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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 28
- 试验地点
- 4
- 主要终点
- PK parameters AUCinf
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age 18-85 years at consent.
- •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.
排除标准
- •Healthy controls only:
- •Any clinically significant disease; Diabetes;
- •lab values i) ALT/AST/ALP >1.5×ULN; ii) WBC/platelets \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 \
研究组 & 干预措施
Group 2
Participants with moderate hepatic impairment (CP Class B, score of 7 to 9).
干预措施: AZD6234 (Drug)
Group 2
Participants with moderate hepatic impairment (CP Class B, score of 7 to 9).
干预措施: AZD9550 (Drug)
Group 1
Participants with severe hepatic impairment (CP Class C, score of 10 to 15).
干预措施: AZD6234 (Drug)
Group 3
Participants with normal hepatic function matched on a group level regarding sex, age, and BMI to the participants with hepatic impairment.
干预措施: AZD9550 (Drug)
Group 3
Participants with normal hepatic function matched on a group level regarding sex, age, and BMI to the participants with hepatic impairment.
干预措施: AZD6234 (Drug)
Group 1
Participants with severe hepatic impairment (CP Class C, score of 10 to 15).
干预措施: AZD9550 (Drug)
结局指标
主要结局
PK parameters AUCinf
时间窗: Day 0 through Day 56
To compare the plasma PK of separate single SC doses of AZD9550 and AZD6234 in participants with severe and moderate hepatic impairment with matched controls with normal hepatic function
PK parameters AUClast
时间窗: Day 0 through Day 56
To compare the plasma PK of separate single SC doses of AZD9550 and AZD6234 in participants with severe and moderate hepatic impairment with matched controls with normal hepatic function
PK parameters Cmax
时间窗: Day 0 through Day 56
To compare the plasma PK of separate single SC doses of AZD9550 and AZD6234 in participants with severe and moderate hepatic impairment with matched controls with normal hepatic function
次要结局
- PK parameters tmax(Day 0 through Day 56)
- Prevalence and incidence of ADAs to AZD9550 and AZD6234(Day 0 through Day 56)
- PK parameters t1/2λz(Day 0 through Day 56)
- PK parameters CL/F(Day 0 through Day 56)
- PK parameters Vz/F(Day 0 through Day 56)