<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/NCT03759379</url>
  </required_header>
  <id_info>
    <org_study_id>ALN-TTRSC02-002</org_study_id>
    <secondary_id>2018-002098-23</secondary_id>
    <nct_id>NCT03759379</nct_id>
  </id_info>
  <brief_title>HELIOS-A: A Study of Vutrisiran (ALN-TTRSC02) in Patients With Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis)</brief_title>
  <official_title>HELIOS-A: A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy and Safety of ALN-TTRSC02 in Patients With Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Alnylam Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Alnylam Pharmaceuticals</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</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 efficacy and safety of vutrisiran (ALN-TTRSC02)&#xD;
      in participants with hereditary transthyretin amyloidosis (hATTR amyloidosis). Participants&#xD;
      will receive vutrisiran subcutaneous (SC) injection once every 3 months (q3M) or the&#xD;
      reference comparator patisiran intravenous (IV) injection once every 3 weeks (q3w) during the&#xD;
      18 month Treatment Period. This study will use the placebo arm of the APOLLO study&#xD;
      (NCT01960348) as an external comparator for the primary and most other efficacy endpoints&#xD;
      during the 18 Month Treatment Period. Following the 18 Month Treatment Period, all&#xD;
      participants will be randomized to receive vutrisiran SC injection once every 6 months (q6M)&#xD;
      or q3M in the Randomized Treatment Extension (RTE) Period.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 14, 2019</start_date>
  <completion_date type="Anticipated">October 2026</completion_date>
  <primary_completion_date type="Actual">November 10, 2020</primary_completion_date>
  <phase>Phase 3</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</measure>
    <time_frame>Baseline, Month 9</time_frame>
    <description>The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</measure>
    <time_frame>Baseline, Month 9</time_frame>
    <description>The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</measure>
    <time_frame>Baseline, Month 9</time_frame>
    <description>The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</measure>
    <time_frame>Baseline, Month 18</time_frame>
    <description>The mNIS+7 is a composite score that quantifies motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Norfolk QoL-DN Total Score at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</measure>
    <time_frame>Baseline, Month 18</time_frame>
    <description>The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in the 10-MWT at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</measure>
    <time_frame>Baseline, Month 18</time_frame>
    <description>The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in the Modified Body Mass Index (mBMI) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</measure>
    <time_frame>Baseline, Month 18</time_frame>
    <description>The mBMI, which is a measure of nutritional status, is calculated as the product of body mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum albumin (g/L) to reflect fluid balance, such as fluid accumulation or dehydration. A negative change from baseline indicates a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</measure>
    <time_frame>Baseline, Month 18</time_frame>
    <description>The R-ODS is a patient-reported measure of level of disability on a scale of 0-48, with 0 being the worst and 48 the best (no limitations); scores are based on activities of daily living and social participation. An increase in R-ODS from baseline suggests improvement in disability, and a decrease from baseline suggests worsening of disability.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Reduction in Serum Transthyretin (TTR) Levels Through Month 18 Between the Vutrisiran Group (HELIOS-A) and the Patisiran Group (HELIOS-A)</measure>
    <time_frame>Up to Month 18</time_frame>
    <description>Serum TTR was assessed at multiple timepoints up to Month 18.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">164</enrollment>
  <condition>Amyloidosis, Hereditary</condition>
  <condition>Transthyretin Amyloidosis</condition>
  <arm_group>
    <arm_group_label>Vutrisiran + Vutrisiran (HELIOS-A)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive vutrisiran 25 mg subcutaneous (SC) injection once every 3 months (q3M) for 18 months during the Treatment Period followed by vutrisiran SC injection once every 6 months (q6M) or q3M during the Randomized Treatment Extension (RTE) Period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Patisiran + Vutrisiran (HELIOS-A)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive patisiran 0.3 mg/kg intravenous (IV) infusion once every 3 weeks (q3w) for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Patisiran</intervention_name>
    <description>Patisiran will be administered by IV infusion.</description>
    <arm_group_label>Patisiran + Vutrisiran (HELIOS-A)</arm_group_label>
    <other_name>ONPATTRO</other_name>
    <other_name>ALN-TTR02</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vutrisiran</intervention_name>
    <description>Vutrisiran will be administered by SC injection.</description>
    <arm_group_label>Patisiran + Vutrisiran (HELIOS-A)</arm_group_label>
    <arm_group_label>Vutrisiran + Vutrisiran (HELIOS-A)</arm_group_label>
    <other_name>ALN-TTRSC02</other_name>
    <other_name>AMVUTTRA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female of 18 to 85 years of age (inclusive);&#xD;
&#xD;
          -  Has a diagnosis of hATTR amyloidosis with transthyretin (TTR) mutation;&#xD;
&#xD;
          -  Has adequate neurologic impairment score (NIS);&#xD;
&#xD;
          -  Has adequate polyneuropathy disability (PND) score;&#xD;
&#xD;
          -  Has adequate Karnofsky Performance Status (KPS).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Had a prior liver transplant or is likely to undergo liver transplantation during the&#xD;
             study;&#xD;
&#xD;
          -  Has known other (non-hATTR) forms of amyloidosis or leptomeningeal amyloidosis;&#xD;
&#xD;
          -  Has New York Heart Association heart failure classification &gt;2;&#xD;
&#xD;
          -  Clinically significant liver function test abnormalities;&#xD;
&#xD;
          -  Has known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B&#xD;
             virus (HBV) infection;&#xD;
&#xD;
          -  Received an experimental drug within 30 days of dosing;&#xD;
&#xD;
          -  Received prior TTR-lowering treatment;&#xD;
&#xD;
          -  Has other known causes of neuropathy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</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>San Diego</city>
        <state>California</state>
        <zip>92120</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02118</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63130</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19140</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Fort Worth</city>
        <state>Texas</state>
        <zip>75246</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Buenos Aires</city>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Box Hill</city>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Westmead</city>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Woolloongabba</city>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Bruxelles</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Rio De Janeiro</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Sofia</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Montréal</city>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Vancouver</city>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Nicosia</city>
        <country>Cyprus</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Créteil</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Mainz</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Münster</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Athens</city>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Messina</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Pavia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Rome</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Kumamoto</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Nagano</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Nagoya</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Osaka</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Junggu</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Kuala Lumpur</city>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Mexico City</city>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Groningen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Lisboa</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Porto</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Huelva</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Solna</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Umeå</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Taipei City</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trial Site</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Australia</country>
    <country>Belgium</country>
    <country>Brazil</country>
    <country>Bulgaria</country>
    <country>Canada</country>
    <country>Cyprus</country>
    <country>France</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Italy</country>
    <country>Japan</country>
    <country>Korea, Republic of</country>
    <country>Malaysia</country>
    <country>Mexico</country>
    <country>Netherlands</country>
    <country>Portugal</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>Taiwan</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>November 28, 2018</study_first_submitted>
  <study_first_submitted_qc>November 28, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 30, 2018</study_first_posted>
  <results_first_submitted>July 12, 2022</results_first_submitted>
  <results_first_submitted_qc>July 12, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">August 11, 2022</results_first_posted>
  <disposition_first_submitted>November 9, 2021</disposition_first_submitted>
  <disposition_first_submitted_qc>November 9, 2021</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">November 15, 2021</disposition_first_posted>
  <last_update_submitted>August 16, 2023</last_update_submitted>
  <last_update_submitted_qc>August 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 21, 2023</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>Amyloid Neuropathies, Familial</mesh_term>
    <mesh_term>Amyloidosis, Familial</mesh_term>
    <mesh_term>Amyloidosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 19, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT03759379/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 24, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT03759379/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants with hATTR amyloidosis were enrolled and treated at 57 sites in Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Cyprus, France, Germany, Greece, Italy, Japan, Korea, Malaysia, Mexico, Netherlands, Portugal, Spain, Sweden, Taiwan, United Kingdom and United States. Data is reported for the 9-Month primary analysis period.</recruitment_details>
      <pre_assignment_details>This study will use the placebo arm of the APOLLO study (NCT01960348) as an external comparator for the primary and most other efficacy endpoints (N=77).</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Vutrisiran + Vutrisiran (HELIOS-A)</title>
          <description>Participants will receive vutrisiran 25 mg subcutaneous (SC) injection once every 3 months (q3M) for 18 months during the Treatment Period followed by vutrisiran SC injection once every 6 months (q6M) or q3M during the Randomized Treatment Extension (RTE) Period.</description>
        </group>
        <group group_id="P2">
          <title>Patisiran + Vutrisiran (HELIOS-A)</title>
          <description>Participants will receive patisiran 0.3 mg/kg intravenous (IV) infusion once every 3 weeks (q3w) for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Treatment Period</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="122"/>
                <participants group_id="P2" count="42"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="122"/>
                <participants group_id="P2" count="42"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Remained in this Period at Time of Data Cut</title>
              <participants_list>
                <participants group_id="P1" count="119"/>
                <participants group_id="P2" count="38"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Randomized Treatment Extension Period</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Safety Population: all participants who received any amount of study drug. Data from the placebo arm of the APOLLO study (NCT01960348) is included as it will be used as an external comparator for the primary and most other efficacy endpoints. The placebo APOLLO arm did not participate in this study.</population>
      <group_list>
        <group group_id="B1">
          <title>External Placebo Comparator (APOLLO)</title>
          <description>Participants in the APOLLO study (NCT01960348) who received at least 1 dose of placebo.</description>
        </group>
        <group group_id="B2">
          <title>Vutrisiran + Vutrisiran (HELIOS-A)</title>
          <description>Participants will receive vutrisiran 25 mg SC injection q3M for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period.</description>
        </group>
        <group group_id="B3">
          <title>Patisiran + Vutrisiran (HELIOS-A)</title>
          <description>Participants will receive patisiran 0.3 mg/kg IV infusion q3w for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="77"/>
            <count group_id="B2" value="122"/>
            <count group_id="B3" value="42"/>
            <count group_id="B4" value="241"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <population>Baseline characteristics data from the external placebo arm of the APOLLO study was not summarized with the data from HELIOS-A. APOLLO placebo data was only used as an external comparator for the primary and most other efficacy endpoints. Therefore APOLLO placebo baseline characteristic data is reported separately directly below.</population>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="122"/>
                    <count group_id="B3" value="42"/>
                    <count group_id="B4" value="164"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B2" value="57.8" spread="13.2"/>
                    <measurement group_id="B3" value="58.0" spread="10.5"/>
                    <measurement group_id="B4" value="57.9" spread="12.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <population>Baseline characteristics data from the external placebo arm of the APOLLO study was not summarized with the data from HELIOS-A. APOLLO placebo data was only used as an external comparator for the primary and most other efficacy endpoints. Therefore APOLLO placebo baseline characteristic data is reported separately.</population>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="77"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="77"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62.2" spread="10.76"/>
                    <measurement group_id="B4" value="62.2" spread="10.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <population>Baseline characteristics data from the external placebo arm of the APOLLO study was not summarized with the data from HELIOS-A. APOLLO placebo data was only used as an external comparator for the primary and most other efficacy endpoints. Therefore APOLLO placebo baseline characteristic data is reported separately directly below.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="122"/>
                    <count group_id="B3" value="42"/>
                    <count group_id="B4" value="164"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B2" value="43"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="58"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B2" value="79"/>
                    <measurement group_id="B3" value="27"/>
                    <measurement group_id="B4" value="106"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <population>Baseline characteristics data from the external placebo arm of the APOLLO study was not summarized with the data from HELIOS-A. APOLLO placebo data was only used as an external comparator for the primary and most other efficacy endpoints. Therefore APOLLO placebo baseline characteristic data is reported separately.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="77"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="77"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B4" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="58"/>
                    <measurement group_id="B4" value="58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <population>Baseline characteristics data from the external placebo arm of the APOLLO study was not summarized with the data from HELIOS-A. APOLLO placebo data was only used as an external comparator for the primary and most other efficacy endpoints. Therefore APOLLO placebo baseline characteristic data is reported separately directly below.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Asian</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="122"/>
                    <count group_id="B3" value="42"/>
                    <count group_id="B4" value="164"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black or African American</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="122"/>
                    <count group_id="B3" value="42"/>
                    <count group_id="B4" value="164"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Multiple</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="122"/>
                    <count group_id="B3" value="42"/>
                    <count group_id="B4" value="164"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="122"/>
                    <count group_id="B3" value="42"/>
                    <count group_id="B4" value="164"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="122"/>
                    <count group_id="B3" value="42"/>
