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A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Risdiplam (RO7034067) in Healthy Japanese Participants

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ClinicalTrials.gov Identifier: NCT03040635
Recruitment Status : Completed
First Posted : February 2, 2017
Last Update Posted : October 4, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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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.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Risdiplam Drug: Placebo Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : March 22, 2017
Actual Primary Completion Date : October 2, 2017
Actual Study Completion Date : October 2, 2017
Arms and Interventions
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Arm Intervention/treatment
Experimental: Risdiplam '2' Milligrams (mg)
A single dose of 2 mg Risdiplam will be administered to all participants randomized to this arm under fasted conditions as an oral drinking solution on Day 1.
 Drug: Risdiplam
Single oral doses of Risdiplam will be administered on Day 1.
Other Name: RO7034067
Experimental: Risdiplam '6' mg
A single dose of 6 mg Risdiplam will be administered to all participants randomized to this arm under fasted conditions as an oral drinking solution on Day 1.
 Drug: Risdiplam
Single oral doses of Risdiplam will be administered on Day 1.
Other Name: RO7034067
Experimental: Risdiplam '12' mg
A single dose of 12 mg Risdiplam will be administered to all participants randomized to this arm under fasted conditions as an oral drinking solution on Day 1.
 Drug: Risdiplam
Single oral doses of Risdiplam will be administered on Day 1.
Other Name: RO7034067
Placebo Comparator: Placebo
A single dose of placebo will be administered to all participants randomized to this arm under fasted conditions as an oral drinking solution on Day 1.
 Drug: Placebo
Single oral doses of Risdiplam matching placebo will be administered on Day 1.


Outcome Measures
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Primary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) of Risdiplam [ Time Frame: 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 ]
  2. Time to Maximum Plasma Concentration (Tmax) of Risdiplam [ Time Frame: 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 ]
  3. Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast) of Risdiplam [ Time Frame: 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 ]
  4. Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Risdiplam [ Time Frame: 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 ]
  5. Area Under the Plasma Concentration-Time Curve up to Time t (AUC0-t) of Risdiplam [ Time Frame: 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 ]
  6. Apparent Terminal Half-Life (t1/2) of Risdiplam [ Time Frame: 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 ]
  7. Apparent Oral Clearance (CL/F) of Risdiplam [ Time Frame: 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 ]
  8. Apparent Oral Volume of Distribution (Vz/F) of Risdiplam [ Time Frame: 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 ]
  9. Cumulative Amount Excreted Unchanged into Urine (Ae) of Risdiplam [ Time Frame: 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) ]
  10. Renal Clearance (CLR) of Risdiplam [ Time Frame: 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) ]
  11. Fraction of Dose Excreted Unchanged Renally (Fe) of Risdiplam [ Time Frame: 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) ]
  12. Percentage of Participants with Adverse Events (AEs) [ Time Frame: Up to approximately 7 weeks ]

Secondary Outcome Measures :
  1. 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 [ Time Frame: Days -1, 1, 2, 3, 4, 6 ]
  2. Change from Baseline in mRNA Levels of Paired Box (PAX) Genes in Blood [ Time Frame: Days -1, 1, 2, 3, 4, 6 ]
  3. Change from Baseline in SMN Protein Levels in Blood [ Time Frame: Day -1, follow-up visit (Day 21) ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03040635


Locations
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United States, California
Collaborative Neuroscience Network, Inc.
Garden Grove, California, United States, 92845
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
More Information
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03040635    
Other Study ID Numbers: NP39625
First Posted: February 2, 2017    Key Record Dates
Last Update Posted: October 4, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Risdiplam
Neuromuscular Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs