Hepatitis B Virus
Conditions
Brief summary
This study will assess the safety and tolerability of RO7049389 compared to placebo in single- and multiple-ascending doses in healthy Chinese participants.
Interventions
DRUGRO7049389
RO7049389 will be administered orally either as a single dose (SAD) or as multiple doses defined by the SAD portion of the study (MAD).
DRUGPlacebo
Placebo will be administered orally at a dose and frequency matched to RO7049389.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Chinese healthy male and female subjects, 18 to 60 years of age, inclusive. * A Body Mass Index (BMI) of between 19 to 27 kg/m2 inclusive, and a body weight of at least 45 kg. * Women should be of non-childbearing potential. Female subjects must be either surgically sterile (by means of hysterectomy and/or bilateral oophorectomy) or post-menopausal for at least one year (defined as amenorrhea \>/=12 consecutive months without another cause, and confirmed by follicle stimulating hormone level \>35 mIU/mL). * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
Exclusion criteria
* Pregnant (positive pregnancy test) or lactating women, and male subjects with partners who are pregnant or lactating. * History or symptoms of any clinically significant gastrointestinal, renal, hepatic, broncho-pulmonary, neurological, psychiatric, cardio-vascular, endocrinological, hematological or allergic disease, metabolic disorder, cancer or cirrhosis. * Personal history of congenital long QT syndrome or family history of sudden death. * History of Gilbert's syndrome. * History of having received or currently receiving any systemic anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic oral or inhaled corticosteroids) \</=6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study. * Subjects who have had significant acute infection, e.g., influenza, local infection, acute gastrointestinal symptoms or any other clinically significant illness within two weeks of dose administration. * Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable). * Electrocardiogram (ECG) with QRS and/or T-wave judged to be unfavorable for a consistently accurate QT measurement (e.g., neuromuscular artifact that cannot be readily eliminated, arrhythmias, indistinct QTS onset, low amplitude T-wave, merged T- and U waves, prominent U-waves) * Creatinine clearance (CrCl) \</=70 mL/min (using the Cockcroft-Gault formula) * Positive test at screening of any of the following: hepatitis A (HAV IgM Ab), hepatitis B (HBsAg), hepatitis C (HCV RNA or HCV Ab) or human immunodeficiency virus 1 and 2 (HIV Ab). * Participation in an investigational drug or device study within 90 days prior to screening or more than 4 times per year. * Donation or loss of blood over 500 mL within 3 months prior to screening. * Any suspicion or history of drug and/or alcohol abuse within the last year. * History (within 3 months of screening) of alcohol consumption exceeding two standard drinks per day on average (1 standard drink = 10 grams of alcohol). Alcohol consumption will be prohibited at least 48 hours before screening, 48 hours before and 48 hours after each dose, and 48 hours before each scheduled visit. * Use of \>5 cigarettes or equivalent nicotine-containing product per day. * Taking any prescribed or over-the-counter medications (including vitamins or herbal remedies) within 2 weeks of first dosing or within 5 times the elimination half-life of the medication prior to first dosing (whichever is longer). Occasional acetaminophen/paracetamol is allowed. * Subjects under judicial supervision, guardianship or curatorship.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events | From the date of first administered dose through 28 days after the last administered dose. | 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. |
Secondary
| Measure | Time frame |
|---|---|
| Time to Maximum Observed Plasma Concentration (Tmax) of RO7049389 | At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD) |
| Area Under the Plasma Concentration vs Time Curve to Last Measurable Concentration (AUClast) of RO7049389 | At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD) |
| Area Under the Plasma Concentration vs Time Curve Extrapolated to Infinity (AUC0-inf) | At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD) |
| Apparent Half-Life (T1/2) of RO7049389 | At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD) |
| Maximum Observed Plasma Concentration (Cmax) of RO7049389 | At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD) |
| Trough Plasma Concentration (Ctrough) of RO7049389 | At pre-defined intervals on Day 14 (MAD) |
| Accumulation Index of RO7049389 | At pre-defined intervals on Day 14 (MAD) |
| Area Under the Concentration vs Time Curve for a Dosing Interval (AUCtau) | At pre-defined intervals on Day 14 (MAD) |
| Clearance (CL/F) of RO7049389 | At pre-defined intervals on Day 1 (SAD) |
Countries
China
Participant flow
Recruitment details
Healthy male Chinese subjects aged 18-60 years.
Pre-assignment details
Total n=31. SAD n=28 (Active treatment n=22 and placebo n=6). 21 participants continued on to the MAD phase of the study. 3 participants chose not to continue. MAD n=24. 3 participants were directly enrolled into the MAD phase of the study in addition to the 21 participants from the SAD phase.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants in both the MAD and SAD cohorts received placebo matched to RO7049389. | 6 |
| RO7049389 - 200 mg Participants in the SAD cohort received a single 200 mg dose of RO7049389. | 2 |
| RO7049389 - 400 mg/200 mg q12h Participants in the SAD cohort received a single 400 mg dose of RO7049389. Participants in the MAD cohort that formerly received the 400 mg single dose received 200 mg of RO7049389 every 12 hours (q12h) for 14 days. | 12 |
| RO7049389 - 600 mg/400 mg q12h Participants in the SAD cohort only received a single 600 mg dose of RO7049389. Participants in the MAD cohort that formerly received the 600 mg single dose received 400 mg of RO7049389 q12h for 14 days. | 11 |
| Total | 31 |
Baseline characteristics
| Characteristic | RO7049389 - 400 mg/200 mg q12h | RO7049389 - 600 mg/400 mg q12h | Total | Placebo | RO7049389 - 200 mg |
|---|---|---|---|---|---|
| Age, Continuous | 31.1 Years STANDARD_DEVIATION 3.3 | 29.0 Years STANDARD_DEVIATION 6.5 | 29.8 Years STANDARD_DEVIATION 5.2 | 29.2 Years STANDARD_DEVIATION 5.7 | 33.5 Years STANDARD_DEVIATION 6.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 10 Participants | 28 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 10 Participants | 24 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 28 Participants | 6 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 2 | 0 / 10 | 0 / 10 | 0 / 4 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 1 / 6 | 0 / 2 | 3 / 10 | 1 / 10 | 2 / 4 | 9 / 10 | 6 / 10 |
| serious Total, serious adverse events | 0 / 6 | 0 / 2 | 0 / 10 | 0 / 10 | 0 / 4 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Percentage of Participants With Adverse Events
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.
Time frame: From the date of first administered dose through 28 days after the last administered dose.
Population: All safety analyses were based on the safety analysis population, which included all subjects that received at least one dose of study medication (RO7049389 or placebo), with at least one safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SAD - Placebo | Percentage of Participants With Adverse Events | 16.7 Percentage of Participants |
| SAD RO7049389 - 200 mg | Percentage of Participants With Adverse Events | 0 Percentage of Participants |
| SAD RO7049389 - 400 mg | Percentage of Participants With Adverse Events | 30.0 Percentage of Participants |
| SAD RO7049389 - 600 mg | Percentage of Participants With Adverse Events | 10.0 Percentage of Participants |
| MAD - Placebo | Percentage of Participants With Adverse Events | 50.0 Percentage of Participants |
| MAD RO7049389 - 200 mg | Percentage of Participants With Adverse Events | 90.0 Percentage of Participants |
| MAD RO7049389 - 400 mg | Percentage of Participants With Adverse Events | 60.0 Percentage of Participants |
Secondary
Accumulation Index of RO7049389
Time frame: At pre-defined intervals on Day 14 (MAD)
Population: This parameter was not collected for SAD cohorts.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| SAD - Placebo | Accumulation Index of RO7049389 | MAD Cohorts - Day 14 Cmax | 0.846 Ratio | Geometric Coefficient of Variation 76.9 |
| SAD - Placebo | Accumulation Index of RO7049389 | MAD Cohorts - Day 14 AUC | 1.03 Ratio | Geometric Coefficient of Variation 47 |
| SAD RO7049389 - 200 mg | Accumulation Index of RO7049389 | MAD Cohorts - Day 14 Cmax | 0.872 Ratio | Geometric Coefficient of Variation 41.7 |
| SAD RO7049389 - 200 mg | Accumulation Index of RO7049389 | MAD Cohorts - Day 14 AUC | 1.05 Ratio | Geometric Coefficient of Variation 37.6 |
Secondary
Apparent Half-Life (T1/2) of RO7049389
Time frame: At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD)
Population: PK sampling was performed only once for single-dose (SAD) cohorts and did not include the placebo arms.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| SAD - Placebo | Apparent Half-Life (T1/2) of RO7049389 | Day 1 | 3.66 Hours (h) | Geometric Coefficient of Variation 0 |
| SAD RO7049389 - 200 mg | Apparent Half-Life (T1/2) of RO7049389 | Day 1 | 7.98 Hours (h) | Geometric Coefficient of Variation 97.8 |
| SAD RO7049389 - 400 mg | Apparent Half-Life (T1/2) of RO7049389 | Day 1 | 10.4 Hours (h) | Geometric Coefficient of Variation 108 |
| SAD RO7049389 - 600 mg | Apparent Half-Life (T1/2) of RO7049389 | Day 14 | 5.06 Hours (h) | Geometric Coefficient of Variation 31.6 |
| SAD RO7049389 - 600 mg | Apparent Half-Life (T1/2) of RO7049389 | Day 1 | 2.29 Hours (h) | Geometric Coefficient of Variation 39.4 |
| MAD - Placebo | Apparent Half-Life (T1/2) of RO7049389 | Day 14 | 6.74 Hours (h) | Geometric Coefficient of Variation 36.4 |
| MAD - Placebo | Apparent Half-Life (T1/2) of RO7049389 | Day 1 | 1.62 Hours (h) | Geometric Coefficient of Variation 33.1 |
Secondary
Area Under the Concentration vs Time Curve for a Dosing Interval (AUCtau)
Time frame: At pre-defined intervals on Day 14 (MAD)
Population: This parameter was not collected for SAD cohorts.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| SAD - Placebo | Area Under the Concentration vs Time Curve for a Dosing Interval (AUCtau) | MAD Cohorts - Day 1 | 5090 h*ng/mL | Geometric Coefficient of Variation 38 |
| SAD - Placebo | Area Under the Concentration vs Time Curve for a Dosing Interval (AUCtau) | MAD Cohorts - Day 14 | 5230 h*ng/mL | Geometric Coefficient of Variation 29.7 |
| SAD RO7049389 - 200 mg | Area Under the Concentration vs Time Curve for a Dosing Interval (AUCtau) | MAD Cohorts - Day 1 | 19400 h*ng/mL | Geometric Coefficient of Variation 72.6 |
| SAD RO7049389 - 200 mg | Area Under the Concentration vs Time Curve for a Dosing Interval (AUCtau) | MAD Cohorts - Day 14 | 20400 h*ng/mL | Geometric Coefficient of Variation 90.7 |
Secondary
Area Under the Plasma Concentration vs Time Curve Extrapolated to Infinity (AUC0-inf)
Time frame: At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD)
Population: PK sampling was performed only once for single-dose (SAD) cohorts and did not include the placebo arms.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| SAD - Placebo | Area Under the Plasma Concentration vs Time Curve Extrapolated to Infinity (AUC0-inf) | Day 1 | 9460 h*ng/mL | — |
| SAD RO7049389 - 200 mg | Area Under the Plasma Concentration vs Time Curve Extrapolated to Infinity (AUC0-inf) | Day 1 | 12300 h*ng/mL | Geometric Coefficient of Variation 84.6 |
| SAD RO7049389 - 400 mg | Area Under the Plasma Concentration vs Time Curve Extrapolated to Infinity (AUC0-inf) | Day 1 | 11100 h*ng/mL | Geometric Coefficient of Variation 120 |
| SAD RO7049389 - 600 mg | Area Under the Plasma Concentration vs Time Curve Extrapolated to Infinity (AUC0-inf) | Day 1 | 5180 h*ng/mL | Geometric Coefficient of Variation 37.7 |
| SAD RO7049389 - 600 mg | Area Under the Plasma Concentration vs Time Curve Extrapolated to Infinity (AUC0-inf) | Day 14 | 5470 h*ng/mL | Geometric Coefficient of Variation 29.1 |
| MAD - Placebo | Area Under the Plasma Concentration vs Time Curve Extrapolated to Infinity (AUC0-inf) | Day 14 | 20900 h*ng/mL | Geometric Coefficient of Variation 90.6 |
| MAD - Placebo | Area Under the Plasma Concentration vs Time Curve Extrapolated to Infinity (AUC0-inf) | Day 1 | 19500 h*ng/mL | Geometric Coefficient of Variation 72.7 |
Secondary
Area Under the Plasma Concentration vs Time Curve to Last Measurable Concentration (AUClast) of RO7049389
Time frame: At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD)
Population: PK sampling was performed only once for single-dose (SAD) cohorts and did not include the placebo arms.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| SAD - Placebo | Area Under the Plasma Concentration vs Time Curve to Last Measurable Concentration (AUClast) of RO7049389 | Day 1 | 5960 h*ng/mL | Geometric Coefficient of Variation 60.9 |
| SAD RO7049389 - 200 mg | Area Under the Plasma Concentration vs Time Curve to Last Measurable Concentration (AUClast) of RO7049389 | Day 1 | 12200 h*ng/mL | Geometric Coefficient of Variation 85.1 |
| SAD RO7049389 - 400 mg | Area Under the Plasma Concentration vs Time Curve to Last Measurable Concentration (AUClast) of RO7049389 | Day 1 | 10800 h*ng/mL | Geometric Coefficient of Variation 121 |
| SAD RO7049389 - 600 mg | Area Under the Plasma Concentration vs Time Curve to Last Measurable Concentration (AUClast) of RO7049389 | Day 1 | 5090 h*ng/mL | Geometric Coefficient of Variation 38 |
| SAD RO7049389 - 600 mg | Area Under the Plasma Concentration vs Time Curve to Last Measurable Concentration (AUClast) of RO7049389 | Day 14 | 5460 h*ng/mL | Geometric Coefficient of Variation 29.2 |
| MAD - Placebo | Area Under the Plasma Concentration vs Time Curve to Last Measurable Concentration (AUClast) of RO7049389 | Day 14 | 20900 h*ng/mL | Geometric Coefficient of Variation 90.7 |
| MAD - Placebo | Area Under the Plasma Concentration vs Time Curve to Last Measurable Concentration (AUClast) of RO7049389 | Day 1 | 19400 h*ng/mL | Geometric Coefficient of Variation 72.6 |
Secondary
Clearance (CL/F) of RO7049389
Time frame: At pre-defined intervals on Day 1 (SAD)
Population: This parameter was not collected for the MAD cohort.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SAD - Placebo | Clearance (CL/F) of RO7049389 | 21.1 L/h | Geometric Coefficient of Variation 0 |
| SAD RO7049389 - 200 mg | Clearance (CL/F) of RO7049389 | 32.6 L/h | Geometric Coefficient of Variation 58.2 |
| SAD RO7049389 - 400 mg | Clearance (CL/F) of RO7049389 | 53.9 L/h | Geometric Coefficient of Variation 61.8 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of RO7049389
Time frame: At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD)
Population: PK sampling was performed only once for single-dose (SAD) cohorts and did not include the placebo arms.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| SAD - Placebo | Maximum Observed Plasma Concentration (Cmax) of RO7049389 | Day 1 | 3840 ng/mL | Geometric Coefficient of Variation 41.3 |
| SAD RO7049389 - 200 mg | Maximum Observed Plasma Concentration (Cmax) of RO7049389 | Day 1 | 5220 ng/mL | Geometric Coefficient of Variation 84.8 |
| SAD RO7049389 - 400 mg | Maximum Observed Plasma Concentration (Cmax) of RO7049389 | Day 1 | 4020 ng/mL | Geometric Coefficient of Variation 116 |
| SAD RO7049389 - 600 mg | Maximum Observed Plasma Concentration (Cmax) of RO7049389 | Day 1 | 3230 ng/mL | Geometric Coefficient of Variation 40.6 |
| SAD RO7049389 - 600 mg | Maximum Observed Plasma Concentration (Cmax) of RO7049389 | Day 14 | 2730 ng/mL | Geometric Coefficient of Variation 35.4 |
| MAD - Placebo | Maximum Observed Plasma Concentration (Cmax) of RO7049389 | Day 14 | 8030 ng/mL | Geometric Coefficient of Variation 60.8 |
| MAD - Placebo | Maximum Observed Plasma Concentration (Cmax) of RO7049389 | Day 1 | 9210 ng/mL | Geometric Coefficient of Variation 51.1 |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) of RO7049389
Time frame: At pre-defined intervals on Day 1 (SAD) and Day 14 (MAD)
Population: PK sampling was performed only once for single-dose (SAD) cohorts and did not include the placebo arms.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| SAD - Placebo | Time to Maximum Observed Plasma Concentration (Tmax) of RO7049389 | Day 1 | 1.5 Hours (h) |
| SAD RO7049389 - 200 mg | Time to Maximum Observed Plasma Concentration (Tmax) of RO7049389 | Day 1 | 1.5 Hours (h) |
| SAD RO7049389 - 400 mg | Time to Maximum Observed Plasma Concentration (Tmax) of RO7049389 | Day 1 | 2 Hours (h) |
| SAD RO7049389 - 600 mg | Time to Maximum Observed Plasma Concentration (Tmax) of RO7049389 | Day 1 | 1.5 Hours (h) |
| SAD RO7049389 - 600 mg | Time to Maximum Observed Plasma Concentration (Tmax) of RO7049389 | Day 14 | 2 Hours (h) |
| MAD - Placebo | Time to Maximum Observed Plasma Concentration (Tmax) of RO7049389 | Day 1 | 2 Hours (h) |
| MAD - Placebo | Time to Maximum Observed Plasma Concentration (Tmax) of RO7049389 | Day 14 | 2 Hours (h) |
Secondary
Trough Plasma Concentration (Ctrough) of RO7049389
Time frame: At pre-defined intervals on Day 14 (MAD)
Population: This outcome measure applied to arms receiving RO7049389 during the MAD phase.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SAD - Placebo | Trough Plasma Concentration (Ctrough) of RO7049389 | 31.1 ng/mL | Geometric Coefficient of Variation 29.8 |
| SAD RO7049389 - 200 mg | Trough Plasma Concentration (Ctrough) of RO7049389 | 66.1 ng/mL | Geometric Coefficient of Variation 133 |