<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03767829</url>
  </required_header>
  <id_info>
    <org_study_id>ALN-AAT02-001</org_study_id>
    <secondary_id>2018-001362-41</secondary_id>
    <nct_id>NCT03767829</nct_id>
  </id_info>
  <brief_title>A Study of ALN-AAT02 in Healthy Participants and Participants With ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Alnylam Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Alnylam Pharmaceuticals</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety and tolerability of single or multiple&#xD;
      doses of ALN-AAT02. The study will be conducted in 2 sequential phases in which Part A will&#xD;
      be a single-ascending dose (SAD) phase in healthy participants, and Part B will be a&#xD;
      multiple-ascending dose (MAD) phase in participants with ZZ type alpha-1 antitrypsin&#xD;
      deficiency (PiZZ) and biopsy-proven alpha-1 antitrypsin (AAT) deficiency-associated liver&#xD;
      disease.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The sponsor decided not to proceed with Part B for business reasons.&#xD;
  </why_stopped>
  <start_date type="Actual">December 5, 2018</start_date>
  <completion_date type="Actual">June 25, 2020</completion_date>
  <primary_completion_date type="Actual">June 25, 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Participants with Treatment Emergent Adverse Events (TEAEs)</measure>
    <time_frame>Part A: up to approximately 12 months; Part B: up to approximately 18 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Serum Levels of Alpha-1 Antitrypsin (AAT)</measure>
    <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</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Observed Plasma Concentration (Cmax) for ALN-AAT02</measure>
    <time_frame>Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Reach Cmax (tmax) for ALN-AAT02</measure>
    <time_frame>Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ALN-AAT02</measure>
    <time_frame>Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent Terminal Elimination Half-life (t1/2) for ALN-AAT02</measure>
    <time_frame>Part A: Days 1, 2, 3, 8 and 15; Part B: Days 1, 2, 3, 29, 85, 86 and 87</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction Eliminated in Urine (fe) of ALN-AAT02</measure>
    <time_frame>Part A: Day 1; Part B: Days 1 and 85</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02</measure>
    <time_frame>Part A: Day 1; Part B: Days 1 and 85</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease</condition>
  <arm_group>
    <arm_group_label>Part A: SAD: ALN-AAT02</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be administered a single dose of ALN-AAT02.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part A: SAD: Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will be administered a single dose of matching placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part B: MAD: ALN-AAT02</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be administered multiple doses of ALN-AAT02.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part B: MAD: Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will be administered multiple doses of matching placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ALN-AAT02</intervention_name>
    <description>ALN-AAT02 will be administered subcutaneously (SC) at dose levels planned for Part A.</description>
    <arm_group_label>Part A: SAD: ALN-AAT02</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Sterile normal saline (0.9% NaCl) matching volume of ALN-AAT02 doses will be administered SC.</description>
    <arm_group_label>Part A: SAD: Placebo</arm_group_label>
    <arm_group_label>Part B: MAD: Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ALN-AAT02</intervention_name>
    <description>ALN-AAT02 will be administered subcutaneously (SC). Part B dose levels to be determined upon review of data from Part A.</description>
    <arm_group_label>Part B: MAD: ALN-AAT02</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female, aged 18 to 65 years, inclusive;&#xD;
&#xD;
          -  Has normal 12-lead electrocardiogram (ECG);&#xD;
&#xD;
          -  Has body mass index (BMI) between 18 and 30 kg/m^2, inclusive;&#xD;
&#xD;
          -  Has been a nonsmoker for at least 5 years before screening;&#xD;
&#xD;
          -  Part A only: Has Alpha-1 antitrypsin (AAT) levels within normal limits;&#xD;
&#xD;
          -  Part A only: Has adequate Forced Expiratory Volume in 1 second (FEV1) and adequate&#xD;
             FEV1/forced vital capacity ratio;&#xD;
&#xD;
          -  Part B only: Has documented ZZ type AAT by genotype;&#xD;
&#xD;
          -  Part B only: Has liver biopsy within 90 days of the first dose of study drug&#xD;
             demonstrating ZZ type alpha-1 antitrypsin deficiency (PiZZ AATD) liver disease;&#xD;
