A Study of RO7239958 to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers and Participants With Chronic Hepatitis B Virus Infection

A Randomized, Placebo-controlled,Observer-blinded Study, to Evaluate Safety,Tolerability, Pharmacokinetics and Pharmacodynamics of RO7239958 in Healthy Volunteers and Patients With Chronic Hepatitis B Virus Infection

This study is designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple ascending doses in healthy volunteers (HV) and participants diagnosed with chronic hepatitis B (CHB).

Study Overview

• Status: Terminated
• Conditions: Hepatitis B Virus Infection
• Intervention / Treatment: Drug: RO7239958; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria, 1407
    • Acibadem City Clinic Tokuda Hospital Ead
  • Sofia, Bulgaria, 1612
    • COMAC Medical; Clinical Research Unit for Phase I
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Pusan National University Hospital
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center.
• New Zealand
  • Auckland, New Zealand, 1010
    • Auckland Clinical Studies Limited
• Poland
  • Myslowice, Poland, 41-400
    • ID Clinic
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical University
  • Tainan, Taiwan, 70457
    • National Cheng Kung University Hospital
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool University Hospital
  • London, United Kingdom, SW17 0QT
    • St George's Hospital
  • London, United Kingdom, SW10 9NH
    • Chelsea & Westminster Hospital
  • London, United Kingdom, SE5 9RS
    • King College Hospital NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All Parts

-Female participants should be of non-childbearing potential and male participants who are with pregnant partners or partners of childbearing potential must agree to remain abstinent or use contraceptive measures

Part 1 (SAD HV only)

• Healthy, as judged by the Investigator
• Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on Day 1, and agrees to remain non-smoker during the study

Part 2 (CHB only)

• Positive serum HBsAg status for > 6 months prior to screening
• Serum HBsAg level ≥ 250 IU/mL at screening
• On stable entecavir or tenofovir (alone or in combination) treatment and having received the same drug in the 3 months prior to randomisation
• HBV DNA below the lower limit of quantification (LLQ) for ≥ 6 months prior to screening by local testing, and confirmed at screening
• Screening laboratory values (including hematology, chemistry, urinalysis) within normal ranges
• No past or current diagnosis of cirrhosis

Exclusion Criteria:

All Parts

• History or presence of significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological disorders, or diagnosed central or peripheral neurological disease, capable of altering the absorption, metabolism, or elimination of drugs, or constituting a risk when taking the study treatment, or of interfering with the interpretation of the data
• History of lymphoma, leukemia, or malignancy within the past five years
• Positive for human immunodeficiency virus (HIV) infection
• Participant under judicial supervision, guardianship or curatorship

Part 1 (SAD HV only)

• Screening ECG showing clinically relevant abnormalities
• Abnormal blood pressure
• History or presence of liver disease, or known hepatic or biliary abnormalities
• Alanine aminotransferase (ALT) ≥1.5 × upper limit of normal (ULN)
• Any clinically significant out of range findings in other laboratory test results or any other clinically significant (as judged by the Investigator) abnormalities in the physical examination at screening and on Day -1
• Positive for hepatitis B surface antigen (HBsAg), or hepatitis B core total antibody [anti-HBc]), or hepatitis C virus (HCV) antibody test result

Part 2 (CHB only)

