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Study of Safety and Tolerability of DCR HBVS

Sponsor
Dicerna Pharmaceuticals, Inc. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03772249
Collaborator
(none)
82
Enrollment
9
Locations
22
Arms
42.1
Anticipated Duration (Months)
9.1
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

DCR-HBVS will be evaluated for safety and efficacy in healthy volunteers and chronic hepatitis B patients.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
82 participants
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.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.
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.
Primary Purpose:
Treatment
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
Actual Study Start Date :
Dec 28, 2018
Anticipated Primary Completion Date :
Jul 1, 2022
Anticipated Study Completion Date :
Jul 1, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort A1 DCR-HBVS

Single dose, Subcutaneous injection of 0.1mg/kg of DCR-HBVS (HV)

Drug: DCR-HBVS
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).
Other Names:
  • DCR-S219

    		•
    Placebo Comparator: Cohort A1 Placebo

    Single dose, Subcutaneous injection of 0.1mg/kg of Placebo for DCR-HBVS (HV)

    Drug: Placebo for DCR-HBVS
    Sterile 9% saline for injection.
    Other Names:
  • Placebo

    		•
    Experimental: Cohort A2 DCR-HBVS

    Single dose, Subcutaneous injection of 1.5mg/kg of DCR-HBVS (HV)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Placebo Comparator: Cohort A2 Placebo

    Single dose, Subcutaneous injection of 1.5mg/kg of Placebo for DCR-HBVS (HV)

    Drug: Placebo for DCR-HBVS
    Sterile 9% saline for injection.
    Other Names:
  • Placebo

    		•
    Experimental: Cohort A3 DCR-HBVS

    Single dose, Subcutaneous injection of 3mg/kg of DCR-HBVS (HV)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Placebo Comparator: Cohort A3 Placebo

    Single dose, Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS (HV)

    Drug: Placebo for DCR-HBVS
    Sterile 9% saline for injection.
    Other Names:
  • Placebo

    		•
    Experimental: Cohort A4 DCR-HBVS

    Single dose, Subcutaneous injection of 6mg/kg of DCR-HBVS (HV)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Placebo Comparator: Cohort A4 Placebo

    Single dose, Subcutaneous injection of 6mg/kg of Placebo for DCR-HBVS (HV)

    Drug: Placebo for DCR-HBVS
    Sterile 9% saline for injection.
    Other Names:
  • Placebo

    		•
    Experimental: Cohort A5 DCR-HBVS

    Single dose, Subcutaneous injection of 12mg/kg of DCR-HBVS (HV)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Placebo Comparator: Cohort A5 Placebo

    Single dose, Subcutaneous injection of 12mg/kg of Placebo for DCR-HBVS (HV)

    Drug: Placebo for DCR-HBVS
    Sterile 9% saline for injection.
    Other Names:
  • Placebo

    		•
    Experimental: Cohort B DCR-HBVS

    Single dose, Subcutaneous injection of 3mg/kg of for DCR-HBVS (NUC naïve, CHB)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Placebo Comparator: Cohort B Placebo

    Single dose, Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS (NUC naïve, CHB)

    Drug: Placebo for DCR-HBVS
    Sterile 9% saline for injection.
    Other Names:
  • Placebo

    		•
    Experimental: Cohort C1 DCR-HBVS

    4 doses- Subcutaneous injection of 1.5mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Placebo Comparator: Cohort C1 Placebo

    4 doses- Subcutaneous injection of 1.5mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB)

    Drug: Placebo for DCR-HBVS
    Sterile 9% saline for injection.
    Other Names:
  • Placebo

    		•
    Experimental: Cohort C2 DCR-HBVS

    4 doses- Subcutaneous injection of 3mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Placebo Comparator: Cohort C2 Placebo

    4 doses- Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB)

    Drug: Placebo for DCR-HBVS
    Sterile 9% saline for injection.
    Other Names:
  • Placebo

    		•
    Experimental: Cohort C3 DCR-HBVS

    4 doses- Subcutaneous injection of 6mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Placebo Comparator: Cohort C3 Placebo

    4 doses- Subcutaneous injection of 6mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB)

    Drug: Placebo for DCR-HBVS
    Sterile 9% saline for injection.
    Other Names:
  • Placebo

    		•
    Experimental: Cohort 4C DCR-HBVS

    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)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Experimental: Cohort 5C1 DCR-HBVS

    4 doses- Subcutaneous injection of 200mg administered every 4 weeks (NUC experienced, CHB)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Experimental: Cohort 5C2 DCR-HBVS

    2 doses- Subcutaneous injection of 200mg administered every 8 weeks (NUC experienced, CHB)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•
    Experimental: Cohort 5C3 DCR-HBVS

    2 doses- Subcutaneous injection of 400mg administered every 12 weeks (NUC experienced, CHB)

    Drug: DCR-HBVS
    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).
    Other Names:
  • DCR-S219

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of healthy volunteers with Adverse Events as assessed by CTCAE v5.0 [4 weeks]

      Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings

    2. Number participants with non-cirrhotic chronic Hepatitis B with Adverse Events as assessed by CTCAE v5.0 [16 weeks]

      Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings

    Secondary Outcome Measures

    1. To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring plasma pharmacokinetics profiles of DCR-S219 [4 weeks]

      Measure the amount of DCR-HBVS excreted in urine

    2. To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring through concentrations of DCR-S219 [4 weeks]

      Measure the amount of DCR-HBVS renal clearance (CLR).

    3. To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring plasma pharmacokinetics profiles of DCR-HBVS. [12 weeks]

      Measure the amount of DCR-HBVS excreted in urine

    4. To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring through concentrations of DCR-HBVS. [12 weeks]

      Measure DCR-HBVS renal clearance (CLR).

    Other Outcome Measures

    1. 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. [12 weeks]

      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

    2. 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. [12 weeks]

      % of participants with HBeAg loss and anti HBe at last scheduled visit (if HBeAg positive at study entry)

    3. 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. [12 weeks]

      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).

    4. To characterize the pharmacodynamics (PD) of DCR-HBVS on plasma levels of HBsAg and HBV in blood. [12 weeks]

      Track post-treatment duration of any observed efficacy effects.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    • Healthy at the time of screening as determined by medical evaluation.

    • Capable of giving informed consent.

    • 12-lead ECG within normal limits or with no clinically significant abnormalities.

    • Negative screen for alcohol or drugs of abuse.

    • Non-smokers for at least 3 months with a negative urinary cotinine concentration at screening.

    • BMI within range 18.0 - 32.0 kg/m2 (inclusive).

    • Female participants not pregnant, not breastfeeding, and not of childbearing potential or willing to follow contraceptive guidance.

    • Chronic hepatitis B infection (Group B and C only).

    • Clinical history compatible with compensated liver disease with no evidence of cirrhosis (Group B and C only).

    • Continuously on nucleotides (NUC) therapy for at least 12 weeks prior to screening (Group C only).

    Exclusion Criteria:

    • History of any medical condition that may interfere with the absorption, distribution, or elimination of study drug.

    • Poorly controlled or unstable hypertension.

    • History of diabetes mellitus treated with insulin or hypoglycemic agents.

    • History of asthma requiring hospital admission within the preceding 12 months.

    • Evidence of G-6-PD deficiency.

    • Currently poorly controlled endocrine conditions, excluding thyroid conditions.

    • History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc.

    • Clinically relevant surgical history.

    • Use of prescription medications (excluding contraception for women) within 4 weeks prior to the administration of study intervention.

    • Use of clinically relevant over-the-counter medication or supplements (excluding routine vitamins) within 7 days of first dosing.

    • Has received an investigational agent within the 3 months prior to dosing or is in follow-up of another study.

    • Antiviral therapy (other than entecavir or tenofovir) within 3 months of screening or treatment with interferon in the last 3 years (Group B and C only).

    • Use within the last 6 months of anticoagulants or systemically administered corticosteroids, immunomodulators, or immunosuppressants (Group B and C only).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Monash Health Clayton Victoria Australia 3168
    2 St Vincent's Hospital Melbourne Fitzroy Victoria Australia 3065
    3 Queen Mary Hospital (The University of Hong Kong) Hong Kong Hong Kong
    4 Seoul National University Hospital Seoul Korea, Republic of
    5 Seoul Metropolitan Government - Seoul National University Boramae Medical Center Soeul Korea, Republic of
    6 Clinical Site Auckland New Zealand 1023
    7 Middlemore Hospital Auckland New Zealand
    8 King Culalongkorn Memorial Hospital Bangkok Thailand
    9 Srinagarind Hospital Khon Kaen Thailand

    Sponsors and Collaborators

    • Dicerna Pharmaceuticals, Inc.

    Investigators

    • Study Director: Mark Pirner, MD, Dicerna Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Dicerna Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT03772249
    Other Study ID Numbers:
    • DCR-HBVS-101
    • U1111-1220-7021
    First Posted:
    Dec 11, 2018
    Last Update Posted:
    Sep 9, 2021
    Last Verified:
    Sep 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Keywords provided by Dicerna Pharmaceuticals, Inc.
    Chronic Hepatitis B
    DNA Virus Infections
    CHB
    HBsAg
    Liver Disease
    RNAi
    Additional relevant MeSH terms:
    Hepatitis A
    Hepatitis B
    Hepatitis B, Chronic
    Hepatitis

    Study Results

    No Results Posted as of Sep 9, 2021