A Drug-drug Interaction Study With Risdiplam Multiple Dose and Midazolam in Healthy Participants

A Phase I, 2-Part, Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of Risdiplam and the Effect of Risdiplam on the Pharmacokinetics of Midazolam Following Oral Administration in Healthy Participants

This will be a Phase I, 2-part, open-label, non-randomized study to investigate the safety, tolerability, and pharmacokinetics (PK) of a multiple-dosing regimen of risdiplam (Part 1) and the effect of risdiplam on the PK of midazolam (Part 2) following oral administration in healthy adult male and female participants.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: Risdiplam; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75247
      • Covance Research Unit - Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy participants as defined by the Investigator
• A body mass index (BMI) of 18.0 to 32.0 kg/m2
• Use of adequate contraception methods during the treatment period and until 4 months after last study drug administration. Males must refrain from donating sperm during this same period
• Willingness and ability to complete all aspects of the study

Exclusion Criteria:

• Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study
• History or evidence of any medical condition potentially altering the absorption, metabolism, or elimination of drugs
• Surgical history of the GI tract affecting gastric motility or altering the GI tract
• History or presence of clinically significant ECG abnormalities or cardiovascular disease
• History of malignancy in the past 5 years
• Positive result on human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B virus, or hepatitis C virus
• Donation of blood or blood products for transfusion
• Participation in an investigational drug medicinal product or medical device study within 90 days prior to Screening
• Any clinically significant history of hypersensitivity or allergic reactions
• History of hypersensitivity to midazolam or any other benzodiazepine or its formulation ingredients

For Part 2 participants:

- History of acute angle glaucoma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part 1; Participants will receive a dose of 5 milligram (mg) risdiplam once daily (QD) for 14 consecutive days	Drug: Risdiplam; Part 1: a dose of 5 milligram (mg) risdiplam QD ; Part 2: precise dose will be based on Part 1 results
EXPERIMENTAL: Part 2; All study participants will receive a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with risdiplam will begin. The precise dose will be based on the results of Part 1, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam)	Drug: Risdiplam; Part 1: a dose of 5 milligram (mg) risdiplam QD ; Part 2: precise dose will be based on Part 1 results; Drug: Midazolam; single dose administration of 2 mg midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and in Combination With Risdiplam	In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for pharmacokinetic (PK) analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.	Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Midazolam Alone and in Combination With Risdiplam	In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.	Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Part 2: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone and in Combination With Risdiplam	In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.	Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Part 2: AUCinf of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam	In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.	Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Part 2: AUClast of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam	In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.	Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Part 2: Cmax of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam	In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.	Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of Risdiplam and Its Metabolite (M1) Following Multiple Oral Doses	In Part 1 of the study, participants received a single oral dose of 5 mg risdiplam once daily (QD) for 14 consecutive days. Blood samples for risdiplam and its metabolite were taken at defined timepoints on Day 1 and on Day 14 for the PK analysis.	Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 2 to Day 13: Predose; Day 14: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose
Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses	In Part 1 of the study, participants received a single oral dose of 5 mg risdiplam once daily (QD) for 14 consecutive days. Blood samples of risdiplam and its metabolite were taken at defined timepoints on Day 1 and on Day 14 for the PK analysis.	Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 2 to Day 13: Predose; Day 14: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose
Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses	In Part 1 of the study, participants received a single oral dose of 5 mg risdiplam once daily (QD) for 14 consecutive days. Blood samples of risdiplam and its metabolite were taken at defined timepoints on Day 1 and on Day 14 for the PK analysis.	Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 2 to Day 13: Predose; Day 14: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose
Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses	In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD.	Day 3: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 4 to Day 15: Predose; Day 16: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose
Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses	In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD.	Day 3: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 4 to Day 15: Predose; Day 16: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose
Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses	In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD.	Day 3: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose; Day 4 to Day 15: Predose; Day 16: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 96, and 144 hours postdose
Part 2: Percentage of Participants With Adverse Events After Midazolam Administration Alone and in Combination With Risdiplam	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination
Part 1 and Part 2: Percentage of Participants With Adverse Events After Administration of Multiple Doses of Risdiplam	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 18, 2019
• Primary Completion (ACTUAL): September 29, 2019
• Study Completion (ACTUAL): September 29, 2019

Study Registration Dates

• First Submitted: June 14, 2019
• First Submitted That Met QC Criteria: June 14, 2019
• First Posted (ACTUAL): June 18, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 19, 2020
• Last Update Submitted That Met QC Criteria: September 23, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Atrophy; Motor Neuron Disease; Muscular Atrophy; Muscular Atrophy, Spinal; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Neuromuscular Agents; Midazolam; Risdiplam
• Other Study ID Numbers: BP41361

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No