Heart Failure With Preserved Ejection Fraction (HFpEF)Phase 1NCT04232345
A Study to Assess the Effect AZD4831 in Japanese and Chinese Healthy Volunteers
A Phase 1 study testing AZD4831 in people with Heart Failure With Preserved Ejection Fraction (HFpEF), run by AstraZeneca at 1 site in United States.
Trial summary
This study is randomized, single-blind, placebo-controlled Phase 1 study aimed to assess the safety and efficacy, pharmacokinetics and pharmacodynamics of multiple doses of oral AZD4831 in healthy Japanese and Chinese volunteers Read more about this study
- Who is it for?
- Ages 18 to 50 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Heart Failure With Preserved Ejection Fraction (HFpEF)
- What is being tested?
- AZD4831
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 32 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Jan 2020to 11 Mar 2021
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Provision of signed and dated, written informed consent prior to any study specific procedures.
- Healthy male Japanese and Chinese subjects aged 18 - 50 years (inclusive at Screening) with suitable veins for cannulation or repeated venipuncture.
- A Japanese subject is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan.
- A Chinese subject is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.
- Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
- Provision of signed, written and dated informed consent for optional genetic/biomarker research. If a subject decline to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol.
Who cannot join
- 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.
- Presence of infection(s) (particularly fungal infection), as judged by the Investigator.
- History of, or current thyroid disease.
- Any ongoing skin disorder, history of or ongoing clinically significant allergy/hypersensitivity.
- Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
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- Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the Investigator at Screening and/or Day -1.
- Alanine transaminase (ALT) not within normal range
- Aspartate aminotransferase (AST) not within normal range
- Creatinine not within normal range
- White blood cell (WBC) count not within normal range
- Hemoglobin not within normal range;
- Estimated Glomerular Filtration Rate (eGFR) not within normal range.
- Any positive result at Screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus (HIV) type 1 and 2.
- Abnormal vital signs, after 10 minutes supine rest, at Screening and/or Day -1, defined as any of the following:
- SBP < 90 mmHg or ≥ 140 mmHg.
- DBP < 50 mmHg or ≥ 90 mmHg.
- Pulse < 45 or > 85 bpm.
- Any clinically significant abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and/or any clinically significant abnormalities in the 12-lead ECG, as judged by the Investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy at Screening and/or Day -1.
- Prolonged QTcF > 450 ms or shortened QTcF < 340 ms or family history of long QT syndrome at Screening and/or Day -1.
- PR(PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation) at Screening and/or Day -1.
- PR(PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third-degree atrioventricular (AV)-block, or AV dissociation at Screening and/or Day -1.
- Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or interventricular conduction delay with QRS > 110 ms. Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation at Screening and/or Day -1.
- Electrocardiogram findings suggesting a metabolic or other non-cardiac condition that may confound interpretation of serial changes (such as hypokalemia) at Screening and/or Day -1.
- Known or suspected history of drug abuse as judged by the Investigator.
- Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within 3 months of Screening.
- History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.
- Positive screen for drugs of abuse, cotinine (nicotine) or alcohol at Screening and/or Day -1.
- History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with myeloperoxidase (MPO) inhibitors and anti-thyroid drugs with similar theorem motifs as AZD4831.
- Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate,) as judged by the Investigator.
- Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
- Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega-dose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life.
- Plasma donation within 1 month of Screening or any blood donation/blood loss > 500 mL during the 3 months before Screening.
- Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 1 month of first administration of IMP in this study (period of exclusion begins 1 month after the final dose of the previous chemical entity or last visit in the previous study, whichever is longest),
- if the previous chemical entity has a half-life that would not indicate complete clearance at the time of screening to this study,
- if the previous chemical entity has significant drug-drug interactions or enzyme inductions that could potentially have an impact on the PK of this study's IMP, even if the previous chemical entity is cleared at the time of screening to this study,
- and if the subject has not completed all follow-up activity in the previous study, including last study visit, unresolved AEs, and abnormal laboratory values.
- Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
- Involvement of any Astra Zeneca, Parexel or study site employee or their close relatives.
- Judgement by the Investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the Screening Period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.
- Subjects who are vegans or have medical dietary restrictions, or any other dietary restrictions.
- Subjects who cannot communicate reliably with the Investigator.
- Previous bone marrow transplant.
- Non leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase I, Randomized, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4831 Following Multiple-ascending Dose Administration in Japanese and Chinese Healthy Volunteers
This study is randomized, single-blind, placebo-controlled Phase 1 study aimed to assess the safety and efficacy, pharmacokinetics and pharmacodynamics of multiple doses of oral AZD4831 in healthy Japanese and Chinese volunteers
Read the detailed description
This is a Phase I, randomized, single-blind, placebo-controlled, multiple-ascending dose (MAD), sequential-group study in healthy Japanese (Part 1, Cohorts 1, 2, and 3) and Chinese (Part 2, Cohort 4) male subjects, conducted at a single study center. Four cohorts are planned, but one additional cohort may be enrolled based on a Safety Review Committee (SRC) decision.
The 4 multiple dose levels are planned as follows:
- Cohort 1: Dose 1
- Cohort 2: Dose 2
- Cohort 3: Dose 3
- Cohort 4: Dose 2
A randomization ratio of 3:1 (AZD4831 versus placebo) will be used.
For each cohort the study will comprise:
- Screening Period of a maximum of 28 days.
- A Treatment Period during which subjects are resident in the study center from the day before first dosing with the Investigational Medicinal Product (Day -1) until at least 48 hours after last dosing on Day 10; subjects will be discharged on Day 12.
- Three Follow-up Visits on Day 14, Day 16 (±1 day), and Day 20 (±1 day).
- A Final Follow-up Visit on Day 24 (±2 days).
Each subject will be involved in the study for 8 to 9 weeks.
- Being tested
- AZD4831, Placebo
- Keywords
- Randomized, Single-blind, Placebo-controlled, Multiple-ascending dose, AZD4831 oral suspension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD4831Drug
Subjects will be fasted for at least 10 hours before receiving the AZD4831 in the form of an oral suspension.
PlaceboDrug
Subjects will be fasted for at least 10 hours before receiving the placebo in the form of an oral suspension.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 (Part 1): AZD4831 Dose 1 | Experimental | Randomized subjects will receive oral suspension of AZD4831 Dose 1 once daily in the morning for a period of 10 days Receives: Drug: AZD4831 |
| Cohort 2 (Part 1): AZD4831 Dose 2 | Experimental | Randomized subjects will receive oral suspension of AZD4831 Dose 2 once daily in the morning for a period of 10 days. Receives: Drug: AZD4831 |
| Cohort 3 (Part 1): AZD4831 Dose 3 | Experimental | Randomized subjects will receive oral suspension of AZD4831 Dose 3 once daily in the morning for a period of 10 days. Receives: Drug: AZD4831 |
| Cohort 4 (Part 2): AZD4831 Dose 2 | Experimental | Randomized subjects will receive oral suspension of AZD4831 Dose 2 once daily in the morning for a period of 10 days. Receives: Drug: AZD4831 |
| Placebo (Part 1) | Experimental | Randomized subjects will receive oral suspension of placebo once daily in the morning for a period of 10 days. Receives: Drug: Placebo |
| Placebo (Part 2) | Experimental | Randomized subjects will receive oral suspension of placebo once daily in the morning for a period of 10 days. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of subjects with adverse events (AEs)/serious adverse events
To assess AEs as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Measured: Screening through follow-up visit (upto 9 weeks)
Number of subjects with abnormal blood pressure (BP) and pulse
To assess BP and pulse rate as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Measured: Screening through follow-up visit (upto 9 weeks)
Number of subjects with abnormal electrocardiogram (ECG)
To assess change ECG as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Measured: Screening through follow-up visit (upto 9 weeks)
Number of subjects with abnormal abnormal clinical chemistry/hematology/urinalysis
To assess clinical chemistry/hematology/urinalysis as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Measured: Screening through follow-up visit (upto 9 weeks)
Number of subjects with abormal physical examination results
To assess physical examination as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Measured: Screening through follow-up visit (upto 9 weeks)
Secondary outcomes (18)
Plasma Cmax: Maximum observed plasma concentration
To characterize the Cmax of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: Pre-dose (pre); 0.25,0.5,1,1.5,2,3,4,6,8,12 h post-dose (post); Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Cmax/D
To characterize the Cmax/D of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma tmax: Time to reach peak or maximum observed concentration following drug administration
To characterize the tmax of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Ctrough: Observed trough plasma concentration
To characterize the Ctrough of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma t1/2λz: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve
To characterize the t1/2λz of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plamsa AUCτ : Area under the plasma concentration-time curve within the dosing interval
To characterize the AUCτ of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma AUCτ/D
To characterize the AUCτ/D of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma CL/F: Apparent total body clearance of drug from plasma after extravascular administration (Day 10)
To characterize the CL/F of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Vz/F:Apparent volume of distribution for parent drug at terminal phase after extravascular administration
To characterize the Vz/F of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma AUCinf: Area under the concentration-time curve from time zero extrapolated to infinity
To characterize the AUCinf of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma AUCinf/D: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by dose
To characterize the AUCinf/D of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Rac(AUC): Accumulation ratio based upon AUC
To characterize the Rac(AUC) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Rac(Cmax): Accumulation ratio based upon Cmax
To characterize the Rac(Cmax) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Urine Ae(t1-t2): Amount of analyte excreted into the urine from time t1 to t2
To characterize the Ae(t1-t2) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine Ae(0-last): Cumulative amount of analyte excreted at the last sampling interval
To characterize the Ae(0-last) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine %fe(t1-t2): Fraction of dose (expressed as a percentage) excreted unchanged into the urine from time t1 to t2
To characterize the %fe(t1-t2) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine %fe(0-last): Percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an analyte
To characterize the %fe(0-last) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine CLR: Renal clearance of drug from plasma, estimated by dividing Ae(0-last) by AUC(0-t)
To characterize the CLR of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Measured: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jan 2020
- Study start16 Jan 2020
- Primary completion11 Mar 2021
- Study completion11 Mar 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart Failure With Preserved Ejection Fraction (HFpEF)Studies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- This study will be a randomized, single-blind, placebo-controlled, MAD sequential-group study in healthy Japanese (Part 1, Cohorts 1, 2, and 3) and Chinese (Part 2, Cohort 4) male subjects, conducted at a single study center. Up to 40 healthy male subjects aged 18 to 50 years (inclusive) are planned to be investigated in 4 cohorts, but up to 5 cohorts may be included if the SRC considers it necessary to repeat a dose level or if additional dose levels are required. Up to 8 subjects will participate in each cohort. Within each cohort 6 subjects will be randomly assigned to receive AZD4831 and 2 subjects to receive placebo. AZD4831 or placebo will be administered once daily for a period of 10 days. It is anticipated this will be sufficient to achieve and maintain steady state pharmacokinetic (PK) profiles for several days, permitting evaluation of the safety and tolerability of multiple dose. The subjects will stay at the study center during the whole dosing period and until 48 hours.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Parexel
- Responsible party
- Sponsor
- Investigators
- David Han, M.D, Principal investigator, PAREXEL Early Phase Clinical Unit-Los Angeles
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04232345
- Sponsor's protocol ID
- D6580C00008
- Status last verified
- Mar 2021
- First submitted
- 3 Jan 2020
- Last updated
- 1 Apr 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
Sunnaker M, Bhattacharya C, Nelander K, Aurell M, Heijer M, Collen A, Han D, Holden J, Trebski M, Garkaviy P, Ericsson H. Pharmacokinetics and Tolerability of the Novel Myeloperoxidase Inhibitor Mitiperstat in Healthy Japanese and Chinese Volunteers. Clin Drug Investig. 2024 Nov;44(11):863-874. doi: 10.1007/s40261-024-01402-x. Epub 2024 Nov 4.
PubMed 39495467
Study at a glance
From the registry record, last updated by the sponsor on 1 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Randomized, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4831 Following Multiple-ascending Dose Administration in Japanese and Chinese Healthy Volunteers
- ClinicalTrials.gov ID
- NCT04232345
- Acronym / sponsor ID
- D6580C00008
- Keywords
- Randomized, Single-blind, Placebo-controlled, Multiple-ascending dose, AZD4831 oral suspension
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 32 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Collaborators
- Parexel
- Study start
- 16 Jan 2020 (actual)
- Primary completion
- 11 Mar 2021 (actual)
- Study completion
- 11 Mar 2021 (actual)
- First posted
- 18 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study is randomized, single-blind, placebo-controlled Phase 1 study aimed to assess the safety and efficacy, pharmacokinetics and pharmacodynamics of multiple doses of oral AZD4831 in healthy Japanese and Chinese volunteers
Detailed description
This is a Phase I, randomized, single-blind, placebo-controlled, multiple-ascending dose (MAD), sequential-group study in healthy Japanese (Part 1, Cohorts 1, 2, and 3) and Chinese (Part 2, Cohort 4) male subjects, conducted at a single study center. Four cohorts are planned, but one additional cohort may be enrolled based on a Safety Review Committee (SRC) decision.
The 4 multiple dose levels are planned as follows:
- Cohort 1: Dose 1
- Cohort 2: Dose 2
- Cohort 3: Dose 3
- Cohort 4: Dose 2
A randomization ratio of 3:1 (AZD4831 versus placebo) will be used.
For each cohort the study will comprise:
- Screening Period of a maximum of 28 days.
- A Treatment Period during which subjects are resident in the study center from the day before first dosing with the Investigational Medicinal Product (Day -1) until at least 48 hours after last dosing on Day 10; subjects will be discharged on Day 12.
- Three Follow-up Visits on Day 14, Day 16 (±1 day), and Day 20 (±1 day).
- A Final Follow-up Visit on Day 24 (±2 days).
Each subject will be involved in the study for 8 to 9 weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Single blind (participant)
- Number of arms
- 6
- Model description
- This study will be a randomized, single-blind, placebo-controlled, MAD sequential-group study in healthy Japanese (Part 1, Cohorts 1, 2, and 3) and Chinese (Part 2, Cohort 4) male subjects, conducted at a single study center. Up to 40 healthy male subjects aged 18 to 50 years (inclusive) are planned to be investigated in 4 cohorts, but up to 5 cohorts may be included if the SRC considers it necessary to repeat a dose level or if additional dose levels are required. Up to 8 subjects will participate in each cohort. Within each cohort 6 subjects will be randomly assigned to receive AZD4831 and 2 subjects to receive placebo. AZD4831 or placebo will be administered once daily for a period of 10 days. It is anticipated this will be sufficient to achieve and maintain steady state pharmacokinetic (PK) profiles for several days, permitting evaluation of the safety and tolerability of multiple dose. The subjects will stay at the study center during the whole dosing period and until 48 hours.
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 (Part 1): AZD4831 Dose 1 | Experimental | Drug: AZD4831Randomized subjects will receive oral suspension of AZD4831 Dose 1 once daily in the morning for a period of 10 days |
| Cohort 2 (Part 1): AZD4831 Dose 2 | Experimental | Drug: AZD4831Randomized subjects will receive oral suspension of AZD4831 Dose 2 once daily in the morning for a period of 10 days. |
| Cohort 3 (Part 1): AZD4831 Dose 3 | Experimental | Drug: AZD4831Randomized subjects will receive oral suspension of AZD4831 Dose 3 once daily in the morning for a period of 10 days. |
| Cohort 4 (Part 2): AZD4831 Dose 2 | Experimental | Drug: AZD4831Randomized subjects will receive oral suspension of AZD4831 Dose 2 once daily in the morning for a period of 10 days. |
| Placebo (Part 1) | Experimental | Drug: PlaceboRandomized subjects will receive oral suspension of placebo once daily in the morning for a period of 10 days. |
| Placebo (Part 2) | Experimental | Drug: PlaceboRandomized subjects will receive oral suspension of placebo once daily in the morning for a period of 10 days. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Provision of signed and dated, written informed consent prior to any study specific procedures.
- Healthy male Japanese and Chinese subjects aged 18 - 50 years (inclusive at Screening) with suitable veins for cannulation or repeated venipuncture.
- A Japanese subject is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan.
- A Chinese subject is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.
- Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
Key exclusion criteria (44 listed)
- 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.
- Presence of infection(s) (particularly fungal infection), as judged by the Investigator.
- History of, or current thyroid disease.
- Any ongoing skin disorder, history of or ongoing clinically significant allergy/hypersensitivity.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AZD4831Subjects will be fasted for at least 10 hours before receiving the AZD4831 in the form of an oral suspension. | Drug | Cohort 1 (Part 1): AZD4831 Dose 1, Cohort 2 (Part 1): AZD4831 Dose 2, Cohort 3 (Part 1): AZD4831 Dose 3, Cohort 4 (Part 2): AZD4831 Dose 2 |
| PlaceboSubjects will be fasted for at least 10 hours before receiving the placebo in the form of an oral suspension. | Drug | Placebo (Part 1), Placebo (Part 2) |
Primary outcome
Number of subjects with adverse events (AEs)/serious adverse events
Time frame: Screening through follow-up visit (upto 9 weeks)
To assess AEs as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Number of subjects with abnormal blood pressure (BP) and pulse
Time frame: Screening through follow-up visit (upto 9 weeks)
To assess BP and pulse rate as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Number of subjects with abnormal electrocardiogram (ECG)
Time frame: Screening through follow-up visit (upto 9 weeks)
To assess change ECG as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Number of subjects with abnormal abnormal clinical chemistry/hematology/urinalysis
Time frame: Screening through follow-up visit (upto 9 weeks)
To assess clinical chemistry/hematology/urinalysis as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Number of subjects with abormal physical examination results
Time frame: Screening through follow-up visit (upto 9 weeks)
To assess physical examination as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
18 secondary outcomes
Plasma Cmax: Maximum observed plasma concentration
Time frame: Day 1: Pre-dose (pre); 0.25,0.5,1,1.5,2,3,4,6,8,12 h post-dose (post); Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Cmax/D
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma tmax: Time to reach peak or maximum observed concentration following drug administration
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Ctrough: Observed trough plasma concentration
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma t1/2λz: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plamsa AUCτ : Area under the plasma concentration-time curve within the dosing interval
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma AUCτ/D
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma CL/F: Apparent total body clearance of drug from plasma after extravascular administration (Day 10)
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Vz/F:Apparent volume of distribution for parent drug at terminal phase after extravascular administration
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma AUCinf: Area under the concentration-time curve from time zero extrapolated to infinity
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma AUCinf/D: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by dose
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Rac(AUC): Accumulation ratio based upon AUC
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Rac(Cmax): Accumulation ratio based upon Cmax
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Urine Ae(t1-t2): Amount of analyte excreted into the urine from time t1 to t2
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine Ae(0-last): Cumulative amount of analyte excreted at the last sampling interval
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine %fe(t1-t2): Fraction of dose (expressed as a percentage) excreted unchanged into the urine from time t1 to t2
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine %fe(0-last): Percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an analyte
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine CLR: Renal clearance of drug from plasma, estimated by dividing Ae(0-last) by AUC(0-t)
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Apr 2021.
- Derived from this study: PubMed 39495467Sunnaker M, Bhattacharya C, Nelander K, Aurell M, Heijer M, Collen A, Han D, Holden J, Trebski M, Garkaviy P, Ericsson H. Pharmacokinetics and Tolerability of the Novel Myeloperoxidase Inhibitor Mitiperstat in Healthy Japanese and Chinese Volunteers. Clin Drug Investig. 2024 Nov;44(11):863-874. doi: 10.1007/s40261-024-01402-x. Epub 2024 Nov 4.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Han, M.D principal investigator
PAREXEL Early Phase Clinical Unit-Los Angeles
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing AZD4831 in people with Heart Failure With Preserved Ejection Fraction (HFpEF), run by AstraZeneca at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 44 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of subjects with adverse events (AEs)/serious adverse events (time frame: Screening through follow-up visit (upto 9 weeks)). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04232345, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2021.