                    <count group_id="B4" value="164"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="122"/>
                    <count group_id="B3" value="42"/>
                    <count group_id="B4" value="164"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="86"/>
                    <measurement group_id="B3" value="29"/>
                    <measurement group_id="B4" value="115"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <population>Baseline characteristics data from the external placebo arm of the APOLLO study was not summarized with the data from HELIOS-A. APOLLO placebo data was only used as an external comparator for the primary and most other efficacy endpoints. Therefore APOLLO placebo baseline characteristic data is reported separately.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Asian</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="77"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="77"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B4" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black or African American</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="77"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="77"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="77"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="77"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50"/>
                    <measurement group_id="B4" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown or Not Reported</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="77"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="77"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Modified Neuropathy Impairment Score +7 (mNIS+7)</title>
          <description>The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.</description>
          <population>Baseline characteristics data from the external placebo arm of the APOLLO study was not summarized with the data from HELIOS-A. APOLLO placebo data was only used as an external comparator for the primary and most other efficacy endpoints. Therefore APOLLO placebo baseline characteristic data is reported separately directly below.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="122"/>
                    <count group_id="B3" value="42"/>
                    <count group_id="B4" value="164"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B2" value="60.55" spread="35.99"/>
                    <measurement group_id="B3" value="57.69" spread="33.71"/>
                    <measurement group_id="B4" value="59.82" spread="35.34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Modified Neuropathy Impairment Score +7 (mNIS+7)</title>
          <description>The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.</description>
          <population>Baseline characteristics data from the external placebo arm of the APOLLO study was not summarized with the data from HELIOS-A. APOLLO placebo data was only used as an external comparator for the primary and most other efficacy endpoints. Therefore APOLLO placebo baseline characteristic data is reported separately.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="77"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="77"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="74.61" spread="37.041"/>
                    <measurement group_id="B4" value="74.61" spread="37.041"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
        <description>The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.</description>
        <time_frame>Baseline, Month 9</time_frame>
        <population>Modified Intent-to-Treat (mITT) Population: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized.</population>
        <group_list>
          <group group_id="O1">
            <title>External Placebo Comparator (APOLLO)</title>
            <description>Participants in the APOLLO study (NCT01960348) who received at least 1 dose of placebo.</description>
          </group>
          <group group_id="O2">
            <title>Vutrisiran + Vutrisiran (HELIOS-A)</title>
            <description>Participants will receive vutrisiran 25 mg subcutaneous (SC) injection once every 3 months (q3M) for 18 months during the Treatment Period followed by vutrisiran SC injection during the Randomized Treatment Extension (RTE) Period.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
          <description>The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.</description>
          <population>Modified Intent-to-Treat (mITT) Population: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized.</population>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="77"/>
                <count group_id="O2" value="122"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.76" spread="2.00"/>
                    <measurement group_id="O2" value="-2.24" spread="1.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Multiple imputation estimates and p-value derived per combining least squares (LS) estimates per Rubin's rules based on 100 datasets where missing Month 9 values were imputed using a regression procedure including select baseline variables. LS estimates derived from analysis of covariance model, controlling for categorical factors (treatment, genotype, age of disease onset) and continuous covariate (baseline value).</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>H0: No difference between vutrisiran and external placebo comparator (APOLLO): difference (vutrisiran - placebo) = 0</non_inferiority_desc>
            <p_value>&lt;0.0000001</p_value>
            <p_value_desc>P=3.542E-12</p_value_desc>
            <method>ANCOVA with Multiple Imputation</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-17.00</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>2.44</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-21.78</ci_lower_limit>
            <ci_upper_limit>-12.22</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
        <description>The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.</description>
        <time_frame>Baseline, Month 9</time_frame>
        <population>Modified Intent-to-Treat (mITT) Population: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized.</population>
        <group_list>
          <group group_id="O1">
            <title>External Placebo Comparator (APOLLO)</title>
            <description>Participants in the APOLLO study (NCT01960348) who received at least 1 dose of placebo.</description>
          </group>
          <group group_id="O2">
            <title>Vutrisiran + Vutrisiran (HELIOS-A)</title>
            <description>Participants will receive vutrisiran 25 mg subcutaneous (SC) injection once every 3 months (q3M) for 18 months during the Treatment Period followed by vutrisiran SC injection during the Randomized Treatment Extension (RTE) Period.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
          <description>The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.</description>
          <population>Modified Intent-to-Treat (mITT) Population: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized.</population>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="77"/>
                <count group_id="O2" value="122"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.9" spread="2.2"/>
                    <measurement group_id="O2" value="-3.3" spread="1.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Multiple imputation estimates and p-value derived per combining least squares (LS) estimates per Rubin's rules based on 100 datasets where missing Month 9 values were imputed using a regression procedure including select baseline variables. LS estimates derived from analysis of covariance model, controlling for categorical factors (treatment, genotype, age of disease onset baseline NIS) and continuous covariate (baseline value).</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>H0: No difference between vutrisiran and external placebo comparator (APOLLO): difference (vutrisiran - placebo) = 0</non_inferiority_desc>
            <p_value>&lt;0.0000001</p_value>
            <p_value_desc>P=5.426E-09</p_value_desc>
            <method>ANCOVA with Multiple Imputation</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-16.2</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>2.8</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-21.7</ci_lower_limit>
            <ci_upper_limit>-10.8</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
        <description>The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.</description>
        <time_frame>Baseline, Month 9</time_frame>
        <population>Modified Intent-to-Treat (mITT) Population: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized.</population>
        <group_list>
          <group group_id="O1">
            <title>External Placebo Comparator (APOLLO)</title>
            <description>Participants in the APOLLO study (NCT01960348) who received at least 1 dose of placebo.</description>
          </group>
          <group group_id="O2">
            <title>Vutrisiran + Vutrisiran (HELIOS-A)</title>
            <description>Participants will receive vutrisiran 25 mg subcutaneous (SC) injection once every 3 months (q3M) for 18 months during the Treatment Period followed by vutrisiran SC injection during the Randomized Treatment Extension (RTE) Period.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
          <description>The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.</description>
          <population>Modified Intent-to-Treat (mITT) Population: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized.</population>
          <units>m/sec</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="77"/>
                <count group_id="O2" value="122"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.133" spread="0.025"/>
                    <measurement group_id="O2" value="-0.001" spread="0.019"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Multiple imputation estimates and p-value derived per combining least squares (LS) estimates per Rubin's rules based on 100 datasets where missing Month 9 values were imputed using a regression procedure including select baseline variables. LS estimates derived from analysis of covariance model, controlling for categorical factors (treatment, genotype, age of disease onset, baseline NIS) and continuous covariate (baseline value).</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>H0: No difference between vutrisiran and external placebo comparator (APOLLO): difference (vutrisiran - placebo) = 0</non_inferiority_desc>
            <p_value>&lt;0.0000001</p_value>
            <p_value_desc>P=3.103E-05</p_value_desc>
            <method>ANCOVA with Multiple Imputation</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>0.131</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.031</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.070</ci_lower_limit>
            <ci_upper_limit>0.193</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
        <description>The mNIS+7 is a composite score that quantifies motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.</description>
        <time_frame>Baseline, Month 18</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Norfolk QoL-DN Total Score at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
        <description>The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.</description>
        <time_frame>Baseline, Month 18</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in the 10-MWT at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
        <description>The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.</description>
        <time_frame>Baseline, Month 18</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in the Modified Body Mass Index (mBMI) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
        <description>The mBMI, which is a measure of nutritional status, is calculated as the product of body mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum albumin (g/L) to reflect fluid balance, such as fluid accumulation or dehydration. A negative change from baseline indicates a better outcome.</description>
        <time_frame>Baseline, Month 18</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]</title>
