Alzheimers Disease
Conditions
Brief summary
Study BP41192 is a randomized, adaptive, placebo-controlled parallel group study to investigate the safety, tolerability, immunogenicity and pharmacokinetics of single-ascending intravenous (IV) doses of RO7126209 in healthy participants. RO7126209 is being developed for the treatment of Alzheimer's Disease.
Detailed description
This study uses a parallel group design, with participants recruited in 5 planned sequential cohorts. Additional cohort(s) may be added if dose escalation stopping criteria are not met after cohort 5. Participants will receive a single IV dose of either RO7126209 or placebo. RO7126209 doses will be administered in ascending order. After the starting dose, subsequent doses will be selected in an adaptive manner during study conduct based on emerging safety, tolerability and PK data.
Interventions
DRUGRO7126209
Participants will be administered single-ascending intravenous doses of RO7126209 with at least 2 weeks between each dose level. After the starting dose, the subsequent doses will be selected in an adaptive design. Sentinel dosing will be employed.
DRUGPlacebo
Participants will be administered a single intravenous dose of matching placebo.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy status is defined by the absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, ophthalmologic examination, hematology, blood chemistry, coagulation, serology, and urinalysis. * Body mass index (BMI) of 18-30 kg/m2 inclusive * During the treatment period and until the final follow up visit, agreement to: (1) Remain abstinent or use contraceptive measures such as a condom plus an additional contraceptive method that together result in a failure rate of \<1% per year, with a partner who is a woman of childbearing potential. (2) With pregnant female partner, remain abstinent or use contraceptive measures such as a condom to avoid exposing the embryo. (3) Refrain from donating sperm from Day 1 of the study until 90 days after last dose.
Exclusion criteria
* Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this study. * History of any clinically significant gastrointestinal, renal, hepatic, broncho-pulmonary, neurological, psychiatric, cardio-vascular, endocrinological, ophthalmologic, hematological or allergic disease, metabolic disorder, cancer or cirrhosis. * Any suspicion or history of alcohol abuse and/or suspicion of regular consumption of drug of abuse within the last 5 years. * Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) 1 and 2. * History or presence of clinically significant ECG abnormalities or cardiovascular disease. * Clinically-significant abnormalities in laboratory test results. * Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration. * Impaired hepatic function as indicated by screening aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>=1.5 x the upper limit of normal (ULN) or abnormal total bilirubin unless due to Gilbert's disease. * Any clinically relevant history of hypersensitivity or allergic reactions, either spontaneous or following drug administration, or exposure to foods or environmental agents. * History of hypersensitivity to biologic agents or any of the excipients in the formulation. * History of raised intra-cerebral pressure or vertebral joint pathology * Use of prohibited medication or herbal remedies as described in the section of concomitant medications * Prior administration of gantenerumab (RO4909832) * Any vaccination within two months prior to Day 1 * Participation in an investigational drug medicinal product or medical device study within 30 days before screening or within seven times the elimination half-life if known, whichever is longer. * Participants who regularly smoke more than 5 cigarettes daily or equivalent and are unable or unwilling not to smoke during the in-house period. * Donation or loss of blood over 500 mL within three months prior to Day 1 and donation of blood for the duration of the study until follow-up. * Evidence of clinically significant brain magnetic resonance imaging (MRI) findings, including lacunar infarct, territorial infarct or macroscopic hemorrhage, microbleed or area of leptomeningeal hemosiderosis, or deep white matter lesions corresponding to an overall Fazekas score of ≥ 2. * Claustrophobia, presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body that would contraindicate an MRI scan.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events (AEs) | Up to approximately 9 weeks | An Adverse Event (AE) 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 abnormal laboratory values or abnormal clinical test results), 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 | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From Zero to 24 h Postdose (AUC0-24h) of RO7126209 | Days 1 and 2 | Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below. |
| Area Under the Plasma Concentration Versus Time Curve From Zero to 168h Postdose (AUC0-168h) of RO7126209 | Days 1, 2, 3, 4, 5 and 8 | Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below. |
| Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO7126209 | Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57 | Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below. |
| Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) | Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57 | Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below. |
| Terminal Rate Constant (Lambda z) of RO7126209 | Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57 | Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below. |
| Concentration at the End of Infusion (Cend) of RO7126209 | Day 1 | Plasma concentrations of RO7126209 were measured by a specific and validated assay at specified timepoints. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below. |
| Total Body Clearance Calculated as Dose/AUC (CL) of RO7126209 | Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57 | Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below. |
| Volume of Distribution at Steady-State (Vss) of RO7126209 | Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57 | Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below. |
| Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 3 and Day 5 | RO7126209 CSF concentrations were measured by a specific and validated method. Geometric Mean and Coefficient of Variation data are presented below. |
| Percentage of Participants With Anti-RO7126209 Antibodies (ADAs) | Days 1, 8, 29 and 57 | The numbers and proportions of Anti-Drug Antibody (ADA) positive participants and ADA negative participants at baseline (baseline prevalence) and after study drug administration (post-baseline incidence during both the treatment and follow-up periods) were summarized per dose group during both the treatment and follow-up period. |
| Apparent Terminal Half-Life (T1/2) of RO7126209 | Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57 | Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 1 center in 1 country.
Pre-assignment details
A total of 36 participants were enrolled at 1 site in the US, out of which 26 participants received active treatment while 10 received placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo In Cohorts 1-5, there were ten participants in total who received placebo, two in each cohort. | 10 |
| RO7126209 (0.1 mg/kg) Healthy volunteers were administered a single intravenous dose of RO7126209 (0.1 mg/kg). | 4 |
| RO7126209 (0.4 mg/kg) Healthy volunteers were administered a single intravenous dose of RO7126209 (0.4 mg/kg). | 4 |
| RO7126209 (1.2 mg/kg) Healthy volunteers were administered a single intravenous dose of RO7126209 (1.2 mg/kg). | 6 |
| RO7126209 (3.6 mg/kg) Healthy volunteers were administered a single intravenous dose of RO7126209 (3.6 mg/kg). | 6 |
| RO7126209 (7.2 mg/kg) Healthy volunteers were administered a single intravenous dose of RO7126209 (7.2 mg/kg). | 6 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | RO7126209 (0.1 mg/kg) | RO7126209 (0.4 mg/kg) | RO7126209 (1.2 mg/kg) | RO7126209 (3.6 mg/kg) | RO7126209 (7.2 mg/kg) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 29.2 years STANDARD_DEVIATION 6.6 | 30.8 years STANDARD_DEVIATION 5.9 | 23.5 years STANDARD_DEVIATION 4.5 | 24.2 years STANDARD_DEVIATION 3.8 | 33.0 years STANDARD_DEVIATION 5.9 | 33.3 years STANDARD_DEVIATION 2.6 | 29.2 years STANDARD_DEVIATION 6.1 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 1 Participants | 13 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 10 Participants | 4 Participants | 4 Participants | 6 Participants | 5 Participants | 4 Participants | 33 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 16 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 4 Participants | 4 Participants | 6 Participants | 6 Participants | 6 Participants | 36 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 4 | 0 / 4 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 8 / 10 | 3 / 4 | 2 / 4 | 5 / 6 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 10 | 0 / 4 | 0 / 4 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Percentage of Participants With Adverse Events (AEs)
An Adverse Event (AE) 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 abnormal laboratory values or abnormal clinical test results), 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: Up to approximately 9 weeks
Population: The Safety Population was defined as all participants randomised to study treatment and who received at least one dose of the study treatment, whether prematurely withdrawn from the study or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adverse Events (AEs) | 80.0 Percentage of Participants |
| RO7126209 (0.1 mg/kg) | Percentage of Participants With Adverse Events (AEs) | 75.0 Percentage of Participants |
| RO7126209 (0.4 mg/kg) | Percentage of Participants With Adverse Events (AEs) | 50.0 Percentage of Participants |
| RO7126209 (1.2 mg/kg) | Percentage of Participants With Adverse Events (AEs) | 83.3 Percentage of Participants |
| RO7126209 (3.6 mg/kg) | Percentage of Participants With Adverse Events (AEs) | 100.0 Percentage of Participants |
| RO7126209 (7.2 mg/kg) | Percentage of Participants With Adverse Events (AEs) | 100.0 Percentage of Participants |
Secondary
Apparent Terminal Half-Life (T1/2) of RO7126209
Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Apparent Terminal Half-Life (T1/2) of RO7126209 | 67.1 hr | Geometric Coefficient of Variation 19.7 |
| RO7126209 (0.1 mg/kg) | Apparent Terminal Half-Life (T1/2) of RO7126209 | 111 hr | Geometric Coefficient of Variation 57 |
| RO7126209 (0.4 mg/kg) | Apparent Terminal Half-Life (T1/2) of RO7126209 | 100 hr | Geometric Coefficient of Variation 59 |
| RO7126209 (1.2 mg/kg) | Apparent Terminal Half-Life (T1/2) of RO7126209 | 170 hr | Geometric Coefficient of Variation 19.5 |
| RO7126209 (3.6 mg/kg) | Apparent Terminal Half-Life (T1/2) of RO7126209 | 159 hr | Geometric Coefficient of Variation 21.8 |
Secondary
Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf)
Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) | 89.1 hr.µg/mL | Geometric Coefficient of Variation 21.7 |
| RO7126209 (0.1 mg/kg) | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) | 417 hr.µg/mL | Geometric Coefficient of Variation 13.7 |
| RO7126209 (0.4 mg/kg) | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) | 947 hr.µg/mL | Geometric Coefficient of Variation 29.3 |
| RO7126209 (1.2 mg/kg) | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) | 3380 hr.µg/mL | Geometric Coefficient of Variation 11.5 |
| RO7126209 (3.6 mg/kg) | Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) | 7080 hr.µg/mL | Geometric Coefficient of Variation 10.9 |
Secondary
Area Under the Plasma Concentration Versus Time Curve From Zero to 168h Postdose (AUC0-168h) of RO7126209
Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Days 1, 2, 3, 4, 5 and 8
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Plasma Concentration Versus Time Curve From Zero to 168h Postdose (AUC0-168h) of RO7126209 | 78.0 hr.µg/mL | Geometric Coefficient of Variation 22.5 |
| RO7126209 (0.1 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to 168h Postdose (AUC0-168h) of RO7126209 | 350 hr.µg/mL | Geometric Coefficient of Variation 14.2 |
| RO7126209 (0.4 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to 168h Postdose (AUC0-168h) of RO7126209 | 807 hr.µg/mL | Geometric Coefficient of Variation 28.5 |
| RO7126209 (1.2 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to 168h Postdose (AUC0-168h) of RO7126209 | 2940 hr.µg/mL | Geometric Coefficient of Variation 11.6 |
| RO7126209 (3.6 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to 168h Postdose (AUC0-168h) of RO7126209 | 6190 hr.µg/mL | Geometric Coefficient of Variation 13.1 |
Secondary
Area Under the Plasma Concentration Versus Time Curve From Zero to 24 h Postdose (AUC0-24h) of RO7126209
Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Days 1 and 2
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Plasma Concentration Versus Time Curve From Zero to 24 h Postdose (AUC0-24h) of RO7126209 | 27.1 hr.µg/mL | Geometric Coefficient of Variation 23.2 |
| RO7126209 (0.1 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to 24 h Postdose (AUC0-24h) of RO7126209 | 124 hr.µg/mL | Geometric Coefficient of Variation 13.3 |
| RO7126209 (0.4 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to 24 h Postdose (AUC0-24h) of RO7126209 | 325 hr.µg/mL | Geometric Coefficient of Variation 27.1 |
| RO7126209 (1.2 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to 24 h Postdose (AUC0-24h) of RO7126209 | 1170 hr.µg/mL | Geometric Coefficient of Variation 13.3 |
| RO7126209 (3.6 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to 24 h Postdose (AUC0-24h) of RO7126209 | 2340 hr.µg/mL | Geometric Coefficient of Variation 16.5 |
Secondary
Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO7126209
Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO7126209 | 86.9 hr.µg/mL | Geometric Coefficient of Variation 21.9 |
