Clinical trial NCT04949438: A Study to Assess the Pharmacokinetics (Uptake of Drugs by the Body), Safety and Tolerability of AZD4831 in Participants With Severe Renal Impairment and Healthy Volunteers
Official title: A Single Dose, Non-Randomised, Open-Label, Parallel Group Study to Assess the Pharmacokinetics, Safety and Tolerability of AZD4831 in Participants With Severe Renal Impairment and Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Keywords: AZD4831
Pharmacokinetics
Estimated glomerular filtration rate
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2021-07-02
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a study to compare AZD4831 pharmacokinetic (PK) parameters between participants with severe renal impairment and matched healthy volunteers following a single dose administration.

Detailed description: All participants will receive a single oral dose of AZD4831 under fasted conditions and will be involved in the study approximately 2 weeks after dosing and up to approximately 38 days from screening.

Approximately 10 participants will be enrolled into each of the 2 cohorts parallelly and receive the study intervention to achieve 8 evaluable participants in each cohort.

* Cohort 1: 10 participants with severe renal impairment (Estimated glomerular filtration rate \[eGFR\] of ≥15 to \<30 mL/min/1.73m\^2)
* Cohort 2: 10 matched healthy volunteers with normal renal function (eGFR of ≥90 mL/min/1.73m\^2).

The study will comprise of the following study periods:

* Screening period (21 days): participants will be screened for eligibility.
* Treatment period (3 days): participants will be admitted to the study centre in the evening of (Day -1) the day before administration of a single oral dose of AZD4831 (Day 1), and will be discharged after at least 24 h post-dose (Day 2).
* Follow-up period (13±2 days): participants will attend 5 visits at the study centre for PK sampling and safety assessments on Days 3, 5, 8, 11 and 15.

Eligibility criteria: Inclusion Criteria:

* All participants must be 18 to 80 (inclusive) years of age, at the time of signing the informed consent.
* The age of participants in Cohort 2 (matched healthy volunteers) must not be lesser than 10 years below the lowest age in Cohort 1 (participants with severe renal impairment) or greater than 10 years above the highest age in Cohort 1.

Healthy volunteers only (Cohort 2):

* Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
* An eGFR of ≥90 mL/min/1.73m\^2 as determined at screening using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.

Participants with severe renal impairment only (Cohort 1):

* An eGFR of ≥15 to \<30 mL/min/1.73m\^2 as determined at screening using the CKD-EPI formula.
* Stable renal function.
* If participants are on statin, ACEi/ARB, beta-blocker, diuretic or on any other cardiorenal relevant treatment, the dose should be stable at least 2 weeks prior to screening (Visit 1).
* Body weight of at least 50 kg and body mass index (BMI) within the range ≥18 to ≤35 kg/m\^2.
* BMI of participants in Cohort 2 (healthy volunteers) must not be more than 20% below the lowest BMI in Cohort 1 (participants with severe renal impairment) or more than 20% above the highest BMI in Cohort 1.
* Male or female of non-childbearing potential.
* There should be an equal number of male and female participants in Cohort 2 (healthy volunteers) as in Cohort 1 (participants with severe renal impairment).

  1. Male participants: All male participants should use methods of contraception consistent with local regulations for those participating in clinical studies.
  2. Highly effective birth control methods are defined as those that can achieve a failure rate of less than 1% per year when used consistently and correctly
  3. Female participants: Must have a negative serum pregnancy test at screening and admission to the study centre (Day -1), must not be lactating and must be of non-childbearing potential confirmed at screening.
* Male participants should not donate sperm for the duration of the study and for at least 90 days after the last study follow-up visit.
* Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research.

Exclusion Criteria:

* Any evidence of a clinically significant disease or disorder.
* Positive hepatitis C antibody, hepatitis B virus surface antigen, hepatitis B virus core antibody, or human immunodeficiency virus I or II at screening (Visit 1).
* History of drug or alcohol abuse within 1 year of screening or positive test for drugs of abuse and alcohol at screening and admission to the study centre.
* History of allergy/hypersensitivity to drugs with a similar chemical structure or class to AZD4831or any of the excipients of the product.
* Any of the following signs or confirmation of Corona Virus 2019 (COVID-19) infection

  a. Participant has a positive severe acute respiratory syndrome coronavirus 2 reverse transcription-polymerase chain reaction test result within 2 weeks before screening (Visit 1) or between screening and admission to study centre (Visit 2).

  (i) Clinical signs and symptoms consistent with COVID-19 (eg, fever, dry cough, dyspnoea, sore throat, fatigue) 2 weeks before screening (Visit 1) or between screening and admission to study centre (Visit 2).

(ii) Participant has been previously hospitalised with COVID-19 infection within the last 3 months.

Healthy volunteers only (Cohort 2):

- History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.

Participants with severe renal impairment only (Cohort 1):

* Renal transplant participants or participants on dialysis.
* Use of concurrent medication, which affect creatinine clearance such as cephalosporin antibiotics, ascorbic acid, trimethoprim, cimetidine, or quinine within days of admission to the study centre (Day -1).
* Use of drugs with enzyme-inducing properties such as St John's Wort within 7 days or 5 half-lives (whichever is longer) prior to screening (Visit 1).
* Any concomitant medications known to be associated with Torsades de Pointes or strong cytochrome P450 3A4 (CYP3A4) inducers or inhibitors.

Healthy volunteers only (Cohort 2):

- Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol), herbal remedies, megadose vitamins and minerals within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the study intervention and until completion of the follow-up visits.

Primary outcomes:
measure: Maximum observed plasma concentration (Cmax)
timeFrame: From Day 1 to Day 15
measure: Time to reach maximum observed plasma concentration (tmax)
timeFrame: From Day 1 to Day 15
measure: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)
timeFrame: From Day 1 to Day 15
measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
timeFrame: From Day 1 to Day 15
measure: Apparent total non-renal body clearance of drug from plasma after extravascular administration (CLNR/F)
timeFrame: From Day 1 to Day 15
measure: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
timeFrame: From Day 1 to Day 15
measure: Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUClast)
timeFrame: From Day 1 to Day 15
measure: Area under plasma concentration-time curve from time zero to infinity (AUCinf)
timeFrame: From Day 1 to Day 15
measure: Renal clearance of drug from plasma (CLR)
timeFrame: Days 1 and 2
Secondary outcomes:
measure: Number of participants with adverse events
timeFrame: From Screening (Day -21 to Day -1) until Day 15 or Early Termination Visit
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: Research Site
Study officials:
References: