Back to resultsA Study of ALN-AAT02 in Healthy Participants and Participants With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
Primary Purpose
ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
Status
Terminated
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
ALN-AAT02
Placebo
ALN-AAT02
Sponsored by
About this trial
This is an interventional treatment trial for ZZ Type Alpha-1 Antitrypsin Deficiency 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.
Sites / Locations
- Clinical Trial Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Placebo Comparator
Experimental
Placebo Comparator
Arm Label
Part A: SAD: ALN-AAT02
Part A: SAD: Placebo
Part B: MAD: ALN-AAT02
Part B: MAD: Placebo
Arm Description
Participants will be administered a single dose of ALN-AAT02.
Participants will be administered a single dose of matching placebo.
Participants will be administered multiple doses of ALN-AAT02.
Participants will be administered multiple doses of matching placebo.
Outcomes
Primary Outcome Measures
Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)
Secondary Outcome Measures
Change From Baseline in Serum Levels of Alpha-1 Antitrypsin (AAT)
Maximum Observed Plasma Concentration (Cmax) for ALN-AAT02
Time to Reach Cmax (tmax) for ALN-AAT02
Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ALN-AAT02
Apparent Terminal Elimination Half-life (t1/2) for ALN-AAT02
Fraction Eliminated in Urine (fe) of ALN-AAT02
Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02
Full Information
NCT ID
NCT03767829
First Posted
December 5, 2018
Last Updated
April 26, 2021
Sponsor
Alnylam Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT03767829
Brief Title
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
2. Study Status
Record Verification Date
April 2021
Overall Recruitment Status
Terminated
Why Stopped
The sponsor decided not to proceed with Part B for business reasons.
Study Start Date
December 5, 2018 (Actual)
Primary Completion Date
June 25, 2020 (Actual)
Study Completion Date
June 25, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alnylam Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
32 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part A: SAD: ALN-AAT02
Arm Type
Experimental
Arm Description
Participants will be administered a single dose of ALN-AAT02.
Arm Title
Part A: SAD: Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will be administered a single dose of matching placebo.
Arm Title
Part B: MAD: ALN-AAT02
Arm Type
Experimental
Arm Description
Participants will be administered multiple doses of ALN-AAT02.
Arm Title
Part B: MAD: Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will be administered multiple doses of matching placebo.
Intervention Type
Drug
Intervention Name(s)
ALN-AAT02
Intervention Description
ALN-AAT02 will be administered subcutaneously (SC) at dose levels planned for Part A.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Sterile normal saline (0.9% NaCl) matching volume of ALN-AAT02 doses will be administered SC.
Intervention Type
Drug
Intervention Name(s)
ALN-AAT02
Intervention Description
ALN-AAT02 will be administered subcutaneously (SC). Part B dose levels to be determined upon review of data from Part A.
Primary Outcome Measure Information:
Title
Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)
Time Frame
Part A: up to approximately 12 months; Part B: up to approximately 18 months
Secondary Outcome Measure Information:
Title
Change From Baseline in Serum Levels of Alpha-1 Antitrypsin (AAT)
Time Frame
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
Title
Maximum Observed Plasma Concentration (Cmax) for ALN-AAT02
Time Frame
Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87
Title
Time to Reach Cmax (tmax) for ALN-AAT02
Time Frame
Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87
Title
Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ALN-AAT02
Time Frame
Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87
Title
Apparent Terminal Elimination Half-life (t1/2) for ALN-AAT02
Time Frame
Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87
Title
Fraction Eliminated in Urine (fe) of ALN-AAT02
Time Frame
Part A: Day 1; Part B: Days 1 and 85
Title
Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02
Time Frame
Part A: Day 1; Part B: Days 1 and 85
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Alnylam Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Trial Site
City
London
Country
United Kingdom
12. IPD Sharing Statement
Learn more about this trial
A Study of ALN-AAT02 in Healthy Participants and Participants With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
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