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

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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

Study Description
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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.

Condition or disease Intervention/treatment Phase
Spinal Muscular Atrophy Drug: Itraconazole Other: Placebo Drug: Risdiplam Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : January 7, 2016
Actual Primary Completion Date : August 4, 2016
Actual Study Completion Date : August 4, 2016

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Part 1: Single Ascending Dose: Placebo
Participants will receive a single dose of matching placebo orally on Day 1 of Part 1.
 Other: Placebo
In Part 1 of the study matching oral placebo will be administered once on Day 1.
Experimental: Part 1: Single Ascending Dose: Risdiplam
Participants will receive a single ascending dose (SAD) of Risdiplam orally on Day 1 of Part 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
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.
 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
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.
 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
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.
 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®

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


Outcome Measures
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Primary Outcome Measures :
  1. 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. ]
  2. 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. ]
  3. 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. ]
  4. 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 ]

Secondary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  2. Time to Maximum Plasma Concentration (Tmax) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. Apparent Terminal Half-Life (t1/2) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  7. Apparent Oral Clearance (CL/F) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  8. Apparent Oral Volume of Distribution (Vz/F) [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  9. Cumulative Amount Excreted Unchanged into Urine (Ae) [ Time Frame: Part 1: Day 1, 2, 3, 4 ]
  10. Renal Clearance (CLR) [ Time Frame: Part 1: Day 1, 2, 3, 4 ]
  11. Fraction of Dose Excreted Unchanged Renally (Fe) [ Time Frame: Part 1: Day 1, 2, 3, 4 ]
  12. 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 ]
  13. 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 ]
  14. Change from Baseline in SMN Protein Levels in Blood [ Time Frame: Part 1: Day -1, 1, 2, 3, 4, 5, 7 ]
  15. 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 ]
  16. Predose Trough Plasma Concentration (Ctrough) of Itraconazole [ Time Frame: Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28 ]
  17. 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 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
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
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): NCT02633709


Locations
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Netherlands
Pra International Group B.V
Groningen, Netherlands, 9728 NZ
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: NCT02633709    
Other Study ID Numbers: BP29840
2015-004605-16 ( EudraCT Number )
First Posted: December 17, 2015    Key Record Dates
Last Update Posted: October 4, 2018
Last Verified: October 2018
Additional relevant MeSH terms:
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Muscular Atrophy
Muscular Atrophy, Spinal
Atrophy
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases
Itraconazole
Risdiplam
 Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors
Neuromuscular Agents
Peripheral Nervous System Agents