&#xD;
          -  Part B only: Has adequate post-bronchodilator FEV1 and adequate diffusing capacity of&#xD;
             the lung for carbon monoxide;&#xD;
&#xD;
          -  Part B only: If on any maintenance medication, is likely to be able to remain on a&#xD;
             stable medication regimen for the duration of the study (no new medications within 30&#xD;
             days prior to first dose of study drug).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Has known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B&#xD;
             virus (HBV) infection;&#xD;
&#xD;
          -  Has clinically significant abnormal laboratory results;&#xD;
&#xD;
          -  Received an experimental drug within 30 days of dosing;&#xD;
&#xD;
          -  Has a history of multiple drug allergies or history of allergic reaction to an&#xD;
             oligonucleotide or N-acetylgalactosamine (GalNAc);&#xD;
&#xD;
          -  Part A only: Has estimated glomerular filtration equal to or below 60 mL/min/1.73 m^2&#xD;
             at screening;&#xD;
&#xD;
          -  Part A only: Has a history of asthma or recurrent or chronic lung disease, excluding&#xD;
             resolved childhood asthma;&#xD;
&#xD;
          -  Part A only: Has a history of chronic liver disease;&#xD;
&#xD;
          -  Part B only: Has estimated glomerular filtration equal to or below 45 mL/min/1.73 m^2&#xD;
             at screening;&#xD;
&#xD;
          -  Part B only: Received an augmentation therapy for AAT deficiency within 8 weeks of&#xD;
             first dose of study drug;&#xD;
&#xD;
          -  Part B only: Has a history of chronic liver disease from any known cause other than ZZ&#xD;
             type AAT deficiency;&#xD;
&#xD;
          -  Part B only: Has a history of hepatic encephalopathy;&#xD;
&#xD;
          -  Part B only: Has a history of gastrointestinal bleeding or ascites.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Medical Director</last_name>
    <role>Study Director</role>
    <affiliation>Alnylam Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>December 5, 2018</study_first_submitted>
  <study_first_submitted_qc>December 5, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 7, 2018</study_first_posted>
  <last_update_submitted>April 26, 2021</last_update_submitted>
  <last_update_submitted_qc>April 26, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 27, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Alpha 1-Antitrypsin Deficiency</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03767829
org study id: ALN-AAT02-001
secondary id: 2018-001362-41
nct id: NCT03767829
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: 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
measure: 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
measure: 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
measure: 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
measure: 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
measure: 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
measure: Fraction Eliminated in Urine (fe) of ALN-AAT02
time frame: Part A: Day 1; Part B: Days 1 and 85
measure: Amount of Full Length Drug Excreted in Urine (Ae) of ALN-AAT02
time frame: Part A: Day 1; Part B: Days 1 and 85
arm group label: Part A: SAD: ALN-AAT02
arm group type: Experimental
description: Participants will be administered a single dose of ALN-AAT02.
arm group label: Part A: SAD: Placebo
arm group type: Placebo Comparator
description: Participants will be administered a single dose of matching placebo.
arm group label: Part B: MAD: ALN-AAT02
arm group type: Experimental
description: Participants will be administered multiple doses of ALN-AAT02.
arm group label: Part B: MAD: Placebo
arm group type: Placebo Comparator
description: Participants will be administered multiple doses of matching placebo.
intervention type: Drug
intervention name: ALN-AAT02
description: ALN-AAT02 will be administered subcutaneously (SC) at dose levels planned for Part A.
arm group label: Part A: SAD: ALN-AAT02
intervention type: Drug
intervention name: Placebo
description: Sterile normal saline (0.9% NaCl) matching volume of ALN-AAT02 doses will be administered SC.
arm group label: Part A: SAD: Placebo
arm group label: Part B: MAD: Placebo
intervention type: Drug
intervention name: ALN-AAT02
description: ALN-AAT02 will be administered subcutaneously (SC). Part B dose levels to be determined upon review of data from Part A.
arm group label: Part B: MAD: ALN-AAT02
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Medical Director
role: Study Director
affiliation: Alnylam Pharmaceuticals
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Liver Diseases
mesh term: Alpha 1-Antitrypsin Deficiency