Spinal Muscular Atrophy
Conditions
Brief summary
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.
Interventions
DRUGItraconazole
Itraconazole will be administered as an oral 200 mg dose twice daily from Day 1 to Day 8 in Part 3.
OTHERPlacebo
In Part 1 of the study matching oral placebo will be administered once on Day 1.
DRUGRisdiplam
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).
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 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| 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 |
| Maximum Observed Plasma Concentration (Cmax) | Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 |
| 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 |
| Fraction of Dose Excreted Unchanged Renally (Fe) | Part 1: Day 1, 2, 3, 4 |
| 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 |
Countries
Netherlands
Outcome results
None listed