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Study of Safety and Tolerability of DCR HBVS

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03772249
Recruitment Status : Completed
First Posted : December 11, 2018
Last Update Posted : September 30, 2022
Sponsor:
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Study Description
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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
Hepatitis B, Chronic Drug: DCR-HBVS Drug: Placebo for DCR-HBVS 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
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Study Type : Interventional  (Clinical Trial)
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.
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 : December 28, 2018
Actual Primary Completion Date : July 12, 2022
Actual Study Completion Date : July 12, 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: DCR-S219


Outcome Measures
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Primary Outcome Measures :
  1. Number of healthy volunteers with Adverse Events as assessed by CTCAE v5.0 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 12 weeks ]
    Track post-treatment duration of any observed efficacy effects.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
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Information from the National Library of Medicine

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

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03772249


Locations
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Australia, Victoria
Monash Health
Clayton, Victoria, Australia, 3168
St Vincent's Hospital Melbourne
Fitzroy, Victoria, Australia, 3065
Hong Kong
Queen Mary Hospital (The University of Hong Kong)
Hong Kong, Hong Kong
Korea, Republic of
Seoul National University Hospital
Seoul, Korea, Republic of
Seoul Metropolitan Government - Seoul National University Boramae Medical Center
Soeul, Korea, Republic of
New Zealand
Clinical Site
Auckland, New Zealand, 1023
Middlemore Hospital
Auckland, New Zealand
Thailand
King Culalongkorn Memorial Hospital
Bangkok, Thailand
Srinagarind Hospital
Khon Kaen, Thailand
Sponsors and Collaborators
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Investigators
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Study Director: Thomas Bowman, MD Dicerna Pharmaceuticals
More Information
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Responsible Party: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
ClinicalTrials.gov Identifier: NCT03772249    
Other Study ID Numbers: DCR-HBVS-101
U1111-1220-7021 ( Other Identifier: World Health Organization (WHO) )
First Posted: December 11, 2018    Key Record Dates
Last Update Posted: September 30, 2022
Last Verified: September 2022

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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., a Novo Nordisk company:
Chronic Hepatitis B
DNA Virus Infections
CHB
 HBsAg
Liver Disease
RNAi
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis B
Hepatitis B, Chronic
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Infections
Enterovirus Infections
 Picornaviridae Infections
RNA Virus Infections
Blood-Borne Infections
Communicable Diseases
Hepadnaviridae Infections
DNA Virus Infections
Hepatitis, Chronic
Chronic Disease
Disease Attributes
Pathologic Processes