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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.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04269031
Recruitment Status : Terminated (AZ has decided not to continue this study, since sufficient data are available to support proposed dosing in future studies, and assessment of higher single doses are limited by tolerability due to the development of Injection Site Reactions.)
First Posted : February 13, 2020
Last Update Posted : September 27, 2021
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: AZD2373 subcutaneous injection Drug: Placebo Phase 1

Detailed Description:

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Masking Description: This study is single-blind (in which the study center staff remain blinded during the clinical conduct of a given cohort) with regard to treatment (AZD2373 or placebo) at each dose level. Study subjects will be blinded to treatment allocation throughout the study.
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 13, 2020
Actual Primary Completion Date : July 8, 2021
Actual Study Completion Date : July 8, 2021

Arm Intervention/treatment
Experimental: Cohort 1
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
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).

Drug: Placebo
Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.

Experimental: Cohort 2
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
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).

Drug: Placebo
Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.

Experimental: Cohort 3
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
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).

Drug: Placebo
Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.

Experimental: Cohort 4
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
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).

Drug: Placebo
Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.

Experimental: Cohort 5
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
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).

Drug: Placebo
Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.

Experimental: Cohort 6
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
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).

Drug: Placebo
Randomised subjects will receive a single ascending dose of placebo (saline solution) by SC injection.




Primary Outcome Measures :
  1. 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 [ Time Frame: Screening Visit to final Follow-up Visit (Week 10 post last dose) ]
    To assess adverse events as a variable of safety and tolerability of subcutaneous (SC) single ascending dose (SAD) administrations of AZD2373


Secondary Outcome Measures :
  1. Area under plasma concentration-time curve from time zero extrapolated to infinity (AUC) [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  2. Area under the plasma concentration curve from time zero to the time of last quantifiable analyte concentration (AUClast) [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  3. Area under the plasma concentration-time curve from time zero to 72 hours after dosing [AUC(0-72)] [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  4. Area under the plasma concentration-time curve from time zero to 48 hours after dosing [AUC (0-48)] [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  5. Observed maximum plasma concentration (Cmax) [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  6. Time to reach peak or maximum observed concentration or response following drug administration (tmax) [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  7. Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  8. Apparent total body clearance of drug from plasma after extravascular administration [CL/F] [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  9. Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  10. Mean residence time of the unchanged drug in the systemic circulation (MRT) [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  11. Terminal elimination rate constant (λz) [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  12. Time of the last quantifiable concentration [tlast Ae(0-last)] [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  13. Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point [fe(0-last)] [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  14. Amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)] [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  15. Fraction of dose excreted unchanged into the urine from time t1 to t2 [fe(t1-t2)] [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  16. 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) [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To characterize the PK of AZD2373 following SC SAD administrations of AZD2373.

  17. Apolipoprotein L1 (APOL1) concentrations and change from baseline [ Time Frame: Visit 2 to final Follow-up Visit (Week 10 post last dose) ]
    To assess the effect of SC SAD administrations of AZD2373 on plasma concentrations of APOL1 protein



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Male 18-55 years
Accepts Healthy Volunteers:   Yes
Criteria

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:

    1. Alanine aminotransferase or aspartate aminotransferase greater than upper limit of normal and clinically significant as determined by the PI.
    2. White blood cell (WBC) count < 3.0 x 10^9/L.
    3. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04269031


Locations
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United States, Maryland
Research Site
Brooklyn, Maryland, United States, 21225
Sponsors and Collaborators
AstraZeneca
Parexel
Investigators
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Principal Investigator: Ronald Goldwater, Dr. PAREXEL Early Phase Clinical Unit Baltimore
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04269031    
Other Study ID Numbers: D6800C00001
First Posted: February 13, 2020    Key Record Dates
Last Update Posted: September 27, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Time Frame:

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Access Criteria:

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
First-in-Human
Randomized
Single-blind
Placebo controlled
AZD2373
Single Ascending Dose
Sentinel Dosing