Clinical trial NCT03762681: A Study of RO7239958 to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Volunteers and Participants With Chronic Hepatitis B Virus Infection
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hepatitis B Virus Infection
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-12-04
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Up to approximately 16 months
measure: Number of Participants With Clinically Significant Changes in Vital Signs
timeFrame: Up to approximately 16 months
measure: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Findings
timeFrame: Up to approximately 16 months
measure: Number of Participants With Clinically Significant Changes in Clinical Laboratory Results
timeFrame: Up to approximately 16 months
measure: Number of Participants With Injection Site Reactions (ISRs)
timeFrame: Up to approximately 16 months
Secondary outcomes:
measure: Maximum Plasma Concentration (Cmax) of RO7239958
timeFrame: 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.
measure: Time to Cmax (Tmax) of RO7239958
timeFrame: 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.
measure: Area Under the Curve From Time 0 to the Last Measurable Concentration (AUClast) of RO7239958
timeFrame: 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.
measure: Area Under the Curve From Time 0 to 24 Hours (AUC0-24) of RO7239958
timeFrame: 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.
measure: Half-life (t1/2) of RO7239958
timeFrame: 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.
measure: Cumulative Amount of Drug Excreted in Urine (Ae)
timeFrame: 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
measure: Part 2a: Change From Baseline in Hepatitis B Surface Antigen (HBsAg) Levels
timeFrame: 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)
measure: Part 2a: Change From Baseline in Hepatitis B Surface Antibody (Anti-HBs) Levels
timeFrame: 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)
measure: Part 2a: Number of Participants With HBsAg Loss
timeFrame: 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)
measure: Part 2a: Number of Participants With Hepatitis B Envelope Antigen (HBeAg) Loss in HBeAg-positive Participants
timeFrame: 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)
measure: Part 2a: Number of Participants With Hepatitis B e Antibody (Anti-HBe) Seroconversion in HBeAg-positive Participants
timeFrame: 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)
measure: Part 2a: Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) Below the Assay Lower Limit of Quantification
timeFrame: 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)
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: Acibadem City Clinic Tokuda Hospital Ead
city: Sofia
country: Bulgaria
facility: COMAC Medical; Clinical Research Unit for Phase I
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center.
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies Limited
city: Myslowice
country: Poland
facility: ID Clinic
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: King College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Chelsea & Westminster Hospital
city: London
country: United Kingdom
facility: St George's Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: