A Phase 2, Randomized, Double-blind, Placebo-Controlled Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose Levels of Belcesiran in Patients With Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 16
- 试验地点
- 23
- 主要终点
- Change From Baseline in Clinical Laboratory Tests: Basophils, Eosinophils, Leucocytes, Lymphocytes, Monocytes, Neutrophils and Platelets
研究概览
简要总结
This is a multiple dose, randomized, placebo-controlled, double-blind study of belcesiran to evaluate the safety, tolerability, PK, and PD in adult patients with PiZZ AATD-associated liver disease (AATLD).
The study will be conducted in 3 separate cohorts. A total of up to 16 participants may be enrolled in Cohort 1 and 2. A total number of 30 subjects will be enrolled in cohort 3. The 3 cohorts are differentiated by the duration of the treatment period, the number of doses administered, and the timing of the second liver biopsy.
详细描述
AATD-associated liver disease is a progressive condition resulting in liver fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. The lack of functional alpha-1 antitrypsin (AAT) in individuals with the PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity of neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism may be addressed by use of intravenous augmentation therapy, which aims to substitute the missing AAT by infusing alpha-1 proteinase inhibitor (A1PI), purified from pooled human plasma.
While augmentation therapy can address the loss of AAT in the lung, no treatment exists for the associated liver disease.
Given the severity of the disease, with approximately 10% of affected patients developing liver cirrhosis and a subgroup of those patients in need of liver transplantation, and the lack of an effective treatment that addresses the toxic hepatic "gain-of-function" mechanism, there is an urgent unmet medical need to develop a therapy that can help this particular patient population.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Double blind
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
- •18 to 75 years, inclusive, at the time of consent.
- •Documented diagnosis of PiZZ-type alpha-1 antitrypsin deficiency, confirmed by genotyping. Historical genotyping data may be used, if available.
- •AATD-associated liver disease documented by liver biopsy at Screening.
- •Consent to undergo paired liver biopsies.
- •Lung, renal and liver function within acceptable limits
- •Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
排除标准
- •History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other than PiZZ-type alpha-1 antitrypsin deficiency.
- •Child-Pugh Score B or C.
- •History of one single severe exacerbation of underlying lung disease in the year prior to randomization.
- •History of clinically significant respiratory infections (including pneumonia and lower respiratory tract infections), as determined by the Investigator, in the 3 months prior to screening
- •Use of an RNAi drug at any time.
研究组 & 干预措施
Belcesiran Cohort 1
干预措施: Belcesiran (Drug)
Placebo Cohort 1
干预措施: Placebo (Other)
Belcesiran Cohort 2
干预措施: Belcesiran (Drug)
Placebo Cohort 2
干预措施: Placebo (Other)
Belcesiran Cohort 3
干预措施: Belcesiran (Drug)
Placebo Cohort 3
干预措施: Placebo (Other)
结局指标
主要结局
Change From Baseline in Clinical Laboratory Tests: Basophils, Eosinophils, Leucocytes, Lymphocytes, Monocytes, Neutrophils and Platelets
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in basophils, eosinophils, leucocytes, lymphocytes, monocytes, neutrophils and platelets is presented.
Change From Baseline in Clinical Laboratory Tests: Basophils/Leucocytes
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in basophils/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Eosinophils/Leucocytes
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in eosinophils/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Haematocrit
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in haematocrit is presented.
Change From Baseline in Clinical Laboratory Tests: Lymphocytes/Leucocytes
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in lymphocytes/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Monocytes/Leucocytes
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in monocytes/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Neutrophils/Leucocytes
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in neutrophils/leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Reticulocytes/Erythrocytes
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in reticulocytes/erythrocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin Concentration and Haemoglobin
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular haemoglobin concentration and haemoglobin is presented.
Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Haemoglobin
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular haemoglobin is presented.
Change From Baseline in Clinical Laboratory Tests: Erythrocyte Mean Corpuscular Volume
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in erythrocyte mean corpuscular volume is presented.
Change From Baseline in Clinical Laboratory Tests: Erythrocytes
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in erythrocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Specific Gravity
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in specific gravity is reported.
Change From Baseline in Clinical Laboratory Tests: Urine Erythrocytes and Urine Leucocytes
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in urine erythrocytes and urine leucocytes is presented.
Change From Baseline in Clinical Laboratory Tests: Potential of Hydrogen (pH)
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in pH is presented.
Change From Baseline in Clinical Laboratory Tests: Activated Partial Thromboplastin Time and Prothrombin Time
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in activated partial thromboplastin time and prothrombin time is presented.
Change From Baseline in Clinical Laboratory Tests: Prothrombin International Normalized Ratio
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in prothrombin international normalized ratio is presented.
Change in Clinical Laboratory Tests: Alpha Fetoprotein, Biomarker Hyaluronic Acid, Biomarker Matrix Metalloproteinase 9, Biomarker Procollagen 3 N-Terminal Propeptide, Biomarker Tissue Inhibitor of Metalloproteinase 1, Complement C3a and Complement C5a
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in alpha fetoprotein, biomarker hyaluronic acid, biomarker matrix metalloproteinase 9, biomarker procollagen 3 N-Terminal propeptide, biomarker tissue inhibitor of metalloproteinase 1, complement C3a and complement C5a is presented.
Change From Baseline in Clinical Laboratory Tests: C-Reactive Protein
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in C-reactive protein is presented.
Change From Baseline in Clinical Laboratory Tests: Complement Bb
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in complement Bb is presented.
Change From Baseline in Clinical Laboratory Tests: Complement Total (CH50)
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in CH50 is presented.
