Clinical trial NCT06592482: A Phase I Study to Investigate the Effect of Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of AZD0780
Official title: A Phase I, Single-Dose, Non-Randomised, Open-Label, Parallel Group Study to Investigate the Effect of Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of AZD0780
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2024-09-19
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase I, multi-centre, single-dose, non-randomised, open-label, parallel-group study to examine the PK, safety, and tolerability of AZD0780 in male and female participants (females of non-childbearing potential) with severe renal impairment not on dialysis, end-stage renal disease (ESRD) on intermittent haemodialysis (HD), or moderate renal impairment (optional) compared with male and female participants (females of non-childbearing potential) with normal renal function. Potential participants will be screened to assess their eligibility to enter the study up to 4 weeks prior to administration of study intervention. Eligible participants will be admitted to the study site on Day -1. On Day 1, an "A" single oral dose of AZD0780 will be administered, and participants will be confined to the study site until after assessments are completed on Day 11.

Detailed description: This is a Phase I, multi-centre, single-dose, non-randomised, open-label, parallel-group study to examine the PK, safety, and tolerability of AZD0780 in male and female participants (females of non-childbearing potential) with severe renal impairment not on dialysis, end-stage renal disease (ESRD) on intermittent haemodialysis (HD), or moderate renal impairment (optional) compared with male and female participants (females of non-childbearing potential) with normal renal function.

Participants will be assigned to the following groups based on body surface area-adjusted estimated glomerular filtration rate (eGFR) determined by a local laboratory at screening by the Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation (2021) using serum creatinine:

Group 1: Participants with severe renal impairment (eGFR \< 30 mL/min), not on dialysis.

Group 2: Participants with ESRD (eGFR \< 15 mL/min) on a stable intermittent HD schedule for at least 3 months prior to planned dosing.

Group 3: Participants with normal renal function demographically matched by sex,age, and body mass index (BMI) to the impaired participants (eGFR of ≥90 mL/min).

Group 4 (optional): Participants with moderate renal impairment (eGFR ≥ 30 to \< 60 mL/min).

Initially, participants with severe renal impairment (Group 1) and ESRD (Group 2) will be enrolled, along with matching participants with normal renalfunction. An analysis of PK datamay be conducted to determine study progression. The decision to trigger the PK analysis and/or proceed with an evaluation of participants with moderate renal impairment (Group 4) will be made by the sponsor.

Each matched participant with normal renal function (Group 3) enrolled in the study will be demographically matched by sex, age (±10 years), and BMI (±20% kg/m2; data obtained at screening) to an enrolled renal impairment participant. Participants with normal renal function cannot be matched to more than one renally impaired participant within an impairment group; however, participants with normal renal function may be matched to 1 participant from more than 1 renal impairment group.

Potential participants will be screened to assess their eligibility to enter the study up to 4 weeks prior to administration of study intervention. Eligible participants will be admitted to the study site on Day -1. On Day 1, a "A" single oral dose of AZD0780 will be administered, and participants will be confined to the study site until after assessments are completed on Day 11.

For participants with ESRD (Group 2), the first post dose HD session should be scheduled to start 26 hours after administration of AZD0780. Subsequent HD sessions should be scheduled as clinically appropriate.

Serial PK (venous) blood samples will be collected up to 240 hours postdose and urine samples will be collected up to 96 hours postdose for the measurement of AZD0780. Urine collection is not required for participants who are anuric (ie, participants with ESRD on HD \[Group 2\]). For participants with ESRD (Group 2), blood samples for PK analysis will also be collected prior to, during, and at the end of HD. The entire dialysate will be collected in separate hourly collections on Day 2 for participants with ESRD (Group 2) for the measurement of AZD0780. The volume of each hourly collection of dialysate from which a sample is taken will be recorded. Physical examinations, 12-lead electrocardiograms, vital sign measurements, and clinical laboratory tests will be performed to assess safety and tolerability.

Eligibility criteria: Inclusion Criteria:

- Participant must be 18 to 85 years of age, inclusive at the time of signing ICF

For Participants with normal renal function:

- Participant must be medically healthy with no clinically significant medical history, physical examination, clinical laboratory profiles, vital signs, or 12-lead ECGs, as deemed by the investigator at screening and Day -1

For Participants with renal impairment:

* Diagnosis of chronic kidney disease, stable renal function in the 6 months prior to dosing
* Received HD for chronic renal failure for at least 3 months prior to dosing (Group 2)
* Participants with renal impairment, as follows, based on CKD-EPI equation (BSA-adjusted eGFR) at screening: Group1 eGFR \< 30 mL/min), not requiring dialysis, Group 2 ESRD (eGFR \< 15 mL/min) on a stable intermittent HD schedule for at least 3 months prior to planned dosing and Group 4 (optional) moderate renal impairment (eGFR ≥ 30 to \< 60 mL/min)
* Male participants:
* Males must be surgically sterile or using, in conjunction with their female partner, a highly effective method of contraception for the duration of the study (from the time of study intervention administration) until 3 months after discharge to prevent pregnancy in a partner.
* Female participants of non-childbearing potential:
* Female participants must not be pregnant and must have a negative pregnancy test at screening and check-in, must not be lactating, and must not be of childbearing potential.

Exclusion Criteria:

For Participants with normal renal function:

* Any clinically significant disease or disorder (eg, cardiovascular, pulmonary, gastrointestinal, liver, renal, neurological, musculoskeletal including bone fractures, endocrine including adrenal insufficiency, metabolic, malignant, psychiatric, major physical impairment).
* Use of any prescription or non-prescription drugs (including vitamins, recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before study intervention, unless, in the opinion of the investigator and sponsor, the medication will not interfere with the study.
* History of any major surgical procedure within 30 days prior to study intervention.

For Participants with renal impairment:

* Presence of unstable medical or psychological conditions which, in the opinion of the investigator, would compromise the participant's safety or successful participation in this study.
* Renal transplant patients (participants on HD with non-functioning renal transplants are not excluded), participants waiting for organ transplant scheduled to occur during the study, and those with a history of acute kidney injury occurring within 3 months prior to screening.
* History of any major surgical procedure within 30 days prior to study intervention.
* Current or previous treatment with drugs for reduction or inhibition of PCSK9 (eg, evolocumab, alirocumab, or inclisiran).
* Use of moderate/strong inhibitors or inducers of CYP3A4/5.
* Unable to refrain from potassium binders, phosphate binders (eg, aluminium hydroxide and calcium carbonate), cholestyramine/colestipol, and ranitidine/nizatidine within 10 hours before and 10 hours after study intervention.
* Receiving or has received within 14 days of screening, medication that contains a black box warning for significant QT prolongation. A list of prohibited medications can be found in protocol.
* Use of concurrent medication which affects calculation of eGFR by affecting serum creatinine (eg, cephalosporin antibiotics, ascorbic acid, trimethoprim, cimetidine, or quinine) within 7 days of Day -1.

Primary outcomes:
measure: AUClast
timeFrame: From Day 1 to Day 11
measure: Cmax
timeFrame: From Day 1 to Day 11
measure: AUCinf
timeFrame: From Day 1 to Day 11
Secondary outcomes:
measure: Number of participants with adverse events (AEs)
timeFrame: From Day 1 to Day 11
measure: Number of participants with abnormal vital signs, abnormal ECGs, and abnormal physical examination findings
timeFrame: From Day 1 to Day 11
measure: Number of participants with abnormal laboratory test results
timeFrame: From Day 1 to Day 11
measure: PK parameters Tmax
timeFrame: From Day 1 to Day 11
measure: PK parameters t1/2λz
timeFrame: From Day 1 to Day 11
measure: PK parameters CL/F
timeFrame: From Day 1 to Day 11
measure: PK parameters CLNR/F
timeFrame: From Day 1 to Day 11
measure: PK parameters Vz/F
timeFrame: From Day 1 to Day 11
measure: PK parameters AUC0-96
timeFrame: From Day 1 to Day 11
measure: PK parameters CLr
timeFrame: From Day 1 to Day 11
measure: PK parameters Ae
timeFrame: From Day 1 to Day 11
measure: PK parameters Fe
timeFrame: From Day 1 to Day 11
Other outcomes:
Locations:
city: Lake Forest
country: United States
facility: Research Site
state: California
city: Hialeah
country: United States
facility: Research Site
state: Florida
city: Orlando
country: United States
facility: Research Site
state: Florida
city: Orlando
country: United States
facility: Research Site
state: Florida
city: Saint Paul
country: United States
facility: Research Site
state: Minnesota
Study officials:
affiliation: Omega Research Orlando
name: Kwabena Ayesu, Medicine
role: PRINCIPAL_INVESTIGATOR
affiliation: Orlando Clinical Research Center
name: Thomas Marbury, Medicine
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Pharmacology of Miami, Inc.
name: Juan Carlos Rondon, Medicine
role: PRINCIPAL_INVESTIGATOR
affiliation: Nucleus Network
name: Trisha Shamp, Medicine
role: PRINCIPAL_INVESTIGATOR
affiliation: Orange County Research Center
name: Joel Neutel, Medicine
role: PRINCIPAL_INVESTIGATOR
References: