NCT05677971招募中3 期
A Randomized, Double-blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Fazirsiran in the Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease With METAVIR Stage F2 to F4 Fibrosis
Takeda143 个研究点 分布在 12 个国家目标入组 160 人开始时间: 2023年3月6日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 160
- 试验地点
- 143
- 主要终点
- Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy at Week 106 in AATD-LD With METAVIR Stage F2 and F3 Fibrosis
研究概览
简要总结
The main aim of this study is to learn if fazirsiran reduces liver scarring (fibrosis) compared to placebo. Other aims are to learn if fazirsiran slows down the disease worsening in the liver, to get information on how fazirsiran affects the body (called pharmacodynamics), to learn if fazirsiran reduces other liver injury (inflammation) and the abnormal Z-AAT protein in the liver, to get information on how the body processes fazirsiran (called pharmacokinetics), to test how well fazirsiran works compared with a placebo in improving measures of liver scarring including imaging and liver biomarkers (substances in the blood that the body normally makes and help show if liver function is improving, staying the same, or getting worse) as well as to check for side effects in participants treated with fazirsiran compared with those who received placebo.
Participants will either receive fazirsiran or placebo. Liver biopsies, a way of collecting a small tissue sample from the liver, will be taken twice during this study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The participant must have a diagnosis of the Z allele homozygotes (PiZZ) genotype AATD. PiZZ diagnosis from source verifiable medical records is permitted. Otherwise, participants must undergo PiZZ confirmatory testing (genotyping for PiS and PiZ alleles) at screening. PiMZ or PiSZ genotypes are not permitted.
- •The participant, of any sex, is aged 18 to 75 years, inclusive.
- •The participant's liver biopsy core sample collected should meet the requirements of the protocol.
- •The participant has evidence of METAVIR stage F2, F3, or F4 liver fibrosis, evaluated by a centrally read baseline liver biopsy during the screening period; or confirmed as meeting all the entry criteria by central reading of a previous biopsy conducted within 6 months before the estimated enrollment date using an adequate liver biopsy and slides as defined in the study laboratory manual.
- •The participant has a pulmonary status meeting the protocol's requirements.
- •It must be confirmed that the participant does not have HCC. Participants will be screened for HCC with alpha-fetoprotein (AFP) and abdominal ultrasound. If the participant has any of the following, they will be required to have contrast-enhanced CT or MRI imaging to exclude HCC before randomization.
- •An adult participant must have a body mass index (BMI) greater than or equal to (>=) 18.0 kilograms per meter square (kg^m2).
- •The participant is a nonsmoker for at least 6 months before screening.
排除标准
- •The participant has a history of liver decompensating events (overt hepatic encephalopathy [West Haven Grade >=2] documented by a physician or healthcare professional, clinically significant ascites, spontaneous bacterial peritonitis, GI bleeding from varices, hepatopulmonary syndrome, hepatorenal syndrome, portal pulmonary hypertension, or bleeding portal hypertensive gastropathy).
- •The participant has a history of the presence of medium or large varices or varices with red wale signs based on a previous esophagogastroduodenoscopy (EGD) within 6 months before the estimated enrollment date. For certain participants, an EGD will be required at screening if there is no EGD available within 6 months before the estimated enrollment date. Presence of small varices with no red wale signs on EGD and no history of bleeding will be acceptable for study eligibility.
- •The participant has evidence of chronic liver disease attributable to other diseases, including viral hepatitis B or C, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis.
- •The participant has alanine transaminase (ALT) or aspartate transaminase (AST) levels >250 units per liter (U/L).
- •The participant has a platelet count <60,000 per cubic millimeter (mm^3) (<60 × 10^9 per liter [10^9/L]).
- •The participant has albumin <=2.8 gram per deciliter (g/dL) (28 grams per liter [g/L]).
- •The participant has international normalized ratio (INR) >=1.
- •The participant is expected to have severe and unavoidable high-level exposure to inhaled pulmonary toxins during the study such as may occur with occupational exposure to mineral dusts or metals.
- •The participant has a history of drug abuse (such as cocaine, phencyclidine) within 1 year before the screening visit or has a positive urine drug screen at screening.
- •The participant has previously been treated with fazirsiran or any other RNAi for AATD-LD.
- •The participant has portal vein thrombosis.
- •The participant has a prior transjugular portosystemic shunt procedure.
- •The participant has a history of malignancy within the last 5 years, except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with other curatively treated malignancies who have no evidence of metastatic disease and a greater than 1-year disease-free interval may be entered after approval by the medical monitor.
研究组 & 干预措施
Fazirsiran
Experimental
Participants will receive fazirsiran 200 milligram per milliliter (mg/ml) subcutaneous (SC) injection on Day 1, at Week 4, and then every 12 weeks (Q12 W) thereafter up to Week 196.
干预措施: Fazirsiran Injection (Drug)
Placebo
Placebo Comparator
Participants will receive placebo on Day 1, at Week 4, and Q12 W thereafter up to Week 196.
干预措施: Placebo (Other)
结局指标
主要结局
Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy at Week 106 in AATD-LD With METAVIR Stage F2 and F3 Fibrosis
时间窗: Baseline, Week 106
Reduction from baseline of at least 1 stage of histologic fibrosis METAVIR staging in the centrally read liver biopsy at Week 106 in AATD-LD with METAVIR stage F2 and F3 fibrosis will be assessed.
次要结局
- Percent Change from Baseline in Intrahepatic Z-AAT Protein in Alpha-1 Antitrypsin Deficiency-Associated Liver Disease (AATD-LD) with METAVIR Stage F2 to F3 Fibrosis at Week 106(Baseline, Week 106)
- Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy(Baseline, Week 106 and Week 202)
- Number of Participants With Liver Related Clinical Events up to Week 202(Baseline up to Week 202)
- Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) Protein(Baseline, Week 106, Week 202)
- Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining(Baseline, Week 106, Week 202)
- Change From Baseline in Intrahepatic Portal Inflammation(Baseline, Week 106, Week 202)
- Change From Baseline in Vibration-Controlled Transient Elastography (VCTE)/Magnetic Resonance Elastography (MRE)-derived Liver Stiffness(Baseline, Week 106, Week 196 and Week 202)
- Change From Baseline in Model of End-Stage Liver Disease (MELD) Score(Baseline, Week 106, and Week 202)
- Change From Baseline in Liver Injury(Baseline, Week 106 and Week 202)
- Percent Change from Baseline in Intrahepatic Z-AAT Protein in AATD-LD With METAVIR Stage F2 to F4 Fibrosis(Baseline, Week 106 and Week 202)
- Observed Plasma Concentrations of Fazirsiran(Pre-dose up to Week 220)
- Number of Participants with Treatment-emergent adverse event (TEAE) and Serious TEAEs(From start of study drug administration up to end of the study (EOS) (Week 230))
- Number of Participants with Clinically Significant Declines in Lung Function Parameters(From start of study drug administration up to EOS (Week 230))
- Change From Baseline in Whole Lung PD15 (15th percentile point) Measured by CT lung Densitometry(Baseline up to Week 196)
- Number of Participants with Clinically Significant Change in Vital Signs(From start of study drug administration up to EOS (Week 230))
- Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters(From start of study drug administration up to EOS (Week 230))
- Number of Participants with Clinically Significant Changes in Clinical Laboratory Assessments(From start of study drug administration up to EOS (Week 230))
研究者
研究点 (143)
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