| RO7126209 (0.1 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO7126209 | 402 hr.µg/mL | Geometric Coefficient of Variation 14.4 |
| RO7126209 (0.4 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO7126209 | 933 hr.µg/mL | Geometric Coefficient of Variation 30.7 |
| RO7126209 (1.2 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO7126209 | 3380 hr.µg/mL | Geometric Coefficient of Variation 11.5 |
| RO7126209 (3.6 mg/kg) | Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO7126209 | 7070 hr.µg/mL | Geometric Coefficient of Variation 10.9 |
Secondary
Cerebrospinal Fluid (CSF) Concentration of RO7126209
RO7126209 CSF concentrations were measured by a specific and validated method. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Day 3 and Day 5
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 3 | 0.00414 µg/mL | Geometric Coefficient of Variation 33 |
| Placebo | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 5 | 0.00228 µg/mL | Geometric Coefficient of Variation 18.7 |
| RO7126209 (0.1 mg/kg) | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 5 | 0.0126 µg/mL | Geometric Coefficient of Variation 26.1 |
| RO7126209 (0.1 mg/kg) | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 3 | 0.0202 µg/mL | Geometric Coefficient of Variation 26.5 |
| RO7126209 (0.4 mg/kg) | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 3 | 0.047 µg/mL | Geometric Coefficient of Variation 29.4 |
| RO7126209 (0.4 mg/kg) | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 5 | 0.0274 µg/mL | Geometric Coefficient of Variation 22.9 |
| RO7126209 (1.2 mg/kg) | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 3 | 0.105 µg/mL | Geometric Coefficient of Variation 40.3 |
| RO7126209 (1.2 mg/kg) | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 5 | 0.0755 µg/mL | Geometric Coefficient of Variation 7.4 |
| RO7126209 (3.6 mg/kg) | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 5 | 0.151 µg/mL | Geometric Coefficient of Variation 9.8 |
| RO7126209 (3.6 mg/kg) | Cerebrospinal Fluid (CSF) Concentration of RO7126209 | Day 3 | 0.284 µg/mL | Geometric Coefficient of Variation 35.9 |
Secondary
Concentration at the End of Infusion (Cend) of RO7126209
Plasma concentrations of RO7126209 were measured by a specific and validated assay at specified timepoints. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Day 1
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Concentration at the End of Infusion (Cend) of RO7126209 | 1.80 µg/mL | Geometric Coefficient of Variation 15.9 |
| RO7126209 (0.1 mg/kg) | Concentration at the End of Infusion (Cend) of RO7126209 | 7.93 µg/mL | Geometric Coefficient of Variation 21.3 |
| RO7126209 (0.4 mg/kg) | Concentration at the End of Infusion (Cend) of RO7126209 | 22.2 µg/mL | Geometric Coefficient of Variation 17.6 |
| RO7126209 (1.2 mg/kg) | Concentration at the End of Infusion (Cend) of RO7126209 | 85.7 µg/mL | Geometric Coefficient of Variation 22.9 |
| RO7126209 (3.6 mg/kg) | Concentration at the End of Infusion (Cend) of RO7126209 | 160 µg/mL | Geometric Coefficient of Variation 26.5 |
Secondary
Percentage of Participants With Anti-RO7126209 Antibodies (ADAs)
The numbers and proportions of Anti-Drug Antibody (ADA) positive participants and ADA negative participants at baseline (baseline prevalence) and after study drug administration (post-baseline incidence during both the treatment and follow-up periods) were summarized per dose group during both the treatment and follow-up period.
Time frame: Days 1, 8, 29 and 57
Population: The Immunogenicity population was defined as all participants who had at least one pre-dose or at least one post dose ADA assessment and were included and analysed according to the treatment they actually received. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Anti-RO7126209 Antibodies (ADAs) | 50.0 Percentage of Participants |
| RO7126209 (0.1 mg/kg) | Percentage of Participants With Anti-RO7126209 Antibodies (ADAs) | 25.0 Percentage of Participants |
| RO7126209 (0.4 mg/kg) | Percentage of Participants With Anti-RO7126209 Antibodies (ADAs) | 66.7 Percentage of Participants |
| RO7126209 (1.2 mg/kg) | Percentage of Participants With Anti-RO7126209 Antibodies (ADAs) | 83.3 Percentage of Participants |
| RO7126209 (3.6 mg/kg) | Percentage of Participants With Anti-RO7126209 Antibodies (ADAs) | 83.3 Percentage of Participants |
Secondary
Terminal Rate Constant (Lambda z) of RO7126209
Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Terminal Rate Constant (Lambda z) of RO7126209 | 0.0103 (1/h) | Geometric Coefficient of Variation 19.7 |
| RO7126209 (0.1 mg/kg) | Terminal Rate Constant (Lambda z) of RO7126209 | 0.00625 (1/h) | Geometric Coefficient of Variation 57 |
| RO7126209 (0.4 mg/kg) | Terminal Rate Constant (Lambda z) of RO7126209 | 0.00690 (1/h) | Geometric Coefficient of Variation 59 |
| RO7126209 (1.2 mg/kg) | Terminal Rate Constant (Lambda z) of RO7126209 | 0.00409 (1/h) | Geometric Coefficient of Variation 19.5 |
| RO7126209 (3.6 mg/kg) | Terminal Rate Constant (Lambda z) of RO7126209 | 0.00436 (1/h) | Geometric Coefficient of Variation 21.8 |
Secondary
Total Body Clearance Calculated as Dose/AUC (CL) of RO7126209
Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Body Clearance Calculated as Dose/AUC (CL) of RO7126209 | 1.14 mL/hr/kg | Geometric Coefficient of Variation 21.3 |
| RO7126209 (0.1 mg/kg) | Total Body Clearance Calculated as Dose/AUC (CL) of RO7126209 | 0.965 mL/hr/kg | Geometric Coefficient of Variation 13.8 |
| RO7126209 (0.4 mg/kg) | Total Body Clearance Calculated as Dose/AUC (CL) of RO7126209 | 1.28 mL/hr/kg | Geometric Coefficient of Variation 29.4 |
| RO7126209 (1.2 mg/kg) | Total Body Clearance Calculated as Dose/AUC (CL) of RO7126209 | 1.07 mL/hr/kg | Geometric Coefficient of Variation 10.9 |
| RO7126209 (3.6 mg/kg) | Total Body Clearance Calculated as Dose/AUC (CL) of RO7126209 | 1.03 mL/hr/kg | Geometric Coefficient of Variation 11.1 |
Secondary
Volume of Distribution at Steady-State (Vss) of RO7126209
Plasma concentrations of RO7126209 were measured by a specific and validated assay. Plasma PK parameters of RO7126209 were read directly from the plasma concentration versus time profiles or calculated by using standard non-compartmental methods. Geometric Mean and Coefficient of Variation data are presented below.
Time frame: Days 1, 2, 3, 4, 5, 8, 10, 15, 22, 29, 43 and 57
Population: The PK Analysis population was defined as all participants who received active (RO7126209) treatment. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete which could have influenced the PK analysis. Data presented below is only for participants included in the actual analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Volume of Distribution at Steady-State (Vss) of RO7126209 | 88.6 mL/kg | Geometric Coefficient of Variation 25.1 |
| RO7126209 (0.1 mg/kg) | Volume of Distribution at Steady-State (Vss) of RO7126209 | 90.3 mL/kg | Geometric Coefficient of Variation 26.3 |
| RO7126209 (0.4 mg/kg) | Volume of Distribution at Steady-State (Vss) of RO7126209 | 108 mL/kg | Geometric Coefficient of Variation 35.5 |
| RO7126209 (1.2 mg/kg) | Volume of Distribution at Steady-State (Vss) of RO7126209 | 88.7 mL/kg | Geometric Coefficient of Variation 22.6 |
| RO7126209 (3.6 mg/kg) | Volume of Distribution at Steady-State (Vss) of RO7126209 | 85.3 mL/kg | Geometric Coefficient of Variation 22.8 |