Clinical trial NCT03772249: Study of Safety and Tolerability of DCR HBVS
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis B, Chronic
Keywords: Chronic Hepatitis B
DNA Virus Infections
CHB
HBsAg
Liver Disease
RNAi
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2018-12-11
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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

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.

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).

Primary outcomes:
measure: Number of healthy volunteers with Adverse Events as assessed by CTCAE v5.0
timeFrame: 4 weeks
measure: Number participants with non-cirrhotic chronic Hepatitis B with Adverse Events as assessed by CTCAE v5.0
timeFrame: 16 weeks
Secondary outcomes:
measure: To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring plasma pharmacokinetics profiles of DCR-S219
timeFrame: 4 weeks
measure: To characterize the pharmacokinetics of DCR-HBVS in healthy volunteers by monitoring through concentrations of DCR-S219
timeFrame: 4 weeks
measure: To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring plasma pharmacokinetics profiles of DCR-HBVS.
timeFrame: 12 weeks
measure: To characterize the pharmacokinetics of DCR-HBVS in participants with non-cirrhotic CHB by monitoring through concentrations of DCR-HBVS.
timeFrame: 12 weeks
Other outcomes:
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.
timeFrame: 12 weeks
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.
timeFrame: 12 weeks
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.
timeFrame: 12 weeks
measure: To characterize the pharmacodynamics (PD) of DCR-HBVS on plasma levels of HBsAg and HBV in blood.
timeFrame: 12 weeks
Locations:
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincent's Hospital Melbourne
state: Victoria
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital (The University of Hong Kong)
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Soeul
country: Korea, Republic of
facility: Seoul Metropolitan Government - Seoul National University Boramae Medical Center
city: Auckland
country: New Zealand
facility: Clinical Site
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Bangkok
country: Thailand
facility: King Culalongkorn Memorial Hospital
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital
Study officials:
affiliation: Dicerna Pharmaceuticals
name: Thomas Bowman, MD
role: STUDY_DIRECTOR
References: