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

Primary Purpose

Spinal Muscular Atrophy

Status

Completed

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

Itraconazole

Placebo

Risdiplam

About this trial

This is an interventional treatment trial for Spinal Muscular Atrophy

Eligibility Criteria

18 Years - 45 Years (Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

Pra International Group B.V

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Placebo Comparator

Experimental

Arm Label

Part 1: Single Ascending Dose: Placebo

Part 1: Single Ascending Dose: Risdiplam

Part 2: Food Effect: Fasted-Fed

Part 2: Food Effect: Fed-Fasted

Part 3: Itraconazole Interaction

Arm Description

Participants will receive a single dose of matching placebo orally on Day 1 of Part 1.

Participants will receive a single ascending dose (SAD) of Risdiplam orally on Day 1 of Part 1.

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.

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.

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.

Outcomes

Primary Outcome Measures

Percentage of Participants with Adverse Events (AEs)

Percentage of Participants with Laboratory Test Abnormalities

Percentage of Participants with Clinically Significant Changes in Safety Measurements, Including Vital Signs and Electrocardiograms (ECGs)

Percentage of Participants with Clinically Significant Changes in Ophthalmological Assessments

Secondary Outcome Measures

Maximum Observed Plasma Concentration (Cmax)

Time to Maximum Plasma Concentration (Tmax)

Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast)

Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC0-inf)

Area Under the Plasma Concentration-Time Curve up to Time t (AUC0-t)

Apparent Terminal Half-Life (t1/2)

Apparent Oral Clearance (CL/F)

Apparent Oral Volume of Distribution (Vz/F)

Cumulative Amount Excreted Unchanged into Urine (Ae)

Renal Clearance (CLR)

Fraction of Dose Excreted Unchanged Renally (Fe)

Metabolite-to-Parent Ratio (AUCm/AUCp) Corrected for Molecular Weight for AUCInf, AUClast or AUC0-t

Change from In Vivo Baseline in Splicing Modifications of SMN mRNAs, Including SMN1, SMN2 FL, and SMNdelta7 mRNA in Blood Ex Vivo

Change from Baseline in SMN Protein Levels in Blood

Metabolite-to-Parent Ratio (Cmax_m/Cmax_p) for Cmax, Corrected for Molecular Weight

Predose Trough Plasma Concentration (Ctrough) of Itraconazole

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

Full Information

NCT ID

NCT02633709

First Posted

December 15, 2015

Last Updated

October 2, 2018

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT02633709

Brief Title

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

2. Study Status

Record Verification Date

October 2018

Overall Recruitment Status

Completed

Study Start Date

January 7, 2016 (Actual)

Primary Completion Date

August 4, 2016 (Actual)

Study Completion Date

August 4, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Spinal Muscular Atrophy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

33 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: Single Ascending Dose: Placebo

Arm Type

Placebo Comparator

Arm Description

Participants will receive a single dose of matching placebo orally on Day 1 of Part 1.

Arm Title

Part 1: Single Ascending Dose: Risdiplam

Arm Type

Experimental

Arm Description

Participants will receive a single ascending dose (SAD) of Risdiplam orally on Day 1 of Part 1.

Arm Title

Part 2: Food Effect: Fasted-Fed

Arm Type

Experimental

Arm Description

Arm Title

Part 2: Food Effect: Fed-Fasted

Arm Type

Experimental

Arm Description

Arm Title

Part 3: Itraconazole Interaction

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Itraconazole

Other Intervention Name(s)

Sporanox®

Intervention Description

Itraconazole will be administered as an oral 200 mg dose twice daily from Day 1 to Day 8 in Part 3.

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

In Part 1 of the study matching oral placebo will be administered once on Day 1.

Intervention Type

Drug

Intervention Name(s)

Risdiplam

Other Intervention Name(s)

RO7034067

Intervention Description

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).

Primary Outcome Measure Information:

Title

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.

Title

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.

Title

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.

Title

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 Measure Information:

Title

Maximum Observed Plasma Concentration (Cmax)

Time Frame

Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28

Title

Time to Maximum Plasma Concentration (Tmax)

Time Frame

Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28

Title

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

Title

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

Title

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

Title

Apparent Terminal Half-Life (t1/2)

Time Frame

Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28

Title

Apparent Oral Clearance (CL/F)

Time Frame

Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28

Title

Apparent Oral Volume of Distribution (Vz/F)

Time Frame

Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28

Title

Cumulative Amount Excreted Unchanged into Urine (Ae)

Time Frame

Part 1: Day 1, 2, 3, 4

Title

Renal Clearance (CLR)

Time Frame

Part 1: Day 1, 2, 3, 4

Title

Fraction of Dose Excreted Unchanged Renally (Fe)

Time Frame

Part 1: Day 1, 2, 3, 4

Title

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

Title

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

Title

Change from Baseline in SMN Protein Levels in Blood

Time Frame

Part 1: Day -1, 1, 2, 3, 4, 5, 7

Title

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

Title

Predose Trough Plasma Concentration (Ctrough) of Itraconazole

Time Frame

Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28

Title

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

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Trials

Organizational Affiliation

Hoffmann-La Roche

Official's Role

Study Director

Facility Information:

Facility Name

Pra International Group B.V

City

Groningen

ZIP/Postal Code

9728 NZ

Country

Netherlands

12. IPD Sharing Statement

Learn more about this trial

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

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