        <description>The R-ODS is a patient-reported measure of level of disability on a scale of 0-48, with 0 being the worst and 48 the best (no limitations); scores are based on activities of daily living and social participation. An increase in R-ODS from baseline suggests improvement in disability, and a decrease from baseline suggests worsening of disability.</description>
        <time_frame>Baseline, Month 18</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Reduction in Serum Transthyretin (TTR) Levels Through Month 18 Between the Vutrisiran Group (HELIOS-A) and the Patisiran Group (HELIOS-A)</title>
        <description>Serum TTR was assessed at multiple timepoints up to Month 18.</description>
        <time_frame>Up to Month 18</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Non-serious AEs from first dose of study drug through Month 9. SAEs from signing of informed consent through Month 9.</time_frame>
      <desc>Adverse events are provided for the vutrisiran group and the reference comparator (patisiran) group as of the data cutoff date (10 November 2020).</desc>
      <group_list>
        <group group_id="E1">
          <title>Vutrisiran + Vutrisiran (HELIOS-A)</title>
          <description>Participants will receive vutrisiran 25 mg SC injection q3M for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period.</description>
        </group>
        <group group_id="E2">
          <title>Patisiran + Vutrisiran (HELIOS-A)</title>
          <description>Participants will receive patisiran 0.3 mg/kg IV infusion q3w for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (23.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Arrhythmia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Atrioventricular block complete</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Cardiac failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Cardiac failure acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Cardiac failure chronic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Cardiogenic shock</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Conduction disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Myocardial ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Ventricular tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cyclic vomiting syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Upper gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Infusion site phlebitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>COVID-19</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>COVID-19 pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Endocarditis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Escherichia urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Infusion site cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Kidney infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pyelonephritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vestibular neuronitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Femur fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Foot fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Fractured sacrum</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Post procedural complication</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Cardiovascular evaluation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Investigation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dyslipidaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Fluid overload</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Endometrial neoplasm</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebrovascular accident</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Neuralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Renal failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Hospitalisation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Iliac artery occlusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Orthostatic hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (23.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="78" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Ligament sprain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vitamin A decreased</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Neuralgia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="122"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>It is intended that after completion of the study, the data are to be submitted for publication in a scientific journal and/or for reporting at a scientific meeting. A copy of any proposed publication (eg, manuscript, abstracts, oral/slide presentations, book chapters) based on this study, must be provided and confirmed/received at the Sponsor at least 30 days before its submission.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Chief Medical Officer</name_or_title>
      <organization>Alnylam Pharmaceuticals Inc.</organization>
      <phone>866-330-0326</phone>
      <email>clinicaltrials@alnylam.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03759379
org study id: ALN-TTRSC02-002
secondary id: 2018-002098-23
nct id: NCT03759379
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to evaluate the efficacy and safety of vutrisiran (ALN-TTRSC02)
      in participants with hereditary transthyretin amyloidosis (hATTR amyloidosis). Participants
      will receive vutrisiran subcutaneous (SC) injection once every 3 months (q3M) or the
      reference comparator patisiran intravenous (IV) injection once every 3 weeks (q3w) during the
      18 month Treatment Period. This study will use the placebo arm of the APOLLO study
      (NCT01960348) as an external comparator for the primary and most other efficacy endpoints
      during the 18 Month Treatment Period. Following the 18 Month Treatment Period, all
      participants will be randomized to receive vutrisiran SC injection once every 6 months (q6M)
      or q3M in the Randomized Treatment Extension (RTE) Period.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
time frame: Baseline, Month 9
description: The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.
measure: Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
time frame: Baseline, Month 9
description: The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.
measure: Change From Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
time frame: Baseline, Month 9
description: The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.
measure: Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
time frame: Baseline, Month 18
description: The mNIS+7 is a composite score that quantifies motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.
measure: Change From Baseline in Norfolk QoL-DN Total Score at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
time frame: Baseline, Month 18
description: The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.
measure: Change From Baseline in the 10-MWT at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
time frame: Baseline, Month 18
description: The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.
measure: Change From Baseline in the Modified Body Mass Index (mBMI) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
time frame: Baseline, Month 18
description: The mBMI, which is a measure of nutritional status, is calculated as the product of body mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum albumin (g/L) to reflect fluid balance, such as fluid accumulation or dehydration. A negative change from baseline indicates a better outcome.
measure: Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
time frame: Baseline, Month 18
description: The R-ODS is a patient-reported measure of level of disability on a scale of 0-48, with 0 being the worst and 48 the best (no limitations); scores are based on activities of daily living and social participation. An increase in R-ODS from baseline suggests improvement in disability, and a decrease from baseline suggests worsening of disability.
measure: Percent Reduction in Serum Transthyretin (TTR) Levels Through Month 18 Between the Vutrisiran Group (HELIOS-A) and the Patisiran Group (HELIOS-A)
time frame: Up to Month 18
description: Serum TTR was assessed at multiple timepoints up to Month 18.
arm group label: Vutrisiran + Vutrisiran (HELIOS-A)
arm group type: Experimental
description: Participants will receive vutrisiran 25 mg subcutaneous (SC) injection once every 3 months (q3M) for 18 months during the Treatment Period followed by vutrisiran SC injection once every 6 months (q6M) or q3M during the Randomized Treatment Extension (RTE) Period.
arm group label: Patisiran + Vutrisiran (HELIOS-A)
arm group type: Active Comparator
description: Participants will receive patisiran 0.3 mg/kg intravenous (IV) infusion once every 3 weeks (q3w) for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period.
intervention type: Drug
intervention name: Patisiran
description: Patisiran will be administered by IV infusion.
arm group label: Patisiran + Vutrisiran (HELIOS-A)
other name: ONPATTRO
other name: ALN-TTR02
intervention type: Drug
intervention name: Vutrisiran
description: Vutrisiran will be administered by SC injection.
arm group label: Patisiran + Vutrisiran (HELIOS-A)
arm group label: Vutrisiran + Vutrisiran (HELIOS-A)
other name: ALN-TTRSC02
other name: AMVUTTRA
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Medical Director
role: Study Director
affiliation: Alnylam Pharmaceuticals
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country: Argentina
country: Australia
country: Belgium
country: Brazil
country: Bulgaria
country: Canada
country: Cyprus
country: France
country: Germany
country: Greece
country: Italy
country: Japan
country: Korea, Republic of
country: Malaysia
country: Mexico
country: Netherlands
country: Portugal
country: Spain
country: Sweden
country: Taiwan
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Amyloid Neuropathies, Familial
mesh term: Amyloidosis, Familial
mesh term: Amyloidosis
sharing ipd: No
provided document: 
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point of contact: 