A Study of ALN-AAT02 in Healthy Participants and Participants With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease

NCT03767829 | Terminated Phase 1

• 2 other identifiers: ALN-AAT02-0012018-001362-41
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

Conditions

ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)

  Part A: up to approximately 12 months; Part B: up to approximately 18 months

Secondary Outcomes (7)

• 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

• 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

• 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

Study Arms (4)

Part A: SAD: ALN-AAT02

EXPERIMENTAL

Participants will be administered a single dose of ALN-AAT02.

Drug: ALN-AAT02

Part A: SAD: Placebo

PLACEBO COMPARATOR

Participants will be administered a single dose of matching placebo.

Drug: Placebo

Part B: MAD: ALN-AAT02

EXPERIMENTAL

Participants will be administered multiple doses of ALN-AAT02.

Drug: ALN-AAT02

Part B: MAD: Placebo

PLACEBO COMPARATOR

Participants will be administered multiple doses of matching placebo.

Drug: Placebo

Interventions

ALN-AAT02 DRUG

ALN-AAT02 will be administered subcutaneously (SC) at dose levels planned for Part A.

Part A: SAD: ALN-AAT02

Placebo DRUG

Sterile normal saline (0.9% NaCl) matching volume of ALN-AAT02 doses will be administered SC.

Part A: SAD: Placebo; Part B: MAD: Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Alnylam Pharmaceuticals: lead

Study Sites (1)

Clinical Trial Site

London, United Kingdom

Location

Study Officials

• Medical Director

  Alnylam Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2018
• First Posted: December 7, 2018
• Study Start: December 5, 2018
• Primary Completion: June 25, 2020
• Study Completion: June 25, 2020
• Last Updated: April 27, 2021

Record last verified: 2021-04

Locations

GB (1)