A Phase I Study to Investigate the Effect of Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of AZD0780

Study identifier:D7960C00007

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Will Be Recruiting

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

Medical condition

Renal Impairment

Phase

Phase 1

Healthy volunteers

Yes

Study drug

AZD0780

Sex

All

Estimated Enrollment

Study type

Interventional

Age

18 Years - 85 Years

Date

Study Start Date: 05 Aug 2024

Estimated Primary Completion Date: 17 Jan 2025

Estimated Study Completion Date: 17 Jan 2025

Study design

Allocation: Non-randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Jun 2024 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

1. Participant must be 18 to 85 years of age, inclusive, at the time of signing the informed consent. (Participant with normal renal function must be matched to participant with renal
impairment by age [±10 years; determined at the time of signing the informed consent].)
- Healthy matched control participants only (Group 3):
2. 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.
3. Have an eGFR of ≥ 90 mL/min determined at screening.
- Renally impaired participants only (Groups 1, 2, and optional Group 4):
4. Diagnosis of chronic kidney disease, stable renal function in the 6 months prior to dosing, as determined by the investigator, based on medical history or eGFR, and not requiring dialysis (Groups 1 and 4; see inclusion criterion #6).
5. Received HD for chronic renal failure for at least 3 months prior to dosing (Group 2; see inclusion criterion #6).
6. Participants with renal impairment, as follows, based on CKD-EPI equation
(BSA-adjusted eGFR) at screening:
(a) Group 1: have severe renal impairment (eGFR < 30 mL/min), not requiring dialysis.
(b) Group 2: have ESRD (eGFR < 15 mL/min) on a stable intermittent HD schedule for at least 3 months prior to planned dosing.
(c) Group 4 (optional): have moderate renal impairment (eGFR ≥ 30 to < 60 mL/min).
7. All renally impaired participants on statin, angiotensin-converting enzyme
inhibitors/angiotensin II receptor blockers, beta-blocker, diuretic, or on any other cardiorenal relevant treatment should be on a stable dose for at least 2 weeks prior to screening.
8. If participants with severe renal impairment, ESRD, or moderate renal impairment have diabetes mellitus, it must be controlled and they must have haemoglobin A1c ≤ 10% at the screening visit.
- All participants (Groups 1 to 3 and optional Group 4):
9 Body weight of at least 50 kg and BMI within the range ≥ 18 to ≤ 40 kg/m2. (Participant with normal renal function must be matched to participant with renal impairment by
BMI [± 20% kg/m2; determined at screening].)
10 Sex: males and females (females of non-childbearing potential).
11 Male participants:
(a) 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. Acceptable methods of contraception include birth control pills, injections, implants, or patches, IUDs, tubal ligation/occlusion, and vasectomy.
A barrier method is not necessary if the female partner is sterilised. Male study participants must not donate or bank sperm during this same time period.
12 Female participants of non childbearing potential:
(a) 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. Women not of childbearing potential are defined as women who are either
permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral
salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to check-in without an alternative medical cause. The following age-specific requirements apply:
(i) Women < 50 years of age would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and FSH levels in the postmenopausal range.
(ii) Women ≥ 50 years of age would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
13 Restrictions for male participants
(a) Non-sterilized male participants should avoid fathering a child by either true abstinence or by using (together with their female partner/spouse) a highly effective contraception form of birth control in combination with a barrier method, starting from the time of study intervention administration until 3 months after discharge.
Acceptable methods of preventing pregnancy include birth control pills, injections, implants, or patches, IUDs, tubal ligation/occlusion, and vasectomy.
(b) Male participants who have been sterilised are required to use one barrier method of contraception (condom) from the time of study intervention administration until after
discharge. A barrier method is not necessary if the female partner is sterilised.
(c) Male participants should not donate sperm from the time of study intervention administration until 3 months after discharge.
14 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
15 Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative (see Appendix D 2).

Exclusion Criteria

- Healthy matched control participants only (Group 3):
1 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) which, in the opinion of the investigator, may put the participant at risk because of participation in the study, influence the results of the study, or affect the
participant’s ability to participate in the study.
2 Abnormal resting vital signs (after resting for 10 minutes) of supine BP > 150 mmHg or < 90 mmHg systolic or > 95 mmHg or < 50 mmHg diastolic or supine pulse rate ≥ 100 bpm or ≤ 45 bpm.
- Renally impaired participants only (Groups 1, 2, and optional Group 4):
3 Evidence of rapidly deteriorating renal function.
4 Haemoglobin < 8 g/dL at screening or check-in (Day -1).
5 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.
6 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.
7 Abnormal resting vital signs (after resting for 10 minutes) of supine BP > 160 mmHg or < 100 mmHg systolic or > 110 mmHg or < 65 mmHg diastolic or supine pulse rate ≥ 100 bpm or ≤ 50 bpm.
- All participants (Groups 1 to 3 and optional Group 4):
8 History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the investigator, at screening or Day -1, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD0780.
9 History of any major surgical procedure within 30 days prior to study intervention.
10 Any clinically or surgically significant condition that may affect AZD0780 absorption and/or excretion in the opinion of the investigator, including gastric restrictions and
bariatric surgery (eg, gastric bypass). Uncomplicated appendectomy and hernia repair will be allowed. Uncomplicated cholecystectomy is allowed at the discretion of the
investigator.
11 Judgement by the investigator that the participant should not participate in the study if they have any ongoing or recent (ie, during the screening period) minor medical complaints that may interfere with the interpretation of study data or if they are considered unlikely to comply with study procedures, restrictions, and requirements.
12 History of long QT syndrome or any clinically significant abnormalities on 12-lead ECG at screening or Day -1, as judged by the investigator, including but not limited to any of the following:
(a) Any significant arrhythmia.
(b) Conduction abnormalities (eg, Wolff-Parkinson-White syndrome, second degree AV block; at the discretion of the investigator).
(c) Prolonged QTcF > 450 ms for all healthy matched control participants and renally impaired participants without complete bundle branch block; > 480 ms for renally impaired participants with complete bundle branch block.
(d) Clinically significant PR (PQ) interval shortening (< 120 ms) or prolongation (> 240 ms); intermittent second- or third-degree AV block, or AV dissociation.
(e) Sinus node dysfunction with significant sinus pause untreated with pacemaker.
13 Any of the following signs or confirmation of COVID-19 infection at screening or Day -1:
(a) Participant has a positive SARS-CoV-2 test result within 2 weeks prior to screening, at screening, or on Day -1.
(b) Clinical signs and symptoms consistent with COVID-19 (eg, fever, dry cough, dyspnoea, sore throat, fatigue) within 2 weeks prior to screening or Day -1.
14 Positive test for human immunodeficiency virus at screening.
15 Positive results for hepatitis B surface antigen or hepatitis C virus at screening.
16 Known history of drug or alcohol abuse within 1 year of screening.
- Healthy matched control participants only (Group 3):
17 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.
- Renally impaired participants only (Groups 1, 2, and optional Group 4):
18 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.
19 Current or previous treatment with drugs for reduction or inhibition of PCSK9 (eg, evolocumab, alirocumab, or inclisiran).
20 Use of moderate/strong inhibitors or inducers of CYP3A4/5.
21 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.
22 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 Appendix G.
- All participants (Groups 1 to 3 and optional Group 4):
23 Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days of study intervention in this study or, if known, 5 half-lives from last dose in the previous study to study intervention in this study,
whichever is longest.
24 Previous enrolment in the present study. Note: participants consented and screened, but not receiving study intervention in this study or a previous Phase I study, are not excluded.
25 Participant smokes cigarettes, e-vapor cigarettes, pipes, or cigars or uses chewing tobacco, nicotine patch, or nicotine gum.
26 Positive screen for drugs of abuse (unless participant has renal impairment and positive screen is due to medication[s] prescribed by physician) and/or alcohol test at screening or Day -1.
27 Receipt of blood products within 2 months prior to Day -1, plasma or platelets donation within 1 month prior to Day -1, or any blood donation/blood loss > 500 mL within 3 months prior to Day -1.
28 Involvement of any AstraZeneca or clinical unit employee or their close relatives.
29 Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
30 Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

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

No locations available

Arms	Assigned Interventions
Other: Group 1 Participants with severe renal impairment (eGFR < 30 mL/min), not on dialysis.	Drug: AZD0780 - Dose formulation: Tablet - Unit dose strength: "B" - Dosage level: "A", single dose (2 × "B"-mg tablets) - Route of administration: Oral -Use: Experimental -IMP or NIMP: IMP -Sourcing: Provided centrally by the sponsor, AstraZeneca (or subsidiary or designee) -Packaging and labelling: AZD0780 will be provided in an HDPE bottle, labelled in accordance with national laws and regulations. The AZD0780 tablets will be provided in an open-label, participant specific bottle. A single "A" dose of AZD0780 (2 × "B" tablets) will be administered in the morning on Day 1 under fasted condition. Study intervention will be administered orally with approximately 240 mL of water.
Other: Group 2 Participants with ESRD (eGFR < 15 mL/min) on a stable intermittent HD schedule for at least 3 months prior to planned dosing.	Drug: AZD0780 - Dose formulation: Tablet - Unit dose strength: "B" - Dosage level: "A", single dose (2 × "B"-mg tablets) - Route of administration: Oral -Use: Experimental -IMP or NIMP: IMP -Sourcing: Provided centrally by the sponsor, AstraZeneca (or subsidiary or designee) -Packaging and labelling: AZD0780 will be provided in an HDPE bottle, labelled in accordance with national laws and regulations. The AZD0780 tablets will be provided in an open-label, participant specific bottle. A single "A" dose of AZD0780 (2 × "B" tablets) will be administered in the morning on Day 1 under fasted condition. Study intervention will be administered orally with approximately 240 mL of water.
Other: 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)	Drug: AZD0780 - Dose formulation: Tablet - Unit dose strength: "B" - Dosage level: "A", single dose (2 × "B"-mg tablets) - Route of administration: Oral -Use: Experimental -IMP or NIMP: IMP -Sourcing: Provided centrally by the sponsor, AstraZeneca (or subsidiary or designee) -Packaging and labelling: AZD0780 will be provided in an HDPE bottle, labelled in accordance with national laws and regulations. The AZD0780 tablets will be provided in an open-label, participant specific bottle. A single "A" dose of AZD0780 (2 × "B" tablets) will be administered in the morning on Day 1 under fasted condition. Study intervention will be administered orally with approximately 240 mL of water.
Other: Group 4 (optional) Participants with moderate renal impairment (eGFR ≥ 30 to < 60 mL/min).	Drug: AZD0780 - Dose formulation: Tablet - Unit dose strength: "B" - Dosage level: "A", single dose (2 × "B"-mg tablets) - Route of administration: Oral -Use: Experimental -IMP or NIMP: IMP -Sourcing: Provided centrally by the sponsor, AstraZeneca (or subsidiary or designee) -Packaging and labelling: AZD0780 will be provided in an HDPE bottle, labelled in accordance with national laws and regulations. The AZD0780 tablets will be provided in an open-label, participant specific bottle. A single "A" dose of AZD0780 (2 × "B" tablets) will be administered in the morning on Day 1 under fasted condition. Study intervention will be administered orally with approximately 240 mL of water.

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]