A Study to Assess the Safety and Tolerability of Single and Multiple Ascending Doses of Oral RO7020531 in Chinese Healthy Participants.

Study Overview
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Brief Summary
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To evaluate the safety and tolerability of single and multiple ascending doses of oral RO7020531 in Chinese healthy participants.

Official Title
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A Randomized, Sponsor-Open, Investigator-Blinded, Subject-Blinded, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of RO7020531 and Metabolites Following Oral Administration to Chinese Healthy Volunteers.

Conditions
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Healthy Participants

Intervention / Treatment
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* Drug: RO7020531
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Chinese healthy male and female participants. Healthy status is defined by 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, hematology, blood chemistry, and urinalysis. A Body Mass Index (BMI) of 19 to less than 28 kg/m2 and a body weight of at least 45 kg. Negative anti-nuclear antibody (ANA) test; or positive with dilutions not greater than 1:40 and with no associated history or symptoms of potential connective tissue disease or other immune-mediated diseases. Women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods. Men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and refrain from donating sperm. Negative pregnancy test on Day -1 for female participants. Non-smokers, or use of < 10 cigarettes (or equivalent nicotine-containing product) per day. Exclusion Criteria Pregnant (positive pregnancy test) or lactating women, and male partners of women who are pregnant or lactating. History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis, multiple sclerosis, or any other autoimmune disease). History or symptoms of any clinically significant disease including (but not limited to), neurological, cardiovascular, endocrine, respiratory, hepatic, ocular, or renal disorder (as per Investigator's judgment). Personal or family history of congenital long QT syndrome or sudden cardiac death. Evidence of an active or suspected cancer or a history of malignancy, where in the Investigator's opinion, there is a risk of recurrence. History of having received or currently receiving any systemic anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic oral or inhaled corticosteroids, IFN or PEG-IFN) within 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. Eye drop-containing and infrequent inhaled corticosteroids are permissible up to 4 weeks prior to the first dose of study drug. History of clinically significant thyroid disease; also, subjects with clinically significant elevated thyroid-stimulating hormone (TSH) concentrations at Screening. Any confirmed clinically significant allergic reactions (anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable). Abnormal renal function. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values at Screening above ULN and judged clinically significant by the Investigator. Positive results for anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA) or thyroid peroxidase antibody. Positive hepatitis A IgM antibody (HAV Ab IgM), hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or positive for human immunodeficiency virus (HIV) at Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Ascending Dose (SAD): Placebo<br>In SAD Cohorts 1-4, there will be eight participants in total receiving placebo, two in each cohort. | Drug: Placebo<br>* Placebo hard capsules will be administered orally as per the dosing schedules described above.<br>|
| Experimental: SAD: Cohort 1<br>Eight participants will be administered 40mg RO7020531 orally on Day 1. | Drug: RO7020531<br>* 4 SAD Cohorts with individual dosages of 40, 100, 140 and 170 mg hard capsules and 3 MAD Cohorts with dosages of 100 and 150mg hard capsules, will be administered orally as per the dosing schedules described above.<br>|
| Experimental: SAD: Cohort 2<br>Eight participants will be administered 100mg RO7020531 orally on Day 1. | Drug: RO7020531<br>* 4 SAD Cohorts with individual dosages of 40, 100, 140 and 170 mg hard capsules and 3 MAD Cohorts with dosages of 100 and 150mg hard capsules, will be administered orally as per the dosing schedules described above.<br>|
| Experimental: SAD: Cohort 3<br>Eight participants will be administered 140mg RO7020531 orally on Day 1. | Drug: RO7020531<br>* 4 SAD Cohorts with individual dosages of 40, 100, 140 and 170 mg hard capsules and 3 MAD Cohorts with dosages of 100 and 150mg hard capsules, will be administered orally as per the dosing schedules described above.<br>|
| Experimental: SAD: Cohort 4<br>Eight participants will be administered 170mg RO7020531 orally on Day 1. | Drug: RO7020531<br>* 4 SAD Cohorts with individual dosages of 40, 100, 140 and 170 mg hard capsules and 3 MAD Cohorts with dosages of 100 and 150mg hard capsules, will be administered orally as per the dosing schedules described above.<br>|
| Experimental: Multiple Ascending Dose (MAD): Placebo<br>In MAD Cohorts 1-3, there will be six participants in total receiving placebo, two in each cohort. | Drug: Placebo<br>* Placebo hard capsules will be administered orally as per the dosing schedules described above.<br>|
| Experimental: MAD: Cohort 1<br>Eight participants will be administered 100mg RO7020531 orally on Day 1 and every other day (QOD) for 14 days. | Drug: RO7020531<br>* 4 SAD Cohorts with individual dosages of 40, 100, 140 and 170 mg hard capsules and 3 MAD Cohorts with dosages of 100 and 150mg hard capsules, will be administered orally as per the dosing schedules described above.<br>|
| Experimental: MAD: Cohorts 2 and 3<br>Sixteen participants will be administered 150mg RO7020531 orally on Day 1 and every other day (QOD) for 14 days. | Drug: RO7020531<br>* 4 SAD Cohorts with individual dosages of 40, 100, 140 and 170 mg hard capsules and 3 MAD Cohorts with dosages of 100 and 150mg hard capsules, will be administered orally as per the dosing schedules described above.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) | An Adverse Event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition, any deterioration in a laboratory value or other clinical test or adverse events that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment. | Screening up until 28 days after the last dose of study drug (up to 1 year). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Cmax will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | 
| Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for AUClast will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | 
| Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for AUCinf will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). Due to insufficient plasma concentration data for RO7020531 and RO7033805, AUCinf for these 2 compounds could not be estimated. | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | 
| Time to Maximum Observed Plasma Concentration (Tmax) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Median and Full Range) for Tmax will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | 
| Half-Life (t1/2) for RO7020531, Main Active Metabolite (RO7011785) and Prodrug Metabolites (RO7018822 and RO7033805) | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for t1/2 will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and SAD Cohorts (1-4) (on Day 13). Due to insufficient plasma concentration data for RO7020531 and RO7033805, t1/2 for these 2 compounds could not be estimated. | SAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48 hours (h) Post-dose Days 1, 2; MAD: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24h Post-dose Days 1, 2 and Days 13, 14; Pre-dose, 2, 6, 24hr Post-dose Days 3, 5, 7, 9 and 11. | 
| Total Amount Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Total Amount Excreted, will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and MAD Cohorts (1-4). | SAD: Pre-dose, 0-4, 4-8, 8-12, 12-24h Day 1 | 
| Fraction Excreted as RO7020531, RO7011785, RO7018822 and RO7033805 | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Fraction Excreted (Molecular Weight corrected) will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and MAD Cohorts (1-4). | SAD: Pre-dose, 0-4, 4-8, 8-12, 12-24h Day 1 | 
| Renal Clearance of RO7020531, RO7011785, RO7018822 and RO7033805 | Non-compartmental analysis using WinNonlin software was used to calculate PK parameters where appropriate. Summary descriptive statistics (Arithmetic Mean and Standard Deviation) for Renal Clearance will be presented by treatment arm. Where appropriate, data maybe pooled and analyzed. Please note that this Outcome Measure was not measured for the Placebo Cohorts and MAD Cohorts (1-4). Due to insufficient urine concentration data for RO7020531 and RO7033805, Renal Clearance for these 2 compounds could not be estimated. | SAD: Pre-dose, 0-4, 4-8, 8-12, 12-24h Day 1 | 
| Mean Concentrations of Protein and Metabolite Markers of Humoral Response | Protein and metabolite markers of humoral response include interferon (IFN)-alfa, IP-10, Tumor Necrosis Factor (TNF)-alfa, interleukin (IL)-6, IL-10, IL-12p40 and Neopterin. Summary descriptive statistics will be presented for the induction of cytokines, chemokines and neopterin and of interferon-response genes separately by treatment arm. Only mean concentrations were collected for IFN-alfa and hence why this data is only presented below. | SAD: Day -1, Pre-dose, 2, 6, 12, 24h Post-dose Day 1 to Day 2, 3, 5, 8; MAD: Day -1, Pre-dose 2, 6, 12, 24h Post-dose Day 1 to Day 2, Pre-dose, 2, 6, 24h Post-dose Days 3, 5, 7, 13 and 20 | 
| Mean Fold Changes of Protein and Metabolite Markers of Humoral Response | Protein and metabolite markers of humoral response include interferon (IFN)-alfa, IP-10, Tumor Necrosis Factor (TNF)-alfa, interleukin (IL)-6, IL-10, IL-12p40 and Neopterin. Summary descriptive statistics will be presented for the induction of cytokines, chemokines and neopterin and of interferon-response genes separately by treatment arm. Mean fold change data is presented below. | SAD: Day -1, Pre-dose, 2, 6, 12, 24, 48 (only Neopterin), 96h (only Neopterin), Post-dose Day 1 to Day 2, 3, 5, 8; MAD: Day -1, Pre-dose 2, 6, 12, 24h Post-dose Day 1 to Day 2, Pre-dose, 2, 6, 24h Post-dose Days 3, 5, 7, 13 and 20 | 
| Mean Fold Changes of Markers of Transcriptional Responses | Markers of transcriptional responses includes ISG15, OAS-1, MX1 and Toll-Like Receptor (TLR)7. Summary descriptive statistics will be presented for these markers separately by treatment arm. | SAD: Day -1, Pre-dose, 2, 6, 12, 24h Post-dose Day 1 to Day 2 and Day 8; MAD: Day -1, Pre-dose 2, 6, 12, 24h Post-dose Day 1 to Day 2, Pre-dose, 2, 6, 24h Post-dose Days 3, 5, 7, 13 and 20 |