Clinical trial NCT03040635: A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Risdiplam (RO7034067) in Healthy Japanese Participants
Official title: An Investigator/Subject Blind, Randomized, Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of RO7034067 in Healthy Japanese Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-02-02
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of Risdiplam in healthy Japanese participants.


Eligibility criteria: Inclusion Criteria:

* Participants of Japanese origin, with Japanese parents (for the provisional Caucasian cohort, participants must be male or female Caucasians with 4 Caucasian grand-parents)
* Healthy participants. Healthy status is defined by the absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including ophthalmological examination, vital signs, 12-lead electrocardiogram (ECG), hematology, blood chemistry, serology and urinalysis
* A body mass index (BMI) between 18 to 30 kilograms per square meter (kg/m\^2) inclusive
* Male participants must agree to use a barrier method of contraception from dosing until completion of the study and for 4 months thereafter
* Female participants must be either surgically sterile or post-menopausal

Exclusion Criteria:

* Medical history of cardiovascular disease, renal disease, liver disease, digestive system disease, blood dyscrasia, immunologic disease, diseases of the nervous system, endocrine disease, metabolic disease, lung disease, or with anamnesis and obstacles in kidney, liver, or cardiopulmonary function
* Participants with any clinically significant eye pathology
* Laboratory test (hematology, biochemistry, physical examination or vital signs) values outside the institutional normal range and rated as clinically significant abnormal at screening
* Any clinically significant abnormalities in ECG at screening
* Inherited long QT syndrome or known family history of arrhythmia
* Systolic blood pressure (SBP) higher than 140 millimeters of mercury (mmHg) or below 90 mmHg, and/or diastolic blood pressure (DBP) higher than 90 mmHg or below 50 mmHg in the supine position, as assessed at screening
* Positive result for human immunodeficiency virus (HIV) antigen and antibody, hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody at screening
* Donation or loss of blood over 500 milliliters (mL) within three months prior to screening
* History of smoking more than 10 cigarettes a day. Participants who have quit smoking or who have reduced their daily cigarette smoking to 10 or less for more than one month prior to screening are allowed
* Daily consumption of food or drink containing a large amount of methylxanthine (caffeine, theophylline, theobromine)
* Present or past history of substance addiction, dependence or abuse, such as abuse of drugs or alcohol
* Concomitant or previous participation in any clinical trial either within 90 days or 5 half-lives of the investigational drug, whichever is longer, before administration of study drug in this study
* Use of prescribed medications which have systemic exposure within one week before enrolment
* Use of any concomitant drug during the study (including over-the-counter medication and medications used in dentistry)
* Inability to meet the study requirements in the opinion of the Investigator

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Risdiplam
timeFrame: Pre-dose (0 hour [hr]), 0.5, 1, 2, 3, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 120, 168, 264 hr postdose from Day 1
measure: Time to Maximum Plasma Concentration (Tmax) of Risdiplam
timeFrame: Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 120, 168, 264 hr postdose from Day 1
measure: Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast) of Risdiplam
timeFrame: Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 120, 168, 264 hr postdose from Day 1
measure: Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Risdiplam
timeFrame: Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 120, 168, 264 hr postdose from Day 1
measure: Area Under the Plasma Concentration-Time Curve up to Time t (AUC0-t) of Risdiplam
timeFrame: Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 120, 168, 264 hr postdose from Day 1
measure: Apparent Terminal Half-Life (t1/2) of Risdiplam
timeFrame: Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 120, 168, 264 hr postdose from Day 1
measure: Apparent Oral Clearance (CL/F) of Risdiplam
timeFrame: Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 120, 168, 264 hr postdose from Day 1
measure: Apparent Oral Volume of Distribution (Vz/F) of Risdiplam
timeFrame: Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 120, 168, 264 hr postdose from Day 1
measure: Cumulative Amount Excreted Unchanged into Urine (Ae) of Risdiplam
timeFrame: Pre-dose (0 hr), and 5 urine samples at different time-ranges postdose (0-6 hr, 6-12 hr, 12-24 hr, 24-48 hr, and 48-72 hr)
measure: Renal Clearance (CLR) of Risdiplam
timeFrame: Pre-dose (0 hr), and 5 urine samples at different time-ranges postdose (0-6 hr, 6-12 hr, 12-24 hr, 24-48 hr, and 48-72 hr)
measure: Fraction of Dose Excreted Unchanged Renally (Fe) of Risdiplam
timeFrame: Pre-dose (0 hr), and 5 urine samples at different time-ranges postdose (0-6 hr, 6-12 hr, 12-24 hr, 24-48 hr, and 48-72 hr)
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: Up to approximately 7 weeks
Secondary outcomes:
measure: Change from Baseline in Splicing Modifications of Survival of Motor Neuron (SMN) Messenger Ribonucleic Acids (mRNAs), Including SMN1, SMN2 Full Length (FL), and SMNdelta7 mRNA in Blood In Vivo
timeFrame: Days -1, 1, 2, 3, 4, 6
measure: Change from Baseline in mRNA Levels of Paired Box (PAX) Genes in Blood
timeFrame: Days -1, 1, 2, 3, 4, 6
measure: Change from Baseline in SMN Protein Levels in Blood
timeFrame: Day -1, follow-up visit (Day 21)
Other outcomes:
Locations:
city: Garden Grove
country: United States
facility: Collaborative Neuroscience Network, Inc.
state: California
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: