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

Phase 1

Completed

• Conditions: Spinal Muscular Atrophy
• Interventions: Other: Placebo; Drug: Risdiplam; Drug: Itraconazole

• Registration Number: NCT02633709
• Lead Sponsor: Hoffmann-La Roche

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-12-15
• Study First Submitted QC: 2015-12-15
• Study First Posted: 2015-12-17
• Study Start: 2016-01-07
• Primary Completion: 2016-08-04
• Study Completion: 2016-08-04
• Status Verified: 2018-10
• Last Update Submitted: 2018-10-02
• Last Update Posted: 2018-10-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 33

Inclusion Criteria

• Healthy men, aged 18 to 45 years of age, inclusive
• Body Mass Index (BMI) of 18 to 30 kilograms/meter square, inclusive

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1: Single Ascending Dose: Placebo	Placebo	Participants will receive a single dose of matching placebo orally on Day 1 of Part 1.
Part 1: Single Ascending Dose: Risdiplam	Risdiplam	Participants will receive a single ascending dose (SAD) of Risdiplam orally on Day 1 of Part 1.
Part 3: Itraconazole Interaction	Itraconazole	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.
Part 2: Food Effect: Fed-Fasted	Risdiplam	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.
Part 2: Food Effect: Fasted-Fed	Risdiplam	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.
Part 3: Itraconazole Interaction	Risdiplam	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.

Primary Outcome Measures

Name	Time	Method
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
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.

Secondary Outcome Measures

Name	Time	Method
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
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 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
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
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
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
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
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

Trial Locations

Locations (1)

Pra International Group B.V; 🇳🇱 Groningen, Netherlands