Cardiovascular DiseasePhase 1NCT03136991
A Phase I, Safety Tolerability and Pharmacokinetics of AZD4831 to Treat Cardiovascular Disease
A Phase 1 study testing AZD4831 in people with Cardiovascular Disease, run by AstraZeneca at 1 site in United States.
Trial summary
This is a Phase I study to investigate the safety and tolerability of AZD4831 in healthy male participants, conducted at a single center. The results from this study will form the basis for decisions on future studies. 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
- Cardiovascular Disease
- 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
- 38 participants
- Where
- 1 siteUnited States
- Study dates
- 15 May 2017to 22 Nov 2017
- 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
- Healthy male participants aged 18 to 50 years (inclusive at Screening) with suitable veins for cannulation or repeated venipuncture.
- Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
Who cannot join
- History of any clinically significant 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 (GI), 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 or current thyroid disease.
- Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
- Any clinically significant abnormalities in biochemistry, hematology, or urinalysis results, as judged by the Investigator at Screening and/or Day 1, including
Show all 23Show fewer
- Alanine aminotransferase (ALT) not within normal range;
- Aspartate aminotransferase (AST) not within normal range;
- Creatinine not within normal range;
- White blood cell (WBC) not within normal range;
- Hemoglobin not within normal range; and
- Estimated Glomerular Filtration Rate (eGFR) not within normal range.
- Any positive result on screening for serum hepatitis B surface antigen (HBsAg), 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:
- Systolic BP (SBP) < 90 mmHg or ≥ 140 mmHg
- Diastolic BP (DBP) < 50 mmHg or ≥ 90 mmHg
- Pulse < 45 or > 85 beats per minute (bpm)
- Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or interventricular conduction delay with QRS > 110 ms. Participants 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.
- Use of any prescribed or non-prescribed medication (other than paracetamol/acetaminophen), including antacids, analgesics, herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks before 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 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest.
- Vulnerable participants, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4831 After Multiple Ascending Dose Administration to Healthy Male Subjects
This is a Phase I study to investigate the safety and tolerability of AZD4831 in healthy male participants, conducted at a single center. The results from this study will form the basis for decisions on future studies. Another purpose of this dose escalation study is to find out the right dose of the experimental drug to be given to study participants in future studies. Even though there were no harmful effects seen in the animals tested, investigator does not know what side effects the experimental drug might cause in humans. However, site personnel managing the study participants will be blinded to the extent possible and as long as possible to minimize any impact on data collection. Study participants will be blinded to treatment allocation.
The study will be conducted in healthy participants to avoid interference from disease processes or other drugs.
The participants will stay at the study center during the whole dosing period and until 48 hours post final dose.
Read the detailed description
This is a Phase I study to investigate the safety and tolerability of AZD4831 in healthy male participants, conducted at a single center.The results from this study will form the basis for decisions on future studies. Another purpose of this dose escalation study is to find out the right dose of the experimental drug to be given to study participants in future studies. The study will be conducted in healthy participants to avoid interference from disease processes or other drugs. The participants will stay at the study center during the whole dosing period and until 48 hours post final dose.
- Conditions
- Cardiovascular Disease
- Being tested
- AZD4831, Placebo
- Keywords
- Oral myeloperoxidase inhibitor
- Medical subject headings
- Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD4831Drug
Participants will receive AZD4831 once daily, orally, for a period of 10 days. Note: Additional doses (for cohorts 2,3\&4) are provisional and could be adjusted based on the emerging data after the review of all available safety or other pertinent data from the previous dose by the Safety Review Committee (SRC).
PlaceboDrug
Participants will receive placebo matching the AZD4831 dose, once daily, orally, for a period of 10 days.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Active comparator | Participants will receive AZD4831 5 mg/placebo oral suspension. Receives: Drug: AZD4831; Drug: Placebo |
| Cohort 2 | Active comparator | Participants will receive AZD4831 (Additional dose 1)/placebo oral suspension. Receives: Drug: AZD4831; Drug: Placebo |
| Cohort 3 | Active comparator | Participants will receive AZD4831 (Additional dose 2)/placebo oral suspension. Receives: Drug: AZD4831; Drug: Placebo |
| Cohort 4 | Active comparator | Participants will receive AZD4831 (Additional dose 3)/placebo oral suspension. Receives: Drug: AZD4831; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with adverse events (AEs)
An AE is the development of an undesirable medical condition or the deterioration of a preexisting medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, ECG).
Measured: From screening (Day -28 to Day -2) until final follow-up (Day 24)
Systolic Blood pressure
Base line Systolic blood pressure (in mmHg) will be measured at the pre-dose assessment on Day 1. Assessment in treatment period on Day 1 at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose. On Day 10 at Pre-dose and 12 hours post-dose. On Day 12 at 48 hours post last dose. Measurements will be collected after the subject had rested in the supine position for at least 10 minutes.
Measured: At screening (Day-28 to Day-2), Day -1, treatment period (Day 1, Day 10 and Day 12) and final follow-up (Day 24)
Twelve lead safety electrocardiography (ECG)
A 12-lead ECG will be performed on Days 1, 2, 3, 6, 10 and 11: (collected at end of dECG recording) and any additional required by PI on Days 4, 5, 7 to 9 at Pre dose and at discharge on Day 12, plus any additional required by PI. A 12-lead ECG will be obtained after the subject rested in the supine position for at least 10 minutes (For time-points coinciding with dECG measurements, a paper printout of the Schiller Cardiovit CS-200 recorder[ at the end of the 5- or 10-minute dECG recording], will be used and the result recorded. For time-points not coinciding with dECG measurements, the ECG recording will be directly recorded in ClinBase™ using ClinBase™ Cardiosoft™).
Measured: At screening (Day-28 to Day-2), treatment period (Day 1 to Day 12), and final follow-up period (Day 24)
Twelve lead digital electrocardiography (dECG)
12-lead continuous dECGs will be recorded over at least 5 minutes on Day 1, 2, 3, 6, 10, 11 \& 12. The AstraZeneca (AZ) ECG Centre will perform the digital ECG (dECG) analysis in this study, using the EClysis© system, version 3.4, or higher. At protocol-indicated time points, 12-lead continuous dECG will be recorded over at least 5 minutes with the Schiller Cardiovit CS-200 recorder (Schiller AG, Baar, Switzerland) and transmitted to the AZ central dECG repository, according to AZ ECG Centre´s standard procedures for settings, recording and transmission of dECGs. Time-points for dECG may be adjusted according to emerging PK data. All ECG recordings will be preceded by a 10-minute controlled rest period.
Measured: Treatment Period (Day 1 to Day 12)
Telemetry
A 2-lead real-time telemetry ECG will be performed for at least 4 hours on Day -1 and from 30 minutes pre-dose until 24 hours post dose. The telemetry monitoring system will be reviewed by the Investigator or research nurse and paper printouts of any clinically important events will be stored as source data.
Measured: At Day -1 and treatment period (Day 1 and Day 10)
Hematology
Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by Haematology: Hematocrit (HCT), hemoglobin (Hb), red blood cell count (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell count (WBC), differential blood count (neutrophils, lymphocytes, monocytes, eosinophils and basophils), reticulocytes absolute count, and platelets. Assessments will be performed during treatment period on Day 1 at pre-dose, Day 10 at pre-dose and on Day 12 at 48 hour post final dose before check-out.
Measured: At screening (Day -28 to Day -2), Day -1, treatment period (Day 1, Day 10 and Day 12), final follow-up (Day 24)
Physical examination
A full physical examination will include the assessment of the following: general appearance, skin, cardiovascular, respiratory, abdomen, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems. A full physical examination will be performed at screening visit and at final follow-up visit (Day 24).
A brief physical examination will include assessment of the following: general appearance, skin, cardiovascular system, respiratory and abdomen. A brief physical examination will performed at Day-1, treatment period (Day 1 to Day12) on Day 2: 24 h post first dose, and on Day 12: 48 h post final dose before check-out.
Measured: At screening (Day-28 to Day-2), Day -1, treatment period (Day 2 and Day 12), and final follow-up period (Day 24)
Diastolic blood pressure
Base line diastolic blood pressure (in mmHg) will be measured at the pre-dose assessment on Day 1. Assessment in treatment period on Day 1 at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose. On Day 10 at Pre-dose and 12 hours post-dose. On Day 12 at 48 hours post last dose. Measurements will be collected after the subject had rested in the supine position for at least 10 minutes.
Measured: At screening (Day-28 to Day-2), Day -1, treatment period (Day 1, Day 10 and Day 12) and final follow-up (Day 24)
Pulse rate
Base line pulse rate (in beats per minute (bpm)) will be measured at the pre-dose assessment on Day 1. Assessment in treatment period on Day 1 at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose. On Day 10 at Pre-dose and 12 hours post-dose. On Day 12 at 48 hours post last dose. Measurements will be collected after the subject had rested in the supine position for at least 10 minutes.
Measured: At screening (Day-28 to Day-2), Day -1, treatment period (Day 1, Day 10 and Day 12) and final follow-up (Day 24)
Oral body temperature
Oral temperature will be collected after the subject has rested in the supine position for at least 10 minutes.
Measured: At screening (Day-28 to Day-2), Day-1, treatment period (Day 1 and Day 10 pre-dose)
Biochemistry
Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by serum biochemistry. Electrolytes: Sodium, potassium, calcium, and phosphate. Enzymes: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), high-sensitivity C-reactive protein (hs-CRP). Substrates: Glucose (fasting), creatinine, total bilirubin, unconjugated bilirubin, conjugated bilirubin, albumin, and urea.
For serum creatinine testing, blood samples will be collected on Day -1, pre-dose on Day 1, Day 5 and Day 10, follow-up (Day 14, Day 16 and Day 20) and final follow-up (Day 24)
Measured: At screening (Day -28 to Day -2), Day -1, treatment period (Day 1 pre-dose, Day 10 pre-dose and Day 12 - 48 hours post final dose before check-out) and final follow-up (Day 24)
Urinalysis
Dipstick analysis will be performed at the centre and includes: glucose, creatinine, protein, and blood.
Measured: At Day -1, treatment period (pre-dose - Day 1, day 5 and Day 10), follow-up (Day 14, day 16 and Day 20) and final follow-up (Day 24)
Microscopy
Microscopy (RBC, WBC and casts [Hyaline, Granular and Cellular]) by thermodilatometry (TDL) may be performed at additional urinalysis time points if clinically relevant abnormalities are detected (positive result for protein or blood in dipstick).
Measured: At Day -1, treatment period (pre-dose - Day 1, day 5 and Day 10), follow-up (Day 14, day 16 and Day 20) and final follow-up (Day 24)
Immunology
Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by Immunology: Anti-neutrophil cytoplasmic antibodies (ANCA - a \& p) testing and complements (C3a, C5a \& Bb). ANCA serum testing will be performed on samples collected on Day -1, pre-dose on Day 1 and on Day 10 and at the final Follow-up Visit (Day 24). Complement testing will be performed on samples collected on Day -1, pre-dose on Day 1, Day 5 and Day 10, follow-up (Day 14, Day 16 and Day 20) and final follow-up (Day 24)
Measured: At Day -1, treatment period (Day 1 to Day 12), follow-up visits
Secondary outcomes (18)
Observed maximum concentration, taken directly from the individual concentration-time curve(Cmax) of AZD4831 and its metabolites
Observed maximum concentration.
Measured: Day 1 and Day 10
Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD4831
Time to reach maximum concentration.
Measured: Day 1 to Day 10
Observed trough plasma concentration [measured concentration at the end of the dosing interval taken just prior to the next administration] (Ctrough) of AZD4831
Observed trough plasma concentration.
Measured: Day 2 to Day 10
Terminal half-life (t1/2λz), estimated as (ln2)/λz) of AZD4831
Terminal elimination half-life.
Measured: Day 10
Area under the plasma concentration-curve over 24 hours (AUCτ) of AZD4831
Area under the plasma concentration over 24 hours.
Measured: Day 1 and Day 10
Area under the plasma concentration-time curve over the dosing interval divided by the dose administered (AUCτ/D) of AZD4831
Area under the plasma concentration-time curve over the dosing interval divided by the dose administered.
Measured: Day 1 and Day 10
Observed maximum plasma concentration divided by the dose administered (Cmax/D) of AZD4831.
Observed maximum plasma concentration divided by the dose administered.
Measured: Day 1 and Day 10
Apparent clearance for parent drug (CL/F) estimated as dose divided by AUCτ of AZD4831.
Apparent clearance for parent drug.
Measured: Day 10
Mean Residence Time (MRT)
Mean Residence Time.
Measured: Day 10
Apparent volume of distribution for parent drug at terminal phase(Vz/F)(extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz of AZD4831.
Apparent volume of distribution for parent drug at terminal phase.
Measured: Day 10
Accumulation ratio calculated as AUCτ Day 10/ AUCτ Day 1 (RacAUC) of AZD4831.
Accumulation ratio calculated as AUCτ Day 10/ AUCτ Day 1.
Measured: Day 10
Accumulation ratio calculated as Cmax Day 10/ Cmax Day 1 (Rac Cmax) of AZD4831.
Accumulation ratio calculated as Cmax Day 10/ Cmax Day 1.
Measured: Day 10
Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2)) of AZD4831.
Amount of analyte excreted into the urine.
Measured: Day 1 and Day 10
Cumulative amount of analyte excreted at time t (Ae(0-t)) of AZD4831.
Cumulative amount of analyte excreted at time t.
Measured: Day 1 and Day 10
Fraction of dose excreted unchanged into the urine from time t1 to t2, estimated by dividing Ae(t1-t2) by dose (fe(t1-t2)) of AZD4831.
Fraction of dose excreted unchanged into the urine.
Measured: Day 1 and Day 10
Fraction of dose excreted unchanged into the urine from time zero to time t, estimated by dividing Ae(0-t) by dose (fe(0-t)) of AZD4831
Fraction of dose excreted unchanged into the urine.
Measured: Day 1 and Day 10
Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t), using appropriate matching time t (CLR) of AZD4831.
Renal clearance.
Measured: Day 1 and Day 10
Terminal rate constant, estimated by log-linear least-squares regression rate constant, estiamteed by log-linear least-squares (λz)
Terminal rate constant
Measured: Day 10
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2017
- Study start15 May 2017
- Primary completion22 Nov 2017
- Study completion22 Nov 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cardiovascular DiseaseStudies 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
- Parallel groups
- Model description
- This study will be a randomized, single-blind (site personnel to remain blinded until SRC meeting), placebo-controlled, MAD, sequential group design study in healthy male subjects, performed at a single study center. Up to 60 healthy male subjects aged 18 to 50 years (inclusive) are planned to be investigated in 4 cohorts, but up to 6 cohorts may be included if the SRC considers it necessary to repeat a dose level or if additional dose levels are required. Up to 10 subjects will participate in each cohort. Within each cohort 8 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 PK profiles for several days, permitting evaluation of the safety and tolerability of multiple dose administrations at steady state. The subjects will stay at the study center during the whole dosing period and until 48h
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Parexel
- Responsible party
- Sponsor
- Investigators
- David Han, MD, Principal investigator, California Clinical Trials Medical Group 1560 East Chevy Chase Dr., Suite 140 Glendale, CA 91206
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03136991
- Sponsor's protocol ID
- D6580C00004
- Status last verified
- Jan 2020
- First submitted
- 27 Apr 2017
- Last updated
- 18 Jan 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4831 After Multiple Ascending Dose Administration to Healthy Male Subjects
- ClinicalTrials.gov ID
- NCT03136991
- Acronym / sponsor ID
- D6580C00004
- Conditions
- Cardiovascular Disease
- Keywords
- Oral myeloperoxidase inhibitor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 38 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Collaborators
- Parexel
- Study start
- 15 May 2017 (actual)
- Primary completion
- 22 Nov 2017 (actual)
- Study completion
- 22 Nov 2017 (actual)
- First posted
- 2 May 2017 (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 is a Phase I study to investigate the safety and tolerability of AZD4831 in healthy male participants, conducted at a single center. The results from this study will form the basis for decisions on future studies. Another purpose of this dose escalation study is to find out the right dose of the experimental drug to be given to study participants in future studies. Even though there were no harmful effects seen in the animals tested, investigator does not know what side effects the experimental drug might cause in humans. However, site personnel managing the study participants will be blinded to the extent possible and as long as possible to minimize any impact on data collection. Study participants will be blinded to treatment allocation.
The study will be conducted in healthy participants to avoid interference from disease processes or other drugs.
The participants will stay at the study center during the whole dosing period and until 48 hours post final dose.
Detailed description
This is a Phase I study to investigate the safety and tolerability of AZD4831 in healthy male participants, conducted at a single center.The results from this study will form the basis for decisions on future studies. Another purpose of this dose escalation study is to find out the right dose of the experimental drug to be given to study participants in future studies. The study will be conducted in healthy participants to avoid interference from disease processes or other drugs. The participants will stay at the study center during the whole dosing period and until 48 hours post final dose.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 4
- Model description
- This study will be a randomized, single-blind (site personnel to remain blinded until SRC meeting), placebo-controlled, MAD, sequential group design study in healthy male subjects, performed at a single study center. Up to 60 healthy male subjects aged 18 to 50 years (inclusive) are planned to be investigated in 4 cohorts, but up to 6 cohorts may be included if the SRC considers it necessary to repeat a dose level or if additional dose levels are required. Up to 10 subjects will participate in each cohort. Within each cohort 8 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 PK profiles for several days, permitting evaluation of the safety and tolerability of multiple dose administrations at steady state. The subjects will stay at the study center during the whole dosing period and until 48h
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Active comparator | Drug: AZD4831, Drug: PlaceboParticipants will receive AZD4831 5 mg/placebo oral suspension. |
| Cohort 2 | Active comparator | Drug: AZD4831, Drug: PlaceboParticipants will receive AZD4831 (Additional dose 1)/placebo oral suspension. |
| Cohort 3 | Active comparator | Drug: AZD4831, Drug: PlaceboParticipants will receive AZD4831 (Additional dose 2)/placebo oral suspension. |
| Cohort 4 | Active comparator | Drug: AZD4831, Drug: PlaceboParticipants will receive AZD4831 (Additional dose 3)/placebo oral suspension. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Healthy male participants aged 18 to 50 years (inclusive at Screening) with suitable veins for cannulation or repeated venipuncture.
- Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
Key exclusion criteria (23 listed)
- History of any clinically significant 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 (GI), 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 or current thyroid disease.
- Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
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 |
|---|---|---|
| AZD4831Participants will receive AZD4831 once daily, orally, for a period of 10 days. Note: Additional doses (for cohorts 2,3\&4) are provisional and could be adjusted based on the emerging data after the review of all available safety or other pertinent data from the previous dose by the Safety Review Committee (SRC). | Drug | Cohort 1, Cohort 2, Cohort 3, Cohort 4 |
| PlaceboParticipants will receive placebo matching the AZD4831 dose, once daily, orally, for a period of 10 days. | Drug | Cohort 1, Cohort 2, Cohort 3, Cohort 4 |
Primary outcome
Number of participants with adverse events (AEs)
Time frame: From screening (Day -28 to Day -2) until final follow-up (Day 24)
An AE is the development of an undesirable medical condition or the deterioration of a preexisting medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, ECG).
Systolic Blood pressure
Time frame: At screening (Day-28 to Day-2), Day -1, treatment period (Day 1, Day 10 and Day 12) and final follow-up (Day 24)
Base line Systolic blood pressure (in mmHg) will be measured at the pre-dose assessment on Day 1. Assessment in treatment period on Day 1 at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose. On Day 10 at Pre-dose and 12 hours post-dose. On Day 12 at 48 hours post last dose. Measurements will be collected after the subject had rested in the supine position for at least 10 minutes.
Twelve lead safety electrocardiography (ECG)
Time frame: At screening (Day-28 to Day-2), treatment period (Day 1 to Day 12), and final follow-up period (Day 24)
A 12-lead ECG will be performed on Days 1, 2, 3, 6, 10 and 11: (collected at end of dECG recording) and any additional required by PI on Days 4, 5, 7 to 9 at Pre dose and at discharge on Day 12, plus any additional required by PI. A 12-lead ECG will be obtained after the subject rested in the supine position for at least 10 minutes (For time-points coinciding with dECG measurements, a paper printout of the Schiller Cardiovit CS-200 recorder[ at the end of the 5- or 10-minute dECG recording], will be used and the result recorded. For time-points not coinciding with dECG measurements, the ECG recording will be directly recorded in ClinBase™ using ClinBase™ Cardiosoft™).
Twelve lead digital electrocardiography (dECG)
Time frame: Treatment Period (Day 1 to Day 12)
12-lead continuous dECGs will be recorded over at least 5 minutes on Day 1, 2, 3, 6, 10, 11 \& 12. The AstraZeneca (AZ) ECG Centre will perform the digital ECG (dECG) analysis in this study, using the EClysis© system, version 3.4, or higher. At protocol-indicated time points, 12-lead continuous dECG will be recorded over at least 5 minutes with the Schiller Cardiovit CS-200 recorder (Schiller AG, Baar, Switzerland) and transmitted to the AZ central dECG repository, according to AZ ECG Centre´s standard procedures for settings, recording and transmission of dECGs. Time-points for dECG may be adjusted according to emerging PK data. All ECG recordings will be preceded by a 10-minute controlled rest period.
Telemetry
Time frame: At Day -1 and treatment period (Day 1 and Day 10)
A 2-lead real-time telemetry ECG will be performed for at least 4 hours on Day -1 and from 30 minutes pre-dose until 24 hours post dose. The telemetry monitoring system will be reviewed by the Investigator or research nurse and paper printouts of any clinically important events will be stored as source data.
Hematology
Time frame: At screening (Day -28 to Day -2), Day -1, treatment period (Day 1, Day 10 and Day 12), final follow-up (Day 24)
Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by Haematology: Hematocrit (HCT), hemoglobin (Hb), red blood cell count (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell count (WBC), differential blood count (neutrophils, lymphocytes, monocytes, eosinophils and basophils), reticulocytes absolute count, and platelets. Assessments will be performed during treatment period on Day 1 at pre-dose, Day 10 at pre-dose and on Day 12 at 48 hour post final dose before check-out.
Physical examination
Time frame: At screening (Day-28 to Day-2), Day -1, treatment period (Day 2 and Day 12), and final follow-up period (Day 24)
A full physical examination will include the assessment of the following: general appearance, skin, cardiovascular, respiratory, abdomen, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems. A full physical examination will be performed at screening visit and at final follow-up visit (Day 24). A brief physical examination will include assessment of the following: general appearance, skin, cardiovascular system, respiratory and abdomen. A brief physical examination will performed at Day-1, treatment period (Day 1 to Day12) on Day 2: 24 h post first dose, and on Day 12: 48 h post final dose before check-out.
Diastolic blood pressure
Time frame: At screening (Day-28 to Day-2), Day -1, treatment period (Day 1, Day 10 and Day 12) and final follow-up (Day 24)
Base line diastolic blood pressure (in mmHg) will be measured at the pre-dose assessment on Day 1. Assessment in treatment period on Day 1 at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose. On Day 10 at Pre-dose and 12 hours post-dose. On Day 12 at 48 hours post last dose. Measurements will be collected after the subject had rested in the supine position for at least 10 minutes.
Pulse rate
Time frame: At screening (Day-28 to Day-2), Day -1, treatment period (Day 1, Day 10 and Day 12) and final follow-up (Day 24)
Base line pulse rate (in beats per minute (bpm)) will be measured at the pre-dose assessment on Day 1. Assessment in treatment period on Day 1 at 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose. On Day 10 at Pre-dose and 12 hours post-dose. On Day 12 at 48 hours post last dose. Measurements will be collected after the subject had rested in the supine position for at least 10 minutes.
Oral body temperature
Time frame: At screening (Day-28 to Day-2), Day-1, treatment period (Day 1 and Day 10 pre-dose)
Oral temperature will be collected after the subject has rested in the supine position for at least 10 minutes.
Biochemistry
Time frame: At screening (Day -28 to Day -2), Day -1, treatment period (Day 1 pre-dose, Day 10 pre-dose and Day 12 - 48 hours post final dose before check-out) and final follow-up (Day 24)
Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by serum biochemistry. Electrolytes: Sodium, potassium, calcium, and phosphate. Enzymes: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), high-sensitivity C-reactive protein (hs-CRP). Substrates: Glucose (fasting), creatinine, total bilirubin, unconjugated bilirubin, conjugated bilirubin, albumin, and urea. For serum creatinine testing, blood samples will be collected on Day -1, pre-dose on Day 1, Day 5 and Day 10, follow-up (Day 14, Day 16 and Day 20) and final follow-up (Day 24)
Urinalysis
Time frame: At Day -1, treatment period (pre-dose - Day 1, day 5 and Day 10), follow-up (Day 14, day 16 and Day 20) and final follow-up (Day 24)
Dipstick analysis will be performed at the centre and includes: glucose, creatinine, protein, and blood.
Microscopy
Time frame: At Day -1, treatment period (pre-dose - Day 1, day 5 and Day 10), follow-up (Day 14, day 16 and Day 20) and final follow-up (Day 24)
Microscopy (RBC, WBC and casts [Hyaline, Granular and Cellular]) by thermodilatometry (TDL) may be performed at additional urinalysis time points if clinically relevant abnormalities are detected (positive result for protein or blood in dipstick).
Immunology
Time frame: At Day -1, treatment period (Day 1 to Day 12), follow-up visits
Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by Immunology: Anti-neutrophil cytoplasmic antibodies (ANCA - a \& p) testing and complements (C3a, C5a \& Bb). ANCA serum testing will be performed on samples collected on Day -1, pre-dose on Day 1 and on Day 10 and at the final Follow-up Visit (Day 24). Complement testing will be performed on samples collected on Day -1, pre-dose on Day 1, Day 5 and Day 10, follow-up (Day 14, Day 16 and Day 20) and final follow-up (Day 24)
18 secondary outcomes
Observed maximum concentration, taken directly from the individual concentration-time curve(Cmax) of AZD4831 and its metabolites
Time frame: Day 1 and Day 10
Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD4831
Time frame: Day 1 to Day 10
Observed trough plasma concentration [measured concentration at the end of the dosing interval taken just prior to the next administration] (Ctrough) of AZD4831
Time frame: Day 2 to Day 10
Terminal half-life (t1/2λz), estimated as (ln2)/λz) of AZD4831
Time frame: Day 10
Area under the plasma concentration-curve over 24 hours (AUCτ) of AZD4831
Time frame: Day 1 and Day 10
Area under the plasma concentration-time curve over the dosing interval divided by the dose administered (AUCτ/D) of AZD4831
Time frame: Day 1 and Day 10
Observed maximum plasma concentration divided by the dose administered (Cmax/D) of AZD4831.
Time frame: Day 1 and Day 10
Apparent clearance for parent drug (CL/F) estimated as dose divided by AUCτ of AZD4831.
Time frame: Day 10
Mean Residence Time (MRT)
Time frame: Day 10
Apparent volume of distribution for parent drug at terminal phase(Vz/F)(extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz of AZD4831.
Time frame: Day 10
Accumulation ratio calculated as AUCτ Day 10/ AUCτ Day 1 (RacAUC) of AZD4831.
Time frame: Day 10
Accumulation ratio calculated as Cmax Day 10/ Cmax Day 1 (Rac Cmax) of AZD4831.
Time frame: Day 10
Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2)) of AZD4831.
Time frame: Day 1 and Day 10
Cumulative amount of analyte excreted at time t (Ae(0-t)) of AZD4831.
Time frame: Day 1 and Day 10
Fraction of dose excreted unchanged into the urine from time t1 to t2, estimated by dividing Ae(t1-t2) by dose (fe(t1-t2)) of AZD4831.
Time frame: Day 1 and Day 10
Fraction of dose excreted unchanged into the urine from time zero to time t, estimated by dividing Ae(0-t) by dose (fe(0-t)) of AZD4831
Time frame: Day 1 and Day 10
Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t), using appropriate matching time t (CLR) of AZD4831.
Time frame: Day 1 and Day 10
Terminal rate constant, estimated by log-linear least-squares regression rate constant, estiamteed by log-linear least-squares (λz)
Time frame: Day 10
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 18 Jan 2020.
- Individual participant dataSharing planned: Undecided
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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, MD principal investigator
California Clinical Trials Medical Group 1560 East Chevy Chase Dr., Suite 140 Glendale, CA 91206
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 Cardiovascular Disease, 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 2 inclusion and 23 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 18 Jan 2020. 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 participants with adverse events (AEs) (time frame: From screening (Day -28 to Day -2) until final follow-up (Day 24)). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 18 Jan 2020.