Study of Safety and Tolerability of DCR HBVS

Study Overview
=================
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.

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

Conditions
-----------------
Hepatitis B, Chronic

Intervention / Treatment
-----------------
* Drug: DCR-HBVS
* Drug: Placebo for DCR-HBVS


Participation Criteria
=================
Eligibility 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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A1 DCR-HBVS<br>Single dose, Subcutaneous injection of 0.1mg/kg of DCR-HBVS (HV) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Placebo Comparator: Cohort A1 Placebo<br>Single dose, Subcutaneous injection of 0.1mg/kg of Placebo for DCR-HBVS (HV) | Drug: Placebo for DCR-HBVS<br>* Sterile 9% saline for injection.<br>* Other names: Placebo;|
| Experimental: Cohort A2 DCR-HBVS<br>Single dose, Subcutaneous injection of 1.5mg/kg of DCR-HBVS (HV) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Placebo Comparator: Cohort A2 Placebo<br>Single dose, Subcutaneous injection of 1.5mg/kg of Placebo for DCR-HBVS (HV) | Drug: Placebo for DCR-HBVS<br>* Sterile 9% saline for injection.<br>* Other names: Placebo;|
| Experimental: Cohort A3 DCR-HBVS<br>Single dose, Subcutaneous injection of 3mg/kg of DCR-HBVS (HV) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Placebo Comparator: Cohort A3 Placebo<br>Single dose, Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS (HV) | Drug: Placebo for DCR-HBVS<br>* Sterile 9% saline for injection.<br>* Other names: Placebo;|
| Experimental: Cohort A4 DCR-HBVS<br>Single dose, Subcutaneous injection of 6mg/kg of DCR-HBVS (HV) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Placebo Comparator: Cohort A4 Placebo<br>Single dose, Subcutaneous injection of 6mg/kg of Placebo for DCR-HBVS (HV) | Drug: Placebo for DCR-HBVS<br>* Sterile 9% saline for injection.<br>* Other names: Placebo;|
| Experimental: Cohort A5 DCR-HBVS<br>Single dose, Subcutaneous injection of 12mg/kg of DCR-HBVS (HV) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Placebo Comparator: Cohort A5 Placebo<br>Single dose, Subcutaneous injection of 12mg/kg of Placebo for DCR-HBVS (HV) | Drug: Placebo for DCR-HBVS<br>* Sterile 9% saline for injection.<br>* Other names: Placebo;|
| Experimental: Cohort B DCR-HBVS<br>Single dose, Subcutaneous injection of 3mg/kg of for DCR-HBVS (NUC naïve, CHB) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Placebo Comparator: Cohort B Placebo<br>Single dose, Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS (NUC naïve, CHB) | Drug: Placebo for DCR-HBVS<br>* Sterile 9% saline for injection.<br>* Other names: Placebo;|
| Experimental: Cohort C1 DCR-HBVS<br>4 doses- Subcutaneous injection of 1.5mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Placebo Comparator: Cohort C1 Placebo<br>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<br>* Sterile 9% saline for injection.<br>* Other names: Placebo;|
| Experimental: Cohort C2 DCR-HBVS<br>4 doses- Subcutaneous injection of 3mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Placebo Comparator: Cohort C2 Placebo<br>4 doses- Subcutaneous injection of 3mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB) | Drug: Placebo for DCR-HBVS<br>* Sterile 9% saline for injection.<br>* Other names: Placebo;|
| Experimental: Cohort C3 DCR-HBVS<br>4 doses- Subcutaneous injection of 6mg/kg of DCR-HBVS administered every 28 days (NUC experienced, CHB) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Placebo Comparator: Cohort C3 Placebo<br>4 doses- Subcutaneous injection of 6mg/kg of Placebo for DCR-HBVS administered every 28 days (NUC experienced, CHB) | Drug: Placebo for DCR-HBVS<br>* Sterile 9% saline for injection.<br>* Other names: Placebo;|
| Experimental: Cohort 4C DCR-HBVS<br>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<br>* 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).<br>* Other names: DCR-S219;|
| Experimental: Cohort 5C1 DCR-HBVS<br>4 doses- Subcutaneous injection of 200mg administered every 4 weeks (NUC experienced, CHB) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Experimental: Cohort 5C2 DCR-HBVS<br>2 doses- Subcutaneous injection of 200mg administered every 8 weeks (NUC experienced, CHB) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|
| Experimental: Cohort 5C3 DCR-HBVS<br>2 doses- Subcutaneous injection of 400mg administered every 12 weeks (NUC experienced, CHB) | Drug: DCR-HBVS<br>* 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).<br>* Other names: DCR-S219;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of healthy volunteers with Adverse Events as assessed by CTCAE v5.0 | Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings | 4 weeks | 
| Number participants with non-cirrhotic chronic Hepatitis B with Adverse Events as assessed by CTCAE v5.0 | Number of participants with abnormalities in vital signs, electrocardiogram (ECG), and clinically significant laboratory findings | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring plasma pharmacokinetics profiles of DCR-S219 | Measure the amount of DCR-HBVS excreted in urine | 4 weeks | 
| To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring through concentrations of DCR-S219 | Measure the amount of DCR-HBVS renal clearance (CLR). | 4 weeks | 
| To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring plasma pharmacokinetics profiles of DCR-HBVS. | Measure the amount of DCR-HBVS excreted in urine | 12 weeks | 
| To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring through concentrations of DCR-HBVS. | Measure DCR-HBVS renal clearance (CLR). | 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic Hepatitis B, DNA Virus Infections, CHB, HBsAg, Liver Disease, RNAi