A 2-Part Safety and Tolerability Study of ALN-AAT02 in Healthy Volunteers and Patients with ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
- Conditions
- ZZ Type Alpha-1 Antitrypsin Deficiency Liver DiseaseMedDRA version: 20.1Level: PTClassification code 10001806Term: Alpha-1 anti-trypsin deficiencySystem Organ Class: 10010331 - Congenital, familial and genetic disordersTherapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
- Registration Number
- EUCTR2018-001362-41-GB
- Lead Sponsor
- Alnylam Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 96
Inclusion Criteria for All Participants in Part A and Part B
- Male or female, aged 18 to 65 years, inclusive
- Body mass index (BMI) =18.0 kg/m2 and =30 kg/m2
- Nonsmoker for at least 5 years before screening
Additional Inclusion Criteria for Subjects in Part A
- AAT levels within normal limits
- FEV1 =85% of predicted and FEV1/forced vital capacity ratio =0.7
Additional Inclusion Criteria for Patients in Part B
- Documented ZZ type AAT by genotype
- Liver biopsy performed within 90 days of the first dose of study drug demonstrating liver histopathology consistent with PiZZ AATD liver disease meeting the following criteria:
a.Presence of diastase-resistant PAS-positive globules in hepatocytes
b.Ishak fibrosis score of <4
- Post-bronchodilator FEV1 =70% of predicted and diffusing capacity of the lung for carbon monoxide =50% of predicted
- Prior/Concomitant Therapy: If on any maintenance medication regimen, likely, in the opinion of the Investigator, to be able to remain on a stable medication regimen for the duration of the study (no new medications within 30 days prior to first dose of study drug)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 96
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range
Exclusion Criteria for All Participants in Part A and Part B
- Has known active human immunodeficiency virus (HIV) infection, or evidence of current or chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection
- Has an estimated glomerular filtration of =45 mL/min/1.73 m2 at screening
- Has any clinical safety laboratory result considered clinically significant and unacceptable by the Investigator during screening or on Day 1
- Received an investigational agent within 30 days or within 5 elimination half-lives, whichever is longer prior to the first dose of study drug, or are in follow-up of another clinical study prior to study enrollment
- Is unwilling or unable to limit alcohol consumption throughout the course of the study. Alcohol intake of >2 units/day is excluded during the study
- Has history of alcohol abuse, within the last 12 months before screening, in the opinion of the Investigator
- Has known history or clinical evidence of drug abuse, within the 12 months before screening.
Additional Exclusion Criteria for Subjects in Part A
- Is positive for the rs1303 single nucleotide polymorphism in the SERPINA1 gene
- Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >upper limit of normal (ULN) at screening
- Has total bilirubin above the ULN
- Has history of asthma or recurrent or chronic lung disease, excluding childhood asthma that has resolved
- Has history of chronic liver disease from any cause
Additional Exclusion Criteria for Patients in Part B
- Has any of the following laboratory parameter assessments at screening:
a. Alanine aminotransferase or AST =1.5× ULN
b. Total bilirubin >ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible.
c. Serum albumin level =80% of the LLN
d. Platelet count =100,000 per microliter
e. International normalized ratio (INR) or prothrombin time (PT) >1.2 of the clinical laboratory reference range
- Receiving augmentation therapy for AAT deficiency or who have received augmentation therapy within 8 weeks of first dose of study drug
- Has history of chronic liver disease from any known cause other than ZZ type AAT deficiency
- Has history of hepatic encephalopathy
- Has history of gastrointestinal bleeding from esophageal or gastric varices complicating portal hypertension or ascites
- Has any history of a bleeding disorder or inability to abstain from medications that may interfere with normal blood clotting such that the risk of bleeding following liver biopsy would be increased
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method