A Phase I Study to Investigate the Effect of Hepatic Impairment of AZD9550 and AZD6234

Официальное название

A Phase I, Multicentre, Single-Dose, Non-Randomised, Open-Label, Parallel-Group Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of AZD9550 and AZD6234

Обзор

The purpose of this study is to examine the safety and tolerability of AZD6234 and AZD9550 in participants with hepatic impairment and participants with normal hepatic function.

Подробное описание

This Phase I, open-label, parallel group study will investigate the single SC dose PK, safety, tolerability, and immunogenicity of separate administrations of AZD9550 and AZD6234 to male and female participants with severe and moderate hepatic impairment compared to matched controls with normal hepatic function.

To minimize any potential impact from AZD9550 administered in Period 1, AZD6234 will be administered in Period 2 following a washout period. Results from separate injections will ultimately inform the single dose PK, safety, and tolerability of AZD9550 and AZD6234 administered.

Approximately 56 participants will be screened to achieve a total of 16 planned for study intervention (8 per group for CP Class C and CP Class B) with 6 evaluable participants in each of the 2 impairment groups (severe and moderate), and up to 12 participants with normal hepatic function. Initially 8 participants with normal hepatic function will be recruited, matched on a group level regarding sex, age, and BMI to the participants with hepatic impairment. Additional participants with normal hepatic function, up to a total of 12, may be included if needed to meet the matching criteria.

Child-Pugh scoring will be used to determine the level of hepatic impairment. Participants will be enrolled into the following groups based on their CP classification score as determined by a local laboratory at screening:

Group 1: Participants with severe hepatic impairment (CP Class C, score of 10 to 15).

Group 2: Participants with moderate hepatic impairment (CP Class B, score of 7 to 9).

Group 3: Participants with normal hepatic function matched on a group level regarding sex, age, and BMI to the participants with hepatic impairment.

Вмешательства

• Препарат AZD6234
  Single subcutaneous dose of AZD6234 in participants from all groups
• Препарат AZD9550
  Single subcutaneous dose of AZD9550 in participants from all groups

Первичные конечные точки

• PK parameters AUCinf [Срок оценки: Day 0 through Day 56]
• PK parameters AUClast [Срок оценки: Day 0 through Day 56]
• PK parameters Cmax [Срок оценки: Day 0 through Day 56]

Вторичные конечные точки (5)

• PK parameters tmax [Срок оценки: Day 0 through Day 56]
• Prevalence and incidence of ADAs to AZD9550 and AZD6234 [Срок оценки: Day 0 through Day 56]
• PK parameters t1/2λz [Срок оценки: Day 0 through Day 56]
• PK parameters CL/F [Срок оценки: Day 0 through Day 56]
• PK parameters Vz/F [Срок оценки: Day 0 through Day 56]

Критерии участия

Критерии включения

• Age 18-85 years at consent.
• Groups:

• Healthy controls: Medically healthy; no clinically significant findings in history, exam, labs, vitals, or 12 lead ECG (per investigator).
• Hepatic impairment: Chronic (≥6 months), stable; documented Child Pugh B (Group 2) or C (Group 1).
• Stable concomitant regimen ≥2 weeks before screening (Groups 1-2).
• T2DM allowed if HbA1c <10% and no severe hypo/hyperglycaemia or hospitalisation within 6 months.
• Body weight ≥50 kg; BMI 18-42 kg/m².
• Sex assigned at birth (male/female); contraception per local regulations. Females of child bearing potential: negative pregnancy tests and condoms plus one highly effective method through 54 days post last dose. Males: condom use; no sperm donation through 54 days post last dose.
• Written informed consent; separate consent for optional genomics.

Критерии исключения

Healthy controls only:

• Any clinically significant disease; Diabetes;
• lab values i) ALT/AST/ALP >1.5×ULN; ii) WBC/platelets <LLN; iii) haemoglobin <11.0 g/dL (female) or <12.0 g/dL (male); aPTT or PT/INR >1.2×ULN; iv) total bilirubin >1.5×ULN (or Gilbert's);
• abnormal resting vital signs i) SBP >150 or <90 mmHg, ii) DBP >95 or <50 mmHg, iii) pulse ≥100 or ≤45 bpm;
• QTcF >450 ms or clinically significant ECG abnormalities;
• severe allergy/hypersensitivity;
• major surgery within 30 days;
• pancreatitis or pancreatic enzymes >2×ULN;
• triglycerides >500 mg/dL (5.6 mmol/L);
• calcitonin >50 ng/L (50 pg/mL);
• severe vitamin D deficiency (<12 ng/mL, 30 nmol/L);
• low corrected or ionised calcium;
• HIV positive; HBV surface/core Ab or HCV Ab positive; drug/alcohol abuse within 1 year.

Hepatically impaired only:

• Unstable medical/psychological conditions or uncontrolled systemic disease;
• eGFR <50 mL/min/1.73 m² (CKD EPI 2021);
• Abnormal resting vital signs i) SBP >160 or <100 mmHg, ii) DBP >110 or <65 mmHg, iii) pulse ≥100 or ≤50 bpm;
• platelets <35×10⁹/L; neutrophils <1.2×10⁹/L; haemoglobin <85 g/L; HbA1c ≥10%;
• oesophageal banding within 3 months or GI bleeding within 6 months;
• ascites requiring paracentesis and albumin ≤4 week intervals; paracentesis within 30 days;
• fluctuating/worsening hepatic function during screening; hepatocellular carcinoma;
• acute liver disease due to infection/drug; hepatic impairment due to non liver disease;
• biliary obstruction or non parenchymal causes; hepatic encephalopathy Grade ≥2;
• functioning organ transplant or anticipated within 2 months; prior porto systemic shunt/TIPS;
• QTcF >480 ms or clinically significant ECG abnormalities;
• pancreatitis or pancreatic enzymes >2×ULN;
• triglycerides >500 mg/dL (5.6 mmol/L); calcitonin >50 ng/L (50 pg/mL); severe vitamin D deficiency (<12 ng/mL, 30 nmol/L); ionised calcium <LLN;
• neoplastic disease within 10 years (except adequately treated BCC/SCC or in situ cervical); MEN2 or medullary thyroid carcinoma (personal or first degree relative); significant gastric emptying abnormality;
• HIV positive; HBV surface/core Ab or HCV Ab positive (may be included if HBV DNA or HCV RNA negative on follow up); drug/alcohol abuse within 1 year.
• Exposure to a new chemical entity within 30 days or 5 half lives (whichever longer) before intervention; prior exposure to AZD9550 or AZD6234;

Prior/concomitant therapy:

Healthy controls:

• use of prescription/non prescription/supplements within 7 days (or 14 days for enzyme inducers) or 5 half lives before intervention unless judged non interfering; current oral contraceptives or oestrogen HRT.

Hepatically impaired:

• prohibited-weight loss medicines (including GLP 1), agents causing significant weight gain (e.g., systemic glucocorticoids, antipsychotics), GLP 1 RAs for diabetes, QT prolonging/prokinetic agents, oral contraceptives for contraception; restricted-short systemic glucocorticoids (≤7 days), 5HT 3 antiemetics at lowest effective dose, combined oral contraceptives for non contraceptive indications. If diabetes develops and requires insulin/SU/GLP 1 RA, discontinue from study.

Other:

• prior enrolment in this study (screened without dosing permitted). Positive drugs of abuse and/or alcohol screen (except prescribed meds in hepatic impairment); recent blood products/donation per protocol thresholds; employees or close relatives; vulnerable populations; unlikely to comply (investigator judgement).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Другое

Центры проведения

США · 4 центра

• Research Site — Chandler
• Research Site — Rialto
• Research Site — Miami Lakes
• Research Site — San Antonio

Идентификаторы

NCT: NCT07546760 · D8460C00003

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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