Clinical trial NCT02633709: A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Risdiplam (RO7034067) Given by Mouth in Healthy Volunteers
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Spinal Muscular Atrophy
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-12-17
Enrollment: 33
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: 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.
measure: Percentage of Participants with Laboratory Test Abnormalities
timeFrame: 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.
measure: Percentage of Participants with Clinically Significant Changes in Safety Measurements, Including Vital Signs and Electrocardiograms (ECGs)
timeFrame: 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.
measure: Percentage of Participants with Clinically Significant Changes in Ophthalmological Assessments
timeFrame: 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 outcomes:
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Time to Maximum Plasma Concentration (Tmax)
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast)
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC0-inf)
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Area Under the Plasma Concentration-Time Curve up to Time t (AUC0-t)
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Apparent Terminal Half-Life (t1/2)
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Apparent Oral Clearance (CL/F)
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Apparent Oral Volume of Distribution (Vz/F)
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Cumulative Amount Excreted Unchanged into Urine (Ae)
timeFrame: Part 1: Day 1, 2, 3, 4
measure: Renal Clearance (CLR)
timeFrame: Part 1: Day 1, 2, 3, 4
measure: Fraction of Dose Excreted Unchanged Renally (Fe)
timeFrame: Part 1: Day 1, 2, 3, 4
measure: Metabolite-to-Parent Ratio (AUCm/AUCp) Corrected for Molecular Weight for AUCInf, AUClast or AUC0-t
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Change from In Vivo Baseline in Splicing Modifications of SMN mRNAs, Including SMN1, SMN2 FL, and SMNdelta7 mRNA in Blood Ex Vivo
timeFrame: Part 1: Day 1
measure: Change from Baseline in SMN Protein Levels in Blood
timeFrame: Part 1: Day -1, 1, 2, 3, 4, 5, 7
measure: Metabolite-to-Parent Ratio (Cmax_m/Cmax_p) for Cmax, Corrected for Molecular Weight
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: Predose Trough Plasma Concentration (Ctrough) of Itraconazole
timeFrame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28
measure: 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
timeFrame: Part 1: Day -1, 1, 2, 3, 4, 5
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: Pra International Group B.V
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: