Hepatitis B, Chronic
Conditions
Keywords
Chronic Hepatitis B, DNA Virus Infections, CHB, HBsAg, Liver Disease, RNAi
Brief summary
DCR-HBVS will be evaluated for safety and efficacy in healthy volunteers and chronic hepatitis B patients.
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.
Interventions
DRUGDCR-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).
DRUGPlacebo for DCR-HBVS
Sterile 9% saline for injection.
Sponsors
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, 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.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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 |
| 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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) |
| 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 |
Countries
Australia, Hong Kong, New Zealand, South Korea, Thailand
Outcome results
None listed