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Trial record 1 of 1 for:    NCT03767829
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A Study of ALN-AAT02 in Healthy Participants and Participants With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease

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ClinicalTrials.gov Identifier: NCT03767829
Recruitment Status : Recruiting
First Posted : December 7, 2018
Last Update Posted : March 12, 2019
Sponsor:
Information provided by (Responsible Party):
Alnylam Pharmaceuticals

Study Description
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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.

Condition or disease Intervention/treatment Phase
ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease Drug: ALN-AAT02 Drug: Placebo Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : December 5, 2018
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Part A: SAD: ALN-AAT02
Participants will be administered a single dose of ALN-AAT02.
 Drug: ALN-AAT02
ALN-AAT02 will be administered subcutaneously (SC) at dose levels planned for Part A.
Placebo Comparator: Part A: SAD: Placebo
Participants will be administered a single dose of matching placebo.
 Drug: Placebo
Sterile normal saline (0.9% NaCl) matching volume of ALN-AAT02 doses will be administered SC.
Experimental: Part B: MAD: ALN-AAT02
Participants will be administered multiple doses of ALN-AAT02.
 Drug: ALN-AAT02
ALN-AAT02 will be administered subcutaneously (SC). Part B dose levels to be determined upon review of data from Part A.
Placebo Comparator: Part B: MAD: Placebo
Participants will be administered multiple doses of matching placebo.
 Drug: Placebo
Sterile normal saline (0.9% NaCl) matching volume of ALN-AAT02 doses will be administered SC.


Outcome Measures
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Primary Outcome Measures :
  1. 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 Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. Fraction Eliminated in Urine (fe) of ALN-AAT02 [ Time Frame: Part A: Day 1; Part B: Days 1 and 85 ]
  7. Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02 [ Time Frame: Part A: Day 1; Part B: Days 1 and 85 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03767829


Contacts
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Contact: Alnylam Clinical Trial Information Line 1-877-ALNYLAM clinicaltrials@alnylam.com
Contact: Alnylam Clinical Trial Information Line 1-877-256-9526

Locations
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United Kingdom
Clinical Trial Site Recruiting
London, United Kingdom
Sponsors and Collaborators
Alnylam Pharmaceuticals
Investigators
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Study Director: Patrick Haslett Alnylam Pharmaceuticals
More Information
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Responsible Party: Alnylam Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03767829     History of Changes
Other Study ID Numbers: ALN-AAT02-001
2018-001362-41 ( EudraCT Number )
First Posted: December 7, 2018    Key Record Dates
Last Update Posted: March 12, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Liver Diseases
Alpha 1-Antitrypsin Deficiency
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
 Pathologic Processes
Alpha 1-Antitrypsin
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action