• History or presence of bridging fibrosis or cirrhosis or decompensated liver disease
• History or presence of a medical condition associated with liver disease other than HBV infection. Other known hepatic or biliary abnormalities
• History of or suspicion of hepatocellular carcinoma or alpha fetoprotein (AFP) ≥13 ng/mL
• History of having received (in the last six months) or currently receiving any systemic antineoplastic (including radiation) or immune-modulatory treatment (including systemic corticosteroids)
• History of organ transplantation
• Estimated glomerular filtration rate (eGFR) <70 mL/min/1.73m^2
• Confirmed QT interval corrected using Fridericia's formula (QTcF) >450 ms
• Expected to need any other systemic antiviral therapy at any time during participation in the study
• Positive hepatitis C antibody test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Single Ascending Dose, HV; Healthy volunteers will be administered a single dose of RO7239958 or placebo subcutaneously (SC).	Drug: RO7239958; Solution for injection, subcutaneous use (SC).; Other: Placebo; Sodium chloride solution for injection, SC
Experimental: Part 2a: Multi-dose, CHB; Participants with chronic hepatitis B will be administered different dose levels of RO7239958 or placebo SC. Dosages will be determined from data collected from Part 1.	Drug: RO7239958; Solution for injection, subcutaneous use (SC).; Other: Placebo; Sodium chloride solution for injection, SC
Experimental: Part 2b: Multi-dose, CHB (Optional); Additional study arm to open based on data collected from Part 2a. Participants with chronic hepatitis B will be administered different doses and frequencies of RO7239958 or placebo SC.	Drug: RO7239958; Solution for injection, subcutaneous use (SC).; Other: Placebo; Sodium chloride solution for injection, SC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs)	An adverse event (AE) was defined as any untoward medical occurrence in a participant who was administered a pharmaceutical product (including investigational drug) during the course of a clinical investigation. An AE could therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease that was temporally associated with the use of the investigational product, regardless of whether it was considered to be related to the investigational product or not.	Up to approximately 16 months
Number of Participants With Clinically Significant Changes in Vital Signs	Number of participants with clinically significant abnormalities in vital signs such as systolic and diastolic blood pressure, heart rate, body temperature were evaluated.	Up to approximately 16 months
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Findings		Up to approximately 16 months
Number of Participants With Clinically Significant Changes in Clinical Laboratory Results	Number of participants with clinically significant abnormalities in clinical laboratory parameters such as serum chemistry, hematology, coagulation, viral serology, urinalysis were evaluated.	Up to approximately 16 months
Number of Participants With Injection Site Reactions (ISRs)	Injection site reactions (ISRs) referred to any localized sign or symptom, including pain, erythema, swelling and pruritus and were graded as follows: Grade 1: mild, Grade 2: moderate; Grade 3: severe. Adverse events related to ISRs were reported.	Up to approximately 16 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax) of RO7239958		Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.
Time to Cmax (Tmax) of RO7239958		Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.
Area Under the Curve From Time 0 to the Last Measurable Concentration (AUClast) of RO7239958		Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.
Area Under the Curve From Time 0 to 24 Hours (AUC0-24) of RO7239958		Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.
Half-life (t1/2) of RO7239958		Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.
Cumulative Amount of Drug Excreted in Urine (Ae)	The cumulative amount of drug excreted in urine (Ae) over a 24 hour period or over defined time periods linked to the pools of urine collected was analyzed.	Part 1: 0-4 h, 0-8 h, 0-12 h and 0-24 h on Day 1; Part 2a: 0-4 h and 0-8 h on Days 1 and 29
Part 2a: Change From Baseline in Hepatitis B Surface Antigen (HBsAg) Levels		Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks)
Part 2a: Change From Baseline in Hepatitis B Surface Antibody (Anti-HBs) Levels		Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks)
Part 2a: Number of Participants With HBsAg Loss	HBsAg loss was defined as a measurement below the lower limit of sensitivity.	Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks)
Part 2a: Number of Participants With Hepatitis B Envelope Antigen (HBeAg) Loss in HBeAg-positive Participants	HBeAg loss was defined as a measurement below lower limit of sensitivity. Positive HBeAg is a marker of an actively replicating HBV virus infection.	Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks)
Part 2a: Number of Participants With Hepatitis B e Antibody (Anti-HBe) Seroconversion in HBeAg-positive Participants	Anti-HbBe was defined as an antibody to HBeAg. Positive HBeAg is a marker of an actively replicating HBV virus infection.	Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks)
Part 2a: Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) Below the Assay Lower Limit of Quantification	Participants with HBV DNA below the assay lower limit of quantification i.e. LLOQ <20 IU/ml at each time-point were analyzed.	Part 2a: Day 1 (pre-dose), 15, 29 (pre-dose); at discontinuation (DC), rebound and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2018
• Primary Completion (Actual): April 6, 2020
• Study Completion (Actual): April 6, 2020

Study Registration Dates

• First Submitted: November 30, 2018
• First Submitted That Met QC Criteria: November 30, 2018
• First Posted (Actual): December 4, 2018

Study Record Updates

• Last Update Posted (Actual): May 11, 2021
• Last Update Submitted That Met QC Criteria: April 20, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Blood-Borne Infections; Disease Attributes; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Infections; Communicable Diseases; Hepatitis B; Hepatitis; Hepatitis A; Virus Diseases; Hepatitis B, Chronic; Herpesviridae Infections
• Other Study ID Numbers: NP40520; 2018-003530-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No