<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/NCT03772249</url>
  </required_header>
  <id_info>
    <org_study_id>DCR-HBVS-101</org_study_id>
    <secondary_id>U1111-1220-7021</secondary_id>
    <nct_id>NCT03772249</nct_id>
  </id_info>
  <brief_title>Study of Safety and Tolerability of DCR HBVS</brief_title>
  <official_title>A Three-Part, Phase 1, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of DCR-HBVS in Healthy Volunteers and Patients With Chronic Hepatitis B</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dicerna Pharmaceuticals, Inc., a Novo Nordisk company</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Dicerna Pharmaceuticals, Inc., a Novo Nordisk company</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      DCR-HBVS will be evaluated for safety and efficacy in healthy volunteers and chronic&#xD;
      hepatitis B patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      DCR HBVS is being developed for the treatment of chronic hepatitis B (CHB) in adults. The&#xD;
      study will be conducted in 3 parts, a single ascending-dose (SAD) phase in normal healthy&#xD;
      volunteers (Group A), a single-dose (SD) phase in patients with CHB (Group B), and a multiple&#xD;
      ascending-dose (MAD) phase in patients with CHB (Group 1c-3c). Cohort 4c is a single&#xD;
      ascending dose with a possible duration of up to 48 weeks. Cohort 5c is a multiple dose&#xD;
      cohort with a possible duration of up to 72 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 28, 2018</start_date>
  <completion_date type="Actual">July 12, 2022</completion_date>
  <primary_completion_date type="Actual">July 12, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Progression from the SAD phase to the first cohort in the MAD phase is contingent upon the Safety Review Committee (SRC) review of a minimum of 14 days post-dose safety and tolerability data from all NHV in at least the first 2 SAD cohorts. The SRC will select one (or more) well-tolerated dose(s) from the SAD phase for administration in the SD and MAD phases. Group B at 3 mg/kg will start in parallel with Group C at the 3 mg/kg dose level. In all study phases, dosing will be staggered with the use of sentinel participants to allow time for the assessment of safety before additional subjects are exposed to study drug. The fixed dosing regimen for Cohorts 4c and 5c was determined following SRC review and assessment of all data up to Cohort 3c. No sentinel dosing will occur in Cohorts 4c and 5c.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>This is a double-blind study in which the study site team, the Sponsor, and the participants will be blinded to treatment assignment. The unblinded pharmacist will cover each syringe, prior to transport to the bedside, to ensure blinding. The drug will be injected by an unblinded nurse or physician who is not part of the study team. Participants will be centrally assigned to randomized study intervention using an Interactive Voice/Web Response System (IVRS/IWRS). Cohorts 4c and 5c will be open label.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of healthy volunteers with Adverse Events as assessed by CTCAE v5.0</measure>
    <time_frame>4 weeks</time_frame>
    <description>Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number participants with non-cirrhotic chronic Hepatitis B with Adverse Events as assessed by CTCAE v5.0</measure>
    <time_frame>16 weeks</time_frame>
    <description>Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring plasma pharmacokinetics profiles of DCR-S219</measure>
    <time_frame>4 weeks</time_frame>
    <description>Measure the amount of DCR-HBVS excreted in urine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring through concentrations of DCR-S219</measure>
    <time_frame>4 weeks</time_frame>
    <description>Measure the amount of DCR-HBVS renal clearance (CLR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring plasma pharmacokinetics profiles of DCR-HBVS.</measure>
    <time_frame>12 weeks</time_frame>
    <description>Measure the amount of DCR-HBVS excreted in urine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring through concentrations of DCR-HBVS.</measure>
    <time_frame>12 weeks</time_frame>
    <description>Measure DCR-HBVS renal clearance (CLR).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>To evaluate the preliminary antiviral efficacy of DCR-HBVS in participants with CHB by monitoring changes in serum HBsAg levels (all Group B and C participants)during and after single dose and 12 weeks of treatment with DCR HBVS.</measure>
    <time_frame>12 weeks</time_frame>
    <description>Proportion of participants achieving at least a 1-log reduction in HBsAg AND achieving a HBsAg level &lt; 100 IU/mL at last scheduled visit Time to HBsAg loss (Kaplan-Mayer) Time to anti-HBs seroconversion</description>
  </other_outcome>
  <other_outcome>
    <measure>To evaluate the preliminary antiviral efficacy of DCR-HBVS in participants with CHB by monitoring HBeAg levels (HBeAg+ participants only) during and after single dose and 12 weeks of treatment with DCR HBVS.</measure>
    <time_frame>12 weeks</time_frame>
    <description>% of participants with HBeAg loss and anti HBe at last scheduled visit (if HBeAg positive at study entry)</description>
  </other_outcome>
  <other_outcome>
    <measure>To evaluate the preliminary antiviral efficacy of DCR-HBVS in participants with CHB by monitoring HBV DNA levels (all Group B and C participants) during and after single dose and 12 weeks of treatment with DCR HBVS.</measure>
    <time_frame>12 weeks</time_frame>
    <description>Proportion of participants achieving HBV DNA &lt; 2000 IU/mL (if &gt; 2,000 IU/mL at Baseline); and proportion of participants achieving PCR-nondetectable HBV DNA (if HBV DNA was detectable at Baseline).</description>
  </other_outcome>
  <other_outcome>
    <measure>To characterize the pharmacodynamics (PD) of DCR-HBVS on plasma levels of HBsAg and HBV in blood.</measure>
    <time_frame>12 weeks</time_frame>
    <description>Track post-treatment duration of any observed efficacy effects.</description>
  </other_outcome>
  <number_of_arms>22</number_of_arms>
  <enrollment type="Actual">82</enrollment>
  <condition>Hepatitis B, Chronic</condition>
  <arm_group>
    <arm_group_label>Cohort A1 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose, Subcutaneous injection of 0.1mg/kg of DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort A1 Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose, Subcutaneous injection of 0.1mg/kg of Placebo for DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort A2 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose, Subcutaneous injection of 1.5mg/kg of DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort A2 Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose, Subcutaneous injection of 1.5mg/kg of Placebo for DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort A3 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose, Subcutaneous injection of 3mg/kg of DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort A3 Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose, Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort A4 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose, Subcutaneous injection of 6mg/kg of DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort A4 Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose, Subcutaneous injection of 6mg/kg of Placebo for DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort A5 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose, Subcutaneous injection of 12mg/kg of DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort A5 Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose, Subcutaneous injection of 12mg/kg of Placebo for DCR-HBVS (HV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort B DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose, Subcutaneous injection of 3mg/kg of for DCR-HBVS (NUC naïve, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort B Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose, Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS (NUC naïve, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort C1 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 doses- Subcutaneous injection of 1.5mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort C1 Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>4 doses- Subcutaneous injection of 1.5mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort C2 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 doses- Subcutaneous injection of 3mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort C2 Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>4 doses- Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort C3 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 doses- Subcutaneous injection of 6mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort C3 Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>4 doses- Subcutaneous injection of 6mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 4C DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1 dose- Subcutaneous injection of 100mg (NUC experienced, CHB)&#xD;
1 dose- Subcutaneous injection of 200mg (NUC experienced, CHB)&#xD;
1 dose- Subcutaneous injection of 400mg (NUC experienced, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 5C1 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 doses- Subcutaneous injection of 200mg administered every 4 weeks (NUC experienced, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 5C2 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2 doses- Subcutaneous injection of 200mg administered every 8 weeks (NUC experienced, CHB)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 5C3 DCR-HBVS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2 doses- Subcutaneous injection of 400mg administered every 12 weeks (NUC experienced, CHB)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>DCR-HBVS</intervention_name>
    <description>DCR-HBVS is a synthetic ribonucleic acid interference (RNAi) drug that consists of a double-stranded oligonucleotide conjugated to N-acetyl-D-galactosamine (GalNAc) ligands. DCR-HBVS is a sterile solution of the siRNA (DCR-S219) at a concentration of 195 mg/mL in water for injection (WFI).</description>
    <arm_group_label>Cohort 4C DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort 5C1 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort 5C2 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort 5C3 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort A1 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort A2 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort A3 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort A4 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort A5 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort B DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort C1 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort C2 DCR-HBVS</arm_group_label>
    <arm_group_label>Cohort C3 DCR-HBVS</arm_group_label>
    <other_name>DCR-S219</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo for DCR-HBVS</intervention_name>
    <description>Sterile 9% saline for injection.</description>
    <arm_group_label>Cohort A1 Placebo</arm_group_label>
    <arm_group_label>Cohort A2 Placebo</arm_group_label>
    <arm_group_label>Cohort A3 Placebo</arm_group_label>
    <arm_group_label>Cohort A4 Placebo</arm_group_label>
    <arm_group_label>Cohort A5 Placebo</arm_group_label>
    <arm_group_label>Cohort B Placebo</arm_group_label>
    <arm_group_label>Cohort C1 Placebo</arm_group_label>
    <arm_group_label>Cohort C2 Placebo</arm_group_label>
    <arm_group_label>Cohort C3 Placebo</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy at the time of screening as determined by medical evaluation.&#xD;
&#xD;
          -  Capable of giving informed consent.&#xD;
&#xD;
          -  12-lead ECG within normal limits or with no clinically significant abnormalities.&#xD;
&#xD;
          -  Negative screen for alcohol or drugs of abuse.&#xD;
&#xD;
          -  Non-smokers for at least 3 months with a negative urinary cotinine concentration at&#xD;
             screening.&#xD;
&#xD;
          -  BMI within range 18.0 - 32.0 kg/m2 (inclusive).&#xD;
&#xD;
          -  Female participants not pregnant, not breastfeeding, and not of childbearing potential&#xD;
             or willing to follow contraceptive guidance.&#xD;
&#xD;
          -  Chronic hepatitis B infection (Group B and C only).&#xD;
&#xD;
          -  Clinical history compatible with compensated liver disease with no evidence of&#xD;
             cirrhosis (Group B and C only).&#xD;
&#xD;
          -  Continuously on nucleotides (NUC) therapy for at least 12 weeks prior to screening&#xD;
             (Group C only).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of any medical condition that may interfere with the absorption, distribution,&#xD;
             or elimination of study drug.&#xD;
&#xD;
          -  Poorly controlled or unstable hypertension.&#xD;
&#xD;
          -  History of diabetes mellitus treated with insulin or hypoglycemic agents.&#xD;
&#xD;
          -  History of asthma requiring hospital admission within the preceding 12 months.&#xD;
&#xD;
          -  Evidence of G-6-PD deficiency.&#xD;
&#xD;
          -  Currently poorly controlled endocrine conditions, excluding thyroid conditions.&#xD;
&#xD;
          -  History of multiple drug allergies or history of allergic reaction to an&#xD;
             oligonucleotide or GalNAc.&#xD;
&#xD;
          -  Clinically relevant surgical history.&#xD;
&#xD;
          -  Use of prescription medications (excluding contraception for women) within 4 weeks&#xD;
             prior to the administration of study intervention.&#xD;
&#xD;
          -  Use of clinically relevant over-the-counter medication or supplements (excluding&#xD;
             routine vitamins) within 7 days of first dosing.&#xD;
&#xD;
          -  Has received an investigational agent within the 3 months prior to dosing or is in&#xD;
             follow-up of another study.&#xD;
&#xD;
          -  Antiviral therapy (other than entecavir or tenofovir) within 3 months of screening or&#xD;
             treatment with interferon in the last 3 years (Group B and C only).&#xD;
&#xD;
          -  Use within the last 6 months of anticoagulants or systemically administered&#xD;
             corticosteroids, immunomodulators, or immunosuppressants (Group B and C only).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas Bowman, MD</last_name>
    <role>Study Director</role>
    <affiliation>Dicerna Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Monash Health</name>
      <address>
        <city>Clayton</city>
        <state>Victoria</state>
        <zip>3168</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Vincent's Hospital Melbourne</name>
      <address>
        <city>Fitzroy</city>
        <state>Victoria</state>
        <zip>3065</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Mary Hospital (The University of Hong Kong)</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seoul National University Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seoul Metropolitan Government - Seoul National University Boramae Medical Center</name>
      <address>
        <city>Soeul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Site</name>
      <address>
        <city>Auckland</city>
        <zip>1023</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Middlemore Hospital</name>
      <address>
        <city>Auckland</city>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King Culalongkorn Memorial Hospital</name>
      <address>
        <city>Bangkok</city>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Srinagarind Hospital</name>
      <address>
        <city>Khon Kaen</city>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Hong Kong</country>
    <country>Korea, Republic of</country>
    <country>New Zealand</country>
    <country>Thailand</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 10, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 11, 2018</study_first_posted>
  <last_update_submitted>September 28, 2022</last_update_submitted>
  <last_update_submitted_qc>September 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 30, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Chronic Hepatitis B</keyword>
  <keyword>DNA Virus Infections</keyword>
  <keyword>CHB</keyword>
  <keyword>HBsAg</keyword>
  <keyword>Liver Disease</keyword>
  <keyword>RNAi</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis B</mesh_term>
    <mesh_term>Hepatitis B, Chronic</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03772249
org study id: DCR-HBVS-101
secondary id: U1111-1220-7021
nct id: NCT03772249
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
DCR-HBVS will be evaluated for safety and efficacy in healthy volunteers and chronic
      hepatitis B patients.
DCR HBVS is being developed for the treatment of chronic hepatitis B (CHB) in adults. The
      study will be conducted in 3 parts, a single ascending-dose (SAD) phase in normal healthy
      volunteers (Group A), a single-dose (SD) phase in patients with CHB (Group B), and a multiple
      ascending-dose (MAD) phase in patients with CHB (Group 1c-3c). Cohort 4c is a single
      ascending dose with a possible duration of up to 48 weeks. Cohort 5c is a multiple dose
      cohort with a possible duration of up to 72 weeks.
allocation: Randomized
intervention model: Sequential Assignment
intervention model description: Progression from the SAD phase to the first cohort in the MAD phase is contingent upon the Safety Review Committee (SRC) review of a minimum of 14 days post-dose safety and tolerability data from all NHV in at least the first 2 SAD cohorts. The SRC will select one (or more) well-tolerated dose(s) from the SAD phase for administration in the SD and MAD phases. Group B at 3 mg/kg will start in parallel with Group C at the 3 mg/kg dose level. In all study phases, dosing will be staggered with the use of sentinel participants to allow time for the assessment of safety before additional subjects are exposed to study drug. The fixed dosing regimen for Cohorts 4c and 5c was determined following SRC review and assessment of all data up to Cohort 3c. No sentinel dosing will occur in Cohorts 4c and 5c.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: This is a double-blind study in which the study site team, the Sponsor, and the participants will be blinded to treatment assignment. The unblinded pharmacist will cover each syringe, prior to transport to the bedside, to ensure blinding. The drug will be injected by an unblinded nurse or physician who is not part of the study team. Participants will be centrally assigned to randomized study intervention using an Interactive Voice/Web Response System (IVRS/IWRS). Cohorts 4c and 5c will be open label.
measure: Number of healthy volunteers with Adverse Events as assessed by CTCAE v5.0
time frame: 4 weeks
description: Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings
measure: Number participants with non-cirrhotic chronic Hepatitis B with Adverse Events as assessed by CTCAE v5.0
time frame: 16 weeks
description: Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings
measure: To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring plasma pharmacokinetics profiles of DCR-S219
time frame: 4 weeks
description: Measure the amount of DCR-HBVS excreted in urine
measure: To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring through concentrations of DCR-S219
time frame: 4 weeks
description: Measure the amount of DCR-HBVS renal clearance (CLR).
measure: To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring plasma pharmacokinetics profiles of DCR-HBVS.
time frame: 12 weeks
description: Measure the amount of DCR-HBVS excreted in urine
measure: To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring through concentrations of DCR-HBVS.
time frame: 12 weeks
description: Measure DCR-HBVS renal clearance (CLR).
measure: To evaluate the preliminary antiviral efficacy of DCR-HBVS in participants with CHB by monitoring changes in serum HBsAg levels (all Group B and C participants)during and after single dose and 12 weeks of treatment with DCR HBVS.
time frame: 12 weeks
description: Proportion of participants achieving at least a 1-log reduction in HBsAg AND achieving a HBsAg level < 100 IU/mL at last scheduled visit Time to HBsAg loss (Kaplan-Mayer) Time to anti-HBs seroconversion
measure: To evaluate the preliminary antiviral efficacy of DCR-HBVS in participants with CHB by monitoring HBeAg levels (HBeAg+ participants only) during and after single dose and 12 weeks of treatment with DCR HBVS.
time frame: 12 weeks
description: % of participants with HBeAg loss and anti HBe at last scheduled visit (if HBeAg positive at study entry)
measure: To evaluate the preliminary antiviral efficacy of DCR-HBVS in participants with CHB by monitoring HBV DNA levels (all Group B and C participants) during and after single dose and 12 weeks of treatment with DCR HBVS.
time frame: 12 weeks
description: Proportion of participants achieving HBV DNA < 2000 IU/mL (if > 2,000 IU/mL at Baseline); and proportion of participants achieving PCR-nondetectable HBV DNA (if HBV DNA was detectable at Baseline).
measure: To characterize the pharmacodynamics (PD) of DCR-HBVS on plasma levels of HBsAg and HBV in blood.
time frame: 12 weeks
description: Track post-treatment duration of any observed efficacy effects.
arm group label: Cohort A1 DCR-HBVS
arm group type: Experimental
description: Single dose, Subcutaneous injection of 0.1mg/kg of DCR-HBVS (HV)
arm group label: Cohort A1 Placebo
arm group type: Placebo Comparator
description: Single dose, Subcutaneous injection of 0.1mg/kg of Placebo for DCR-HBVS (HV)
arm group label: Cohort A2 DCR-HBVS
arm group type: Experimental
description: Single dose, Subcutaneous injection of 1.5mg/kg of DCR-HBVS (HV)
arm group label: Cohort A2 Placebo
arm group type: Placebo Comparator
description: Single dose, Subcutaneous injection of 1.5mg/kg of Placebo for DCR-HBVS (HV)
arm group label: Cohort A3 DCR-HBVS
arm group type: Experimental
description: Single dose, Subcutaneous injection of 3mg/kg of DCR-HBVS (HV)
arm group label: Cohort A3 Placebo
arm group type: Placebo Comparator
description: Single dose, Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS (HV)
arm group label: Cohort A4 DCR-HBVS
arm group type: Experimental
description: Single dose, Subcutaneous injection of 6mg/kg of DCR-HBVS (HV)
arm group label: Cohort A4 Placebo
arm group type: Placebo Comparator
description: Single dose, Subcutaneous injection of 6mg/kg of Placebo for DCR-HBVS (HV)
arm group label: Cohort A5 DCR-HBVS
arm group type: Experimental
description: Single dose, Subcutaneous injection of 12mg/kg of DCR-HBVS (HV)
arm group label: Cohort A5 Placebo
arm group type: Placebo Comparator
description: Single dose, Subcutaneous injection of 12mg/kg of Placebo for DCR-HBVS (HV)
arm group label: Cohort B DCR-HBVS
arm group type: Experimental
description: Single dose, Subcutaneous injection of 3mg/kg of for DCR-HBVS (NUC naïve, CHB)
arm group label: Cohort B Placebo
arm group type: Placebo Comparator
description: Single dose, Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS (NUC naïve, CHB)
arm group label: Cohort C1 DCR-HBVS
arm group type: Experimental
description: 4 doses- Subcutaneous injection of 1.5mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB)
arm group label: Cohort C1 Placebo
arm group type: Placebo Comparator
description: 4 doses- Subcutaneous injection of 1.5mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB)
arm group label: Cohort C2 DCR-HBVS
arm group type: Experimental
description: 4 doses- Subcutaneous injection of 3mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB)
arm group label: Cohort C2 Placebo
arm group type: Placebo Comparator
description: 4 doses- Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB)
arm group label: Cohort C3 DCR-HBVS
arm group type: Experimental
description: 4 doses- Subcutaneous injection of 6mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB)
arm group label: Cohort C3 Placebo
arm group type: Placebo Comparator
description: 4 doses- Subcutaneous injection of 6mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB)
arm group label: Cohort 4C DCR-HBVS
arm group type: Experimental
description: 1 dose- Subcutaneous injection of 100mg (NUC experienced, CHB)
1 dose- Subcutaneous injection of 200mg (NUC experienced, CHB)
1 dose- Subcutaneous injection of 400mg (NUC experienced, CHB)
arm group label: Cohort 5C1 DCR-HBVS
arm group type: Experimental
description: 4 doses- Subcutaneous injection of 200mg administered every 4 weeks (NUC experienced, CHB)
arm group label: Cohort 5C2 DCR-HBVS
arm group type: Experimental
description: 2 doses- Subcutaneous injection of 200mg administered every 8 weeks (NUC experienced, CHB)
arm group label: Cohort 5C3 DCR-HBVS
arm group type: Experimental
description: 2 doses- Subcutaneous injection of 400mg administered every 12 weeks (NUC experienced, CHB)
intervention type: Drug
intervention name: DCR-HBVS
description: DCR-HBVS is a synthetic ribonucleic acid interference (RNAi) drug that consists of a double-stranded oligonucleotide conjugated to N-acetyl-D-galactosamine (GalNAc) ligands. DCR-HBVS is a sterile solution of the siRNA (DCR-S219) at a concentration of 195 mg/mL in water for injection (WFI).
arm group label: Cohort 4C DCR-HBVS
arm group label: Cohort 5C1 DCR-HBVS
arm group label: Cohort 5C2 DCR-HBVS
arm group label: Cohort 5C3 DCR-HBVS
arm group label: Cohort A1 DCR-HBVS
arm group label: Cohort A2 DCR-HBVS
arm group label: Cohort A3 DCR-HBVS
arm group label: Cohort A4 DCR-HBVS
arm group label: Cohort A5 DCR-HBVS
arm group label: Cohort B DCR-HBVS
arm group label: Cohort C1 DCR-HBVS
arm group label: Cohort C2 DCR-HBVS
arm group label: Cohort C3 DCR-HBVS
other name: DCR-S219
intervention type: Drug
intervention name: Placebo for DCR-HBVS
description: Sterile 9% saline for injection.
arm group label: Cohort A1 Placebo
arm group label: Cohort A2 Placebo
arm group label: Cohort A3 Placebo
arm group label: Cohort A4 Placebo
arm group label: Cohort A5 Placebo
arm group label: Cohort B Placebo
arm group label: Cohort C1 Placebo
arm group label: Cohort C2 Placebo
arm group label: Cohort C3 Placebo
other name: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Thomas Bowman, MD
role: Study Director
affiliation: Dicerna Pharmaceuticals
facility: 
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country: Australia
country: Hong Kong
country: Korea, Republic of
country: New Zealand
country: Thailand
responsible party type: Sponsor
mesh term: Hepatitis A
mesh term: Hepatitis B
mesh term: Hepatitis B, Chronic
mesh term: Hepatitis