This randomized study will be conducted in two parts to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of subcutaneous administration of RO7062931. Part 1 will include only healthy participants and Part 2 will include only participants with chronic hepatitis B (CHB). Part 1 is an adaptive, single-ascending dose study with an adaptive dose-escalating schedule to determine the best dose to be evaluated in participants with CHB. Part 2 is an adaptive, parallel multiple-dose study comprised of three sub-parts which will be used to further refine the dose and dosing regimen, and to evaluate the safety and efficacy of RO7062931 when administered with standard-of-care (SoC) therapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
119
Administered subcutaneously in Parts 1 and 2. Part 1 will be administered in single-ascending doses after 0.1 mg/kg starting dose. Subsequent doses of 0.3, 1, 2 and 4 mg/kg may be administered based upon tolerability. In Part 2a, participants will receive two monthly doses of either 0.4, 0.8, 1.2 times the saturation dose or placebo. In Part 2b, a dose selected from Part 2a will be administered to participants randomized into 4 cohorts QW or Q2W. In Part 2c, participants will receive RO7062831 QW on top of another therapy for up to 24 or 48 weeks.
Part 1 cohorts: active drug vs placebo 4:1. Part 2a 4 parallel cohorts of 3 active drug doses and placebo in 1:1:1:1. Part 2b active drug vs placebo in 3:1 in 2 parallel cohorts.
Participants in Part 2c will receive an immune modulator subcutaneously QW for up to 48 weeks.
Royal Melbourne Hospital
Parkville, Victoria, Australia
Linear Clinical Research Limited
Nedlands, Western Australia, Australia
Queen Mary Hospital
Hong Kong, Hong Kong
Prince of Wales Hospital
Shatin, New Territories, Hong Kong
Auckland Clinical Studies
Auckland, New Zealand
Middlemore Hospital
Auckland, New Zealand
National University Hospital; Dept of Gastroenterology & Hepatology
Singapore, Singapore
Singapore General Hospital; Gastroenterology & Hepatology
Singapore, Singapore
Chuncheon Sacred Heart Hospital
Gangwon-Do, South Korea
Gangnam Severance Hospital
Seoul, South Korea
...and 9 more locations
Percentage of Participants With Adverse Events (AEs) and AEs of Special Interest
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs of Special Interest were defined as: i.) elevated ALT/AST in combination with elevated bilirubin/clinical jaundice, ii.) suspected transmission of infectious agent by the study drug, iii.) severe injection site reactions, iv.) ALT elevation ≥10x ULN, v.) creatinine elevation ≥1.5x ULN or ≥50% from baseline.
Time frame: Up to day 113
Percentage of Participants With Laboratory Abnormalities Based on Hematology, Blood Chemistry, Coagulation, and Urinalysis Test Results - Part 1
Marked reference range has been predefined for each laboratory parameter. The marked reference range is broader than the standard reference range. Values falling outside the marked reference range that also represent a defined change from baseline will be considered marked laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not available for a study subject, the midpoint of the standard reference range will be used as the study participant baseline value for the purposes of determining marked laboratory abnormalities.
Time frame: Screening, Days -1, 2, 8, 15, 29, 85
Percentage of Participants With Laboratory Abnormalities Based on Hematology, Blood Chemistry, Coagulation, and Urinalysis Test Results - Part 2
Marked reference range has been predefined for each laboratory parameter. The marked reference range is broader than the standard reference range. Values falling outside the marked reference range that also represent a defined change from baseline will be considered marked laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not available for a study subject, the midpoint of the standard reference range will be used as the study participant baseline value for the purposes of determining marked laboratory abnormalities.
Time frame: Screening, Days -1, 2, 8, 15, 29, at discontinuation, Days 36, 43, 57, 85, 113
Percentage of Participants With Electrocardiogram (ECG) Abnormalities Based on ECG Interpretation - Part 1
Participants were monitored for clinically-significant RO7062931-related ECG changes, defined as QTcF \> 500 msec, or \> 60 msec longer than the pre-dose baseline, within the first 48 hours post-dose.
Time frame: Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85
Percentage of Participants With Electrocardiogram (ECG) Abnormalities Based on ECG Interpretation - Part 2
Participants were monitored for clinically-significant RO7062931-related ECG changes, defined as QTcF \> 500 msec, or \> 60 msec longer than the pre-dose baseline, within the first 48 hours post-dose.
Time frame: Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113
Percentage of Participants With T-Wave Abnormalities Based on T-Wave Assessment - Part 1
Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.
Time frame: Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85
Percentage of Participants With U-Wave Abnormalities Based on U-Wave Assessment - Part 1
Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.
Time frame: Day 1 (1,4,8,12h), Days 2 and 8, Follow Up Days 15, 29, 85
Percentage of Participants With T-Wave Abnormalities Based on T-Wave Assessment - Part 2
Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.
Time frame: Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113
Percentage of Participants With U-Wave Based on U-Wave Assessment - Part 2
Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.
Time frame: Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113
Percentage of Participants With QTcF Values Between 450 Msec - 480 Msec - Part 2
Table entries provide the percentage of participants with abnormalities during treatment assessment. Abnormalities reported in participants with missing baseline values are included. Baseline is the Participant's last observation prior to initiation of study drug.
Time frame: Day 1 (1,4,8h), Days 2,8,15,22 (1h and 8h), Day 23, Day 29 (1,4,8h), Day 30, Follow Up Days 36, 43, 50, 57, 78, 85, 106, 113
Maximum Plasma Concentration (Cmax) After Single Ascending Doses - Part 1
Cmax values are the the peak plasma concentration reached after administration of RO7062931.
Time frame: Days 1-8
Cmax After Multiple Ascending Doses - Part 2
Cmax values are the the peak plasma concentration reached after administration of RO7062931.
Time frame: Days 1-113
Time to Reach Maximum Plasma Concentration (Tmax) After Single-Ascending Doses - Part 1
Tmax values are the amount of time to maximum concentration in plasma after administration of RO7062931.
Time frame: Days 1-8
Tmax After Multiple Ascending Doses - Part 2
Tmax values are the amount of time to maximum concentration in plasma after administration of RO7062931.
Time frame: Days 1-113
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After Single-Ascending Doses - Part 1
AUC0-inf was calculated based on non-compartmental analysis.
Time frame: Days 1-8
AUC0-inf After Multiple Ascending Doses - Part 2
AUC0-inf was calculated based on non-compartmental analysis.
Time frame: Days 1,22,29
Area Under the Plasma Concentration-Time Curve From Time Zero Until the Last Quantifiable Time-Point (AUC0-last) After Single Ascending Doses - Part 1
AUC0-last was calculated based on non-compartmental analysis.
Time frame: Days 1-8
AUC0-last After Multiple Ascending Doses - Part 2
AUC0-last was calculated based on non-compartmental analysis.
Time frame: Days 1,22,29
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Terminal Elimination Half-Life (t1/2) After Single Ascending Doses - Part 1
T1/2 was calculated based on non-compartmental analysis.
Time frame: Days 1-8
Terminal Elimination Half-Life (t1/2) After Multiple Ascending Doses - Part 2
T1/2 was calculated based on non-compartmental analysis.
Time frame: Days 1-113
Total Clearance (CL) After Single Ascending Doses - Part 1
Apparent oral clearance was calculated from Dose/AUCinf.
Time frame: Days 1-8
Total Clearance (CL) After Multiple Ascending Doses - Part 2
Apparent oral clearance was calculated from Dose/AUCinf.
Time frame: Days 1-113
Volume of Distribution (Vss) After Single Ascending Doses - Part 1
Vss was calculated from dose/AUCinf
Time frame: Days 1-8
Volume of Distribution (Vss) After Multiple Ascending Doses - Part 2
Vss was calculated from dose/AUCinf
Time frame: Days 1-113
Cumulative Amount Excreted Unchanged in Urine (Ae) After Single Ascending Doses - Part 1
Ae: cumulative amount of drug excreted in urine over a 24 hour period or over defined time periods linked to the pools of urine collected.
Time frame: Hours 0-4, 0-8, 0-12, and 0-24
Cumulative Amount Excreted Unchanged in Urine (Ae) After Multiple Ascending Doses - Part 2
Ae: cumulative amount of drug excreted in urine over a 24 hour period or over defined time periods linked to the pools of urine collected.
Time frame: Days 1-113
Change From Baseline of Quantitative HBsAg (qHBsAg) (log10) After Multiple Ascending Doses - Part 2
HBsAg is a viral parameter that can be affected by the action of RO7062931. A change from baseline in qHBsAg can indicate the drug's effect.
Time frame: Days 1-113
Summary of Maximum qHBsAg Decrease on Days 1-113 - Part 2
HBsAg is a viral parameter that can be affected by the action of RO7062931. A change from baseline in qHBsAg can indicate the drug's effect.
Time frame: Day 1 - Day 113
Summary of Time to Maximum qHBsAg Decrease on Day 1-113 - Part 2
HBsAg is a viral parameter that can be affected by the action of RO7062931. A change from baseline in qHBsAg can indicate the drug's effect.
Time frame: Day 1 - Day 113