A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Risdiplam (RO7034067) Given by Mouth in Healthy Volunteers

Study Overview
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Brief Summary
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The objective of this study is to assess the safety and tolerability of Risdiplam (RO7034067) in healthy people. The study will assess what the body does to Risdiplam (RO7034067) and what Risdiplam (RO7034067) does to the body. Risdiplam (RO7034067) will be given by mouth in gradually increasing doses. The data from this study will help to define the dose to further explore Risdiplam (RO7034067) in patients with Spinal Muscular Atrophy.

Official Title
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A Single-Center, Randomized, Investigator/Subject-Blind, Adaptive Single-Ascending-Dose(SAD), Placebo-Controlled, Parallel Study to Investigate the Safety, Tolerability, Pharmacokinetics (Including the Effect of Food and the Effect of Itraconazole on the Pharmacokinetics of a Single Oral Dose of RO7034067), and Pharmacodynamics of RO7034067 Following Oral Administration in Healthy Subjects

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Drug: Itraconazole
* Other: Placebo
* Drug: Risdiplam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy men, aged 18 to 45 years of age, inclusive Body Mass Index (BMI) of 18 to 30 kilograms/meter square, inclusive Exclusion Criteria: History or evidence of any medical condition potentially altering the absorption, metabolism or elimination of drugs History of malignancy in the past 5 years A history of clinically significant hypersensitivity (e.g. drugs, excipients) or allergic reactions Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first study drug administration History or presence of clinically significant electrocardiogram (ECG) abnormalities or cardiovascular disease Clinically significant abnormalities in laboratory test results Confirmed resting pulse rate (PR) greater than 100 or less than 40 bpm Confirmed systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg Positive result on HIV1 and HIV2, hepatitis C (HCV) or hepatitis B (HBV) History of any clinically significant gastrointestinal, renal, hepatic, broncho-pulmonary, neurological, psychiatric, cardio-vascular, endocrinological, ophthalmological, dermatological, hematological or allergic disease, metabolic disorder, hypofertility, cancer or cirrhosis History or evidence of (neuro)muscular disorders Hypersensitivity to itraconazole, to any of the other ingredients, or to any other triazole antifungal Any other known contraindications to itraconazole

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part 1: Single Ascending Dose: Placebo<br>Participants will receive a single dose of matching placebo orally on Day 1 of Part 1. | Other: Placebo<br>* In Part 1 of the study matching oral placebo will be administered once on Day 1.<br>|
| Experimental: Part 1: Single Ascending Dose: Risdiplam<br>Participants will receive a single ascending dose (SAD) of Risdiplam orally on Day 1 of Part 1. | Drug: Risdiplam<br>* Single ascending oral doses of Risdiplam will be administered on Day 1 of Part 1. In Part 2 a single dose of Risdiplam will be once administered under fasted and once under fed conditions. In Part 3 a single dose of Risdiplam will be once administered alone (Period 1) and once concomitantly to itraconazole (Period 2).<br>* Other names: RO7034067;|
| Experimental: Part 2: Food Effect: Fasted-Fed<br>This arm consists of two periods. In Period 1 participants will receive one oral dose of Risdiplam in the fasted state on Day 1. In Period 2 participants will receive one oral dose of Risdiplam in the fed state on Day 1. | Drug: Risdiplam<br>* Single ascending oral doses of Risdiplam will be administered on Day 1 of Part 1. In Part 2 a single dose of Risdiplam will be once administered under fasted and once under fed conditions. In Part 3 a single dose of Risdiplam will be once administered alone (Period 1) and once concomitantly to itraconazole (Period 2).<br>* Other names: RO7034067;|
| Experimental: Part 2: Food Effect: Fed-Fasted<br>This arm consists of two periods. In Period 1 participants will receive one oral dose of Risdiplam in the fed state on Day 1. In Period 2 participants will receive one oral dose of Risdiplam in the fasted state on Day 1. | Drug: Risdiplam<br>* Single ascending oral doses of Risdiplam will be administered on Day 1 of Part 1. In Part 2 a single dose of Risdiplam will be once administered under fasted and once under fed conditions. In Part 3 a single dose of Risdiplam will be once administered alone (Period 1) and once concomitantly to itraconazole (Period 2).<br>* Other names: RO7034067;|
| Experimental: Part 3: Itraconazole Interaction<br>In Period 1 a single oral dose of Risdiplam will be administered. After a wash-out period in Period 2 participants will be administered oral doses of itraconazole twice daily from Day 1 to Day 8. On Day 4 participants will receive a single oral dose of Risdiplam in the fed state in combination with itraconazole. | Drug: Itraconazole<br>* Itraconazole will be administered as an oral 200 mg dose twice daily from Day 1 to Day 8 in Part 3.<br>* Other names: Sporanox®;Drug: Risdiplam<br>* Single ascending oral doses of Risdiplam will be administered on Day 1 of Part 1. In Part 2 a single dose of Risdiplam will be once administered under fasted and once under fed conditions. In Part 3 a single dose of Risdiplam will be once administered alone (Period 1) and once concomitantly to itraconazole (Period 2).<br>* Other names: RO7034067;|

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) |  | Parts 1 and 2: Up to 21 days after last dose of study drug. Part 3: Up to 28 days after last dose of study drug. | 
| Percentage of Participants with Laboratory Test Abnormalities |  | Parts 1 and 2: Up to 21 days after last dose of study drug. Part 3: Up to 28 days after last dose of study drug. | 
| Percentage of Participants with Clinically Significant Changes in Safety Measurements, Including Vital Signs and Electrocardiograms (ECGs) |  | Parts 1 and 2: Up to 21 days after last dose of study drug. Part 3: Up to 28 days after last dose of study drug. | 
| Percentage of Participants with Clinically Significant Changes in Ophthalmological Assessments |  | Part 1: Up to 26 weeks; Part 2 (Treatment Period [TP] 1 and 2): Up to 29 weeks; Part 3 (TP 1, 2): Up to 30 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Time to Maximum Plasma Concentration (Tmax) |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast) |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Area Under the Plasma Concentration-Time Curve up to Time t (AUC0-t) |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Apparent Terminal Half-Life (t1/2) |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Apparent Oral Clearance (CL/F) |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Apparent Oral Volume of Distribution (Vz/F) |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Cumulative Amount Excreted Unchanged into Urine (Ae) |  | Part 1: Day 1, 2, 3, 4 | 
| Renal Clearance (CLR) |  | Part 1: Day 1, 2, 3, 4 | 
| Fraction of Dose Excreted Unchanged Renally (Fe) |  | Part 1: Day 1, 2, 3, 4 | 
| Metabolite-to-Parent Ratio (AUCm/AUCp) Corrected for Molecular Weight for AUCInf, AUClast or AUC0-t |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Change from In Vivo Baseline in Splicing Modifications of SMN mRNAs, Including SMN1, SMN2 FL, and SMNdelta7 mRNA in Blood Ex Vivo |  | Part 1: Day 1 | 
| Change from Baseline in SMN Protein Levels in Blood |  | Part 1: Day -1, 1, 2, 3, 4, 5, 7 | 
| Metabolite-to-Parent Ratio (Cmax_m/Cmax_p) for Cmax, Corrected for Molecular Weight |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Predose Trough Plasma Concentration (Ctrough) of Itraconazole |  | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 | 
| Change from Baseline in Splicing Modifications of Survival of Motor Neuron (SMN) Messenger Ribonucleic Acids (mRNAs), Including SMN1, SMN2 FL, and SMNdelta7 mRNA in Blood In Vivo |  | Part 1: Day -1, 1, 2, 3, 4, 5 |