects) or matching placebo (2 subjects). | Drug: AZD2373 subcutaneous injection<br>* Randomised subjects will receive a single ascending dose of AZD2373 by SC injection (dose 1, dose 2, dose 3, dose 4, dose 5 and dose 6).<br>Drug: Placebo<br>* Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.<br>|
| Experimental: Cohort 3<br>On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 3 (6 subjects) or matching placebo (2 subjects). | Drug: AZD2373 subcutaneous injection<br>* Randomised subjects will receive a single ascending dose of AZD2373 by SC injection (dose 1, dose 2, dose 3, dose 4, dose 5 and dose 6).<br>Drug: Placebo<br>* Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.<br>|
| Experimental: Cohort 4<br>On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 4 (6 subjects) or matching placebo (2 subjects). | Drug: AZD2373 subcutaneous injection<br>* Randomised subjects will receive a single ascending dose of AZD2373 by SC injection (dose 1, dose 2, dose 3, dose 4, dose 5 and dose 6).<br>Drug: Placebo<br>* Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.<br>|
| Experimental: Cohort 5<br>On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 5 (6 subjects) or matching placebo (2 subjects). | Drug: AZD2373 subcutaneous injection<br>* Randomised subjects will receive a single ascending dose of AZD2373 by SC injection (dose 1, dose 2, dose 3, dose 4, dose 5 and dose 6).<br>Drug: Placebo<br>* Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.<br>|
| Experimental: Cohort 6<br>On Day 1, randomized subjects will receive a SC injection of AZD2373 dose 6 (6 subjects) or matching placebo (2 subjects). | Drug: AZD2373 subcutaneous injection<br>* Randomised subjects will receive a single ascending dose of AZD2373 by SC injection (dose 1, dose 2, dose 3, dose 4, dose 5 and dose 6).<br>Drug: Placebo<br>* Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events and/or abnormal findings in vital signs, and/or clinical laboratory assessments and/or physical examination and/or electrocardiogram (ECG) evaluation and/or telemetry and/or injection site reactions | To assess adverse events as a variable of safety and tolerability of subcutaneous (SC) single ascending dose (SAD) administrations of AZD2373 | Screening Visit to final Follow-up Visit (Week 10 post last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under plasma concentration-time curve from time zero extrapolated to infinity (AUC) | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Area under the plasma concentration curve from time zero to the time of last quantifiable analyte concentration (AUClast) | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Area under the plasma concentration-time curve from time zero to 72 hours after dosing [AUC(0-72)] | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Area under the plasma concentration-time curve from time zero to 48 hours after dosing [AUC (0-48)] | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Observed maximum plasma concentration (Cmax) | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Time to reach peak or maximum observed concentration or response following drug administration (tmax) | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Apparent total body clearance of drug from plasma after extravascular administration [CL/F] | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Mean residence time of the unchanged drug in the systemic circulation (MRT) | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Terminal elimination rate constant (λz) | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Time of the last quantifiable concentration [tlast Ae(0-last)] | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point [fe(0-last)] | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)] | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Fraction of dose excreted unchanged into the urine from time t1 to t2 [fe(t1-t2)] | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC (CLR) | To characterize the PK of AZD2373 following SC SAD administrations of AZD2373. | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 
| Apolipoprotein L1 (APOL1) concentrations and change from baseline | To assess the effect of SC SAD administrations of AZD2373 on plasma concentrations of APOL1 protein | Visit 2 to final Follow-up Visit (Week 10 post last dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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First-in-Human, Randomized, Single-blind, Placebo controlled, AZD2373, Single Ascending Dose, Sentinel Dosing