ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease Clinical Trial
Official title:
A Phase 1/2, Randomized, Double-blind, Placebo-controlled, Single-ascending and Multiple-dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN-AAT02 in Healthy Adult Subjects and Patients With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
| Verified date | April 2021 |
| Source | Alnylam Pharmaceuticals |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Terminated |
| Enrollment | 32 |
| Est. completion date | June 25, 2020 |
| Est. primary completion date | June 25, 2020 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | All |
| Age group | 18 Years to 65 Years |
| Eligibility | 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. |
| Country | Name | City | State |
|---|---|---|---|
| United Kingdom | Clinical Trial Site | London |
| Lead Sponsor | Collaborator |
|---|---|
| Alnylam Pharmaceuticals |
United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) | Part A: up to approximately 12 months; Part B: up to approximately 18 months | ||
| Secondary | 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 | ||
| Secondary | 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 | ||
| Secondary | 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 | ||
| Secondary | 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 | ||
| Secondary | 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 | ||
| Secondary | Fraction Eliminated in Urine (fe) of ALN-AAT02 | Part A: Day 1; Part B: Days 1 and 85 | ||
| Secondary | Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02 | Part A: Day 1; Part B: Days 1 and 85 |