Clinical trial NCT03767829: A Study of ALN-AAT02 in Healthy Participants and Participants With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
Lead sponsor: Alnylam Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2018-12-07
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)
timeFrame: Part A: up to approximately 12 months; Part B: up to approximately 18 months
Secondary outcomes:
measure: Change From Baseline in Serum Levels of Alpha-1 Antitrypsin (AAT)
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) for ALN-AAT02
timeFrame: Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87
measure: Time to Reach Cmax (tmax) for ALN-AAT02
timeFrame: Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ALN-AAT02
timeFrame: Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87
measure: Apparent Terminal Elimination Half-life (t1/2) for ALN-AAT02
timeFrame: Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87
measure: Fraction Eliminated in Urine (fe) of ALN-AAT02
timeFrame: Part A: Day 1; Part B: Days 1 and 85
measure: Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02
timeFrame: Part A: Day 1; Part B: Days 1 and 85
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Clinical Trial Site
Study officials:
affiliation: Alnylam Pharmaceuticals
name: Medical Director
role: STUDY_DIRECTOR
References: