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

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05134727
Recruitment Status : Recruiting
First Posted : November 26, 2021
Last Update Posted : April 8, 2022
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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
Idiopathic Pulmonary Fibrosis Drug: AZD5055 Drug: Placebo 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 18, 2021
Estimated Primary Completion Date : February 9, 2023
Estimated Study Completion Date : February 9, 2023


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




Primary Outcome Measures :
  1. Part 1a and 1b: Number of participants with adverse events (AEs) [ Time Frame: 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)

  2. Part 2: Number of participants with AEs [ Time Frame: 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 :
  1. Part 1a and 1b: Maximum observed plasma (peak) drug concentration (Cmax) [ Time Frame: 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

  2. Part 2: Maximum observed plasma (peak) drug concentration (Cmax) [ Time Frame: 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

  3. Part 1a and 1b: Area under plasma concentration time curve from zero to infinity (AUCinf) [ Time Frame: 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

  4. Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf) [ Time Frame: 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

  5. Part 1a and 1b: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) [ Time Frame: 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

  6. Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) [ Time Frame: 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

  7. Part 1a and 1b: Time to reach maximum observed concentration (tmax) [ Time Frame: 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

  8. Part 2: Time to reach maximum observed concentration (tmax) [ Time Frame: 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

  9. Part 1a and 1b: Partial area under the plasma concentration-time curve from 0 to time 12 hours post dose [AUC(0-12)] [ Time Frame: 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

  10. Part 2: Partial area under the plasma concentration-time curve from 0 to time 12 hours post dose [AUC(0-12)] [ Time Frame: 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

  11. Part 1a and 1b: Partial area under the plasma concentration-time curve from 0 to time 24 hours post dose [AUC(0-24)] [ Time Frame: 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

  12. Part 2: Partial area under the plasma concentration-time curve from 0 to time 24 hours post dose [AUC(0-24)] [ Time Frame: 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

  13. Part 1a and 1b: Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) [ Time Frame: 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

  14. Part 2: Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) [ Time Frame: 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

  15. Part 1a and 1b: Mean residence time of the unchanged drug in the systemic circulation (MRTinf) [ Time Frame: 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

  16. Part 2: Mean residence time of the unchanged drug in the systemic circulation (MRTinf) [ Time Frame: 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

  17. Part 1a and 1b: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) [ Time Frame: 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

  18. Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) [ Time Frame: 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

  19. Part 1a and 1b: Apparent volume of distribution following extravascular administration based on terminal phase (Vz/F) [ Time Frame: 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

  20. Part 2: Apparent volume of distribution following extravascular administration based on terminal phase (Vz/F) [ Time Frame: 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

  21. Part 1a and 1b: Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] [ Time Frame: 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

  22. Part 2: Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] [ Time Frame: Day 1 and Day 14 ]
    To characterize the PK of AZD5055 following oral administration of MAD to healthy participants

  23. Part 1a and 1b: Cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)] [ Time Frame: 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

  24. Part 2: Cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)] [ Time Frame: Day 1 and Day 14 ]
    To characterize the PK of AZD5055 following oral administration of MAD to healthy participants

  25. Part 1a and 1b: Renal clearance of drug from plasma (CLR) [ Time Frame: 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

  26. Part 2: Renal clearance of drug from plasma (CLR) [ Time Frame: Day 1 and Day 14 ]
    To characterize the PK of AZD5055 following oral administration of MAD to healthy participants

  27. Part 2: Accumulation ratio (Rac) [ Time Frame: 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

  28. Part 2: Temporal change parameter in systemic exposure (TCP) [ Time Frame: 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria

  • Healthy male and female (of non-childbearing potential) subjects aged 18 to 45 years, 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 and no more than 100 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 15 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.
  • 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.

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): NCT05134727


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, Maryland
Research Site Recruiting
Brooklyn, Maryland, United States, 21225
Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT05134727    
Other Study ID Numbers: D8960C00001
First Posted: November 26, 2021    Key Record Dates
Last Update Posted: April 8, 2022
Last Verified: March 2022
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 rerefer 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 a sponsor approved 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:
AZD5055
Single ascending dose
Multiple ascending dose
Porcupine (PORCN) inhibitor
Healthy participants
Oral suspension
Additional relevant MeSH terms:
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Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Lung Diseases
Respiratory Tract Diseases