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

Hepatitis B Virus Infection Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03762681
• Other study ID #: NP40520
• Secondary ID: 2018-003530-32
• Status: Terminated
• Phase: Phase 1
• Start date: December 14, 2018
• Est. completion date: April 6, 2020

Study information

• Verified date: April 2021
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 55
• Est. completion date: April 6, 2020
• Est. primary completion date: April 6, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B Virus Infection
• Hepatitis B, Chronic
• Herpesviridae Infections
• Infection
• Virus Diseases

Intervention

Drug:
• RO7239958
Solution for injection, subcutaneous use (SC).

Other:
• Placebo
Sodium chloride solution for injection, SC

Locations

Country	Name	City	State
Bulgaria	Acibadem City Clinic Tokuda Hospital Ead	Sofia
Bulgaria	COMAC Medical; Clinical Research Unit for Phase I	Sofia
Hong Kong	Queen Mary Hospital	Hong Kong
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Asan Medical Center.	Seoul
New Zealand	Auckland Clinical Studies Limited	Auckland
Poland	ID Clinic	Myslowice
Taiwan	Kaohsiung Medical University	Kaohsiung
Taiwan	National Cheng Kung University Hospital	Tainan
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Royal Liverpool University Hospital	Liverpool
United Kingdom	Chelsea & Westminster Hospital	London
United Kingdom	King College Hospital NHS Foundation Trust	London
United Kingdom	St George's Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Bulgaria,  Hong Kong,  Korea, Republic of,  New Zealand,  Poland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Findings		Up to approximately 16 months
Primary	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
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)