A Study of ALN-AAT02 in Healthy Participants and Participants With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
Phase 1
Terminated
- Conditions
- ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
- Interventions
- Drug: Placebo
- Registration Number
- NCT03767829
- Lead Sponsor
- Alnylam Pharmaceuticals
- Brief Summary
The purpose of this study is to evaluate the safety and tolerability of single or multiple doses of ALN-AAT02. The study will be conducted in 2 sequential phases in which Part A will be a single-ascending dose (SAD) phase in healthy participants, and Part B will be a multiple-ascending dose (MAD) phase in participants with ZZ type alpha-1 antitrypsin deficiency (PiZZ) and biopsy-proven alpha-1 antitrypsin (AAT) deficiency-associated liver disease.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 32
Inclusion Criteria
- Male or female, aged 18 to 65 years, inclusive;
- Has normal 12-lead electrocardiogram (ECG);
- Has body mass index (BMI) between 18 and 30 kg/m^2, inclusive;
- Has been a nonsmoker for at least 5 years before screening;
- Part A only: Has Alpha-1 antitrypsin (AAT) levels within normal limits;
- Part A only: Has adequate Forced Expiratory Volume in 1 second (FEV1) and adequate FEV1/forced vital capacity ratio;
- Part B only: Has documented ZZ type AAT by genotype;
- Part B only: Has liver biopsy within 90 days of the first dose of study drug demonstrating ZZ type alpha-1 antitrypsin deficiency (PiZZ AATD) liver disease;
- Part B only: Has adequate post-bronchodilator FEV1 and adequate diffusing capacity of the lung for carbon monoxide;
- Part B only: If on any maintenance medication, is likely 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).
Exclusion Criteria
- Has known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV) infection;
- Has clinically significant abnormal laboratory results;
- Received an experimental drug within 30 days of dosing;
- Has a history of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc);
- Part A only: Has estimated glomerular filtration equal to or below 60 mL/min/1.73 m^2 at screening;
- Part A only: Has a history of asthma or recurrent or chronic lung disease, excluding resolved childhood asthma;
- Part A only: Has a history of chronic liver disease;
- Part B only: Has estimated glomerular filtration equal to or below 45 mL/min/1.73 m^2 at screening;
- Part B only: Received an augmentation therapy for AAT deficiency within 8 weeks of first dose of study drug;
- Part B only: Has a history of chronic liver disease from any known cause other than ZZ type AAT deficiency;
- Part B only: Has a history of hepatic encephalopathy;
- Part B only: Has a history of gastrointestinal bleeding or ascites.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part B: MAD: Placebo Placebo Participants will be administered multiple doses of matching placebo. Part A: SAD: ALN-AAT02 ALN-AAT02 Participants will be administered a single dose of ALN-AAT02. Part A: SAD: Placebo Placebo Participants will be administered a single dose of matching placebo. Part B: MAD: ALN-AAT02 ALN-AAT02 Participants will be administered multiple doses of ALN-AAT02.
- Primary Outcome Measures
Name Time Method Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) Part A: up to approximately 12 months; Part B: up to approximately 18 months
- Secondary Outcome Measures
Name Time Method Change From Baseline in Serum Levels of Alpha-1 Antitrypsin (AAT) Part A: baseline up to Day 85 and every 84 days up to approximately 12 months; Part B: baseline up to Day 169 and every 84 days up to approximately 18 months Maximum Observed Plasma Concentration (Cmax) for ALN-AAT02 Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87 Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ALN-AAT02 Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87 Apparent Terminal Elimination Half-life (t1/2) for ALN-AAT02 Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87 Fraction Eliminated in Urine (fe) of ALN-AAT02 Part A: Day 1; Part B: Days 1 and 85 Time to Reach Cmax (tmax) for ALN-AAT02 Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87 Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02 Part A: Day 1; Part B: Days 1 and 85
Trial Locations
- Locations (1)
Clinical Trial Site
🇬🇧London, United Kingdom