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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02633709
Recruitment Status : Completed
First Posted : December 17, 2015
Last Update Posted : October 4, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE December 15, 2015
First Posted Date  ICMJE December 17, 2015
Last Update Posted Date October 4, 2018
Actual Study Start Date  ICMJE January 7, 2016
Actual Primary Completion Date August 4, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 15, 2015)
  • Percentage of Participants with Adverse Events (AEs) [ Time Frame: 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 [ Time Frame: 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 Safety Measurements, Including Vital Signs and Electrocardiograms (ECGs) [ Time Frame: 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 [ Time Frame: 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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 15, 2015)
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  • Time to Maximum Plasma Concentration (Tmax) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  • Area Under the Plasma Concentration-Time Curve up to Time t (AUC0-t) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  • Apparent Terminal Half-Life (t1/2) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  • Apparent Oral Clearance (CL/F) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  • Apparent Oral Volume of Distribution (Vz/F) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  • Cumulative Amount Excreted Unchanged into Urine (Ae) [ Time Frame: Part 1: Day 1, 2, 3, 4 ]
  • Renal Clearance (CLR) [ Time Frame: Part 1: Day 1, 2, 3, 4 ]
  • Fraction of Dose Excreted Unchanged Renally (Fe) [ Time Frame: Part 1: Day 1, 2, 3, 4 ]
  • Metabolite-to-Parent Ratio (AUCm/AUCp) Corrected for Molecular Weight for AUCInf, AUClast or AUC0-t [ Time Frame: 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 [ Time Frame: Part 1: Day 1 ]
  • Change from Baseline in SMN Protein Levels in Blood [ Time Frame: Part 1: Day -1, 1, 2, 3, 4, 5, 7 ]
  • Metabolite-to-Parent Ratio (Cmax_m/Cmax_p) for Cmax, Corrected for Molecular Weight [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  • Predose Trough Plasma Concentration (Ctrough) of Itraconazole [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  • 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 [ Time Frame: Part 1: Day -1, 1, 2, 3, 4, 5 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Risdiplam (RO7034067) Given by Mouth in Healthy Volunteers
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Spinal Muscular Atrophy
Intervention  ICMJE
  • Drug: Itraconazole
    Itraconazole will be administered as an oral 200 mg dose twice daily from Day 1 to Day 8 in Part 3.
    Other Name: Sporanox®
  • 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).
    Other Name: RO7034067
Study Arms  ICMJE
  • Placebo Comparator: Part 1: Single Ascending Dose: Placebo
    Participants will receive a single dose of matching placebo orally on Day 1 of Part 1.
    Intervention: Other: Placebo
  • Experimental: Part 1: Single Ascending Dose: Risdiplam
    Participants will receive a single ascending dose (SAD) of Risdiplam orally on Day 1 of Part 1.
    Intervention: Drug: Risdiplam
  • Experimental: Part 2: Food Effect: Fasted-Fed
    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.
    Intervention: Drug: Risdiplam
  • Experimental: Part 2: Food Effect: Fed-Fasted
    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.
    Intervention: Drug: Risdiplam
  • Experimental: Part 3: Itraconazole Interaction
    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.
    Interventions:
    • Drug: Itraconazole
    • Drug: Risdiplam
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 1, 2016)
33
Original Estimated Enrollment  ICMJE
 (submitted: December 15, 2015)
93
Actual Study Completion Date  ICMJE August 4, 2016
Actual Primary Completion Date August 4, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02633709
Other Study ID Numbers  ICMJE BP29840
2015-004605-16 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP