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

Spinal Muscular Atrophy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02633709
• Other study ID #: BP29840
• Secondary ID: 2015-004605-16
• Status: Completed
• Phase: Phase 1
• Start date: January 7, 2016
• Est. completion date: August 4, 2016

Study information

• Verified date: October 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: August 4, 2016
• Est. primary completion date: August 4, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Atrophy
• Muscular Atrophy
• Muscular Atrophy, Spinal
• Spinal Muscular Atrophy

Intervention

Drug:
• Itraconazole
Itraconazole will be administered as an oral 200 mg dose twice daily from Day 1 to Day 8 in Part 3.

Other:
• Placebo
In Part 1 of the study matching oral placebo will be administered once on Day 1.

Drug:
• Risdiplam
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).

Locations

Country	Name	City	State
Netherlands	Pra International Group B.V	Groningen

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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.
Primary	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.
Primary	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	Maximum Observed Plasma Concentration (Cmax)		Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
Secondary	Time to Maximum Plasma Concentration (Tmax)		Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
Secondary	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
Secondary	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
Secondary	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
Secondary	Apparent Terminal Half-Life (t1/2)		Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
Secondary	Apparent Oral Clearance (CL/F)		Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
Secondary	Apparent Oral Volume of Distribution (Vz/F)		Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
Secondary	Cumulative Amount Excreted Unchanged into Urine (Ae)		Part 1: Day 1, 2, 3, 4
Secondary	Renal Clearance (CLR)		Part 1: Day 1, 2, 3, 4
Secondary	Fraction of Dose Excreted Unchanged Renally (Fe)		Part 1: Day 1, 2, 3, 4
Secondary	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
Secondary	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
Secondary	Change from Baseline in SMN Protein Levels in Blood		Part 1: Day -1, 1, 2, 3, 4, 5, 7
Secondary	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
Secondary	Predose Trough Plasma Concentration (Ctrough) of Itraconazole		Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
Secondary	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