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Study of Safety and Tolerability of DCR HBVS

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ClinicalTrials.gov Identifier: NCT03772249
Recruitment Status : Recruiting
First Posted : December 11, 2018
Last Update Posted : March 7, 2019
Sponsor:
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc.

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 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 C).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 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 HV 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. 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.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: This is a double-blind placebo-controlled 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. Participants will be centrally assigned to randomized study intervention using an Interactive Voice/Web Response System (IVRS/IWRS).
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
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine


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 double-stranded oligonucleotides conjugated to an N-acetyl-D-galactosamine (GalNAc) ligand. DCR-HBVS, sterile solution of the siRNA (DCR-S219) at a concentration of 185 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 double-stranded oligonucleotides conjugated to an N-acetyl-D-galactosamine (GalNAc) ligand. DCR-HBVS, sterile solution of the siRNA (DCR-S219) at a concentration of 185 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 double-stranded oligonucleotides conjugated to an N-acetyl-D-galactosamine (GalNAc) ligand. DCR-HBVS, sterile solution of the siRNA (DCR-S219) at a concentration of 185 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 double-stranded oligonucleotides conjugated to an N-acetyl-D-galactosamine (GalNAc) ligand. DCR-HBVS, sterile solution of the siRNA (DCR-S219) at a concentration of 185 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 double-stranded oligonucleotides conjugated to an N-acetyl-D-galactosamine (GalNAc) ligand. DCR-HBVS, sterile solution of the siRNA (DCR-S219) at a concentration of 185 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 double-stranded oligonucleotides conjugated to an N-acetyl-D-galactosamine (GalNAc) ligand. DCR-HBVS, sterile solution of the siRNA (DCR-S219) at a concentration of 185 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 double-stranded oligonucleotides conjugated to an N-acetyl-D-galactosamine (GalNAc) ligand. DCR-HBVS, sterile solution of the siRNA (DCR-S219) at a concentration of 185 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 double-stranded oligonucleotides conjugated to an N-acetyl-D-galactosamine (GalNAc) ligand. DCR-HBVS, sterile solution of the siRNA (DCR-S219) at a concentration of 185 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 double-stranded oligonucleotides conjugated to an N-acetyl-D-galactosamine (GalNAc) ligand. DCR-HBVS, sterile solution of the siRNA (DCR-S219) at a concentration of 185 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




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.



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.


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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).

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


Contacts
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Contact: Sr Director, Clinical Development 617-612-6260 mcioffi@dicerna.com

Locations
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New Zealand
Clinical Site Recruiting
Auckland, New Zealand, 1023
Sponsors and Collaborators
Dicerna Pharmaceuticals, Inc.
Investigators
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Study Director: Ralf Rosskamp, MD Dicerna Pharmaceuticals

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Responsible Party: Dicerna Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03772249     History of Changes
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: March 7, 2019
Last Verified: March 2019

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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.:
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
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Hepatitis, Chronic