Cohort 1: Change From Baseline in Serum Alpha-1 Antitrypsin (AAT) Protein Concentrations
时间窗: Baseline (Day 1), week 24
Change from baseline (Day 1) to week 24 in serum AAT protein concentrations in Cohort 1 is presented.
Cohort 2: Change From Baseline in Serum AAT Protein Concentrations
时间窗: Baseline (Day 1), week 48
Change from baseline (Day 1) to week 48 in serum AAT protein concentrations in Cohort 2 is presented.
Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: Up to 2.6 years
Number of TEAEs and SAEs is presented. An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs were defined as TEAEs if they had a start date on or after the administration of study drug during the treatment period, or if they occurred prior to the administration of study drug and worsened in severity/grade or relationship to the study intervention after the administration of study intervention during the treatment period. A SAE was defined as any untoward medical occurrence that, at any dose: a) resulted in death, b) is life-threatening, c) required inpatient hospitalization or prolongation of existing hospitalization, d) resulted in persistent disability/incapacity, e) was a congenital anomaly/birth defect.
Number of Participants With TEAEs and SAEs
时间窗: Up to 2.6 years
Number of participants with TEAEs and SAEs is presented. An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs were defined as TEAEs if they had a start date on or after the administration of study drug during the treatment period, or if they occurred prior to the administration of study drug and worsened in severity/grade or relationship to the study intervention after the administration of study intervention during the treatment period. A SAE was defined as any untoward medical occurrence that, at any dose: a) resulted in death, b) is life-threatening, c) required inpatient hospitalization or prolongation of existing hospitalization, d) resulted in persistent disability/incapacity, e) was a congenital anomaly/birth defect.
Change From Baseline in Pulmonary Function Tests (PFTs): Forced Vital Capacity (FVC)
时间窗: Baseline (Day 1), week 96
Change in FVC from baseline (Day 1) to week 96 is presented. FVC is the maximal volume of air exhaled with maximally forced effort from a maximal inspiration, that is, VC performed with a maximally forced expiratory effort.
Change From Baseline in PFT: Forced Expiratory Volume in One Second (FEV1)
时间窗: Baseline (Day 1), week 96
Change in FEV1 from baseline (Day 1) to week 96 is presented. FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration.
Change From Baseline in PFT: FEV1/FVC Ratio
时间窗: Baseline (Day 1), week 96
Change in FEV1/FVC ratio from baseline (Day 1) to week 96 is presented. FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. FVC is the maximal volume of air exhaled with maximally forced effort from a maximal inspiration, that is, VC performed with a maximally forced expiratory effort.
Change From Baseline in PFT: Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)
时间窗: Baseline (Day 1), week 96
Change in DLCO from baseline (Day 1) to week 96 is presented. DLCO is a measure of the quantity of carbon monoxide (CO) transferred per minute from alveolar gas to red blood cells (specifically hemoglobin) in pulmonary capillaries. It is expressed as millimoles per minute per kilopascal (mmol/min/kPa).
Change From Baseline in 12 -Lead Electrochardiograms (ECGs): Mean Heart Rate
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in mean heart rate is presented.
Change From Baseline in 12 -Lead ECGs: Mean Ventricular Rate
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in mean ventricular rate is presented.
Change From Baseline in 12 -Lead ECGs: PR Interval, QRS Interval, QT Interval, QTcF Interval and RR Interval
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in PR interval, QRS interval, QT interval, QTcF interval and RR interval is presented.
Number of Participants With Physical Examination Findings
时间窗: At week 96
Number of participants with physical examination findings at week 96 is presented. The data is presented under categories:a) Normal, b) Abnormal, not clinically significant, c) Abnormal, clinically significant.
Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in diastolic blood pressure and systolic blood pressure is presented.
Change From Baseline in Vital Signs: Heart Rate
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in heart rate is presented.
Vital Signs: Height at Baseline
时间窗: Baseline (Day 1)
Height at baseline is presented.
Change From Baseline in Vital Signs: Respiratory Rate
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in respiratory rate is presented.
Change From Baseline in Vital Signs: Temperature
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in temperature is presented.
Change From Baseline in Vital Signs: Weight
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in weight is presented.
Change in Clinical Laboratory Tests: Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Creatine Kinase, Glutamate Dehydrogenase, Lactate Dehydrogenase, Biomarker Creatine Kinase (M30) and Biomarker Creatine Kinase (M65)
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, creatine kinase, glutamate dehydrogenase, lactate dehydrogenase, biomarker creatine kinase (M30) and biomarker creatine kinase (M65) is presented.
Change From Baseline in Clinical Laboratory Tests: Albumin, Apolipoprotein A1, Protein, Biomarker Haptoglobin
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in albumin, apolipoprotein A1, protein and biomarker haptoglobin is presented.
Change From Baseline in Clinical Laboratory Tests: Bilirubin, Creatinine and Direct Bilirubin
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in bilirubin, creatinine and direct bilirubin is presented.
Change From Baseline in Clinical Laboratory Tests: Chloride, Cholesterol, Glucose, Potassium, Sodium, Triglycerides and Urea Nitrogen
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in chloride, cholesterol, glucose, potassium, sodium, triglycerides and urea nitrogen is presented.
Change From Baseline in Clinical Laboratory Tests: Gamma Glutamyl Transferase
时间窗: Baseline (Day 1), week 96
Change from baseline (Day 1) to week 96 in gamma glutamyl transferase is presented.
次要结局
- Change From Baseline in Liver Fibrosis Ishak Score(Baseline (Day 1), week 48)