Clinical trial NCT03988907: A Drug-drug Interaction Study With Risdiplam Multiple Dose and Midazolam in Healthy Participants
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Spinal Muscular Atrophy
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-06-18
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and in Combination With Risdiplam
timeFrame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
measure: 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
timeFrame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
measure: Part 2: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone and in Combination With Risdiplam
timeFrame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
measure: Part 2: AUCinf of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
timeFrame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
measure: Part 2: AUClast of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
timeFrame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
measure: Part 2: Cmax of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
timeFrame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Secondary outcomes:
measure: 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
timeFrame: 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
measure: Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
timeFrame: 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
measure: Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
timeFrame: 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
measure: Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
timeFrame: 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
measure: Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
timeFrame: 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
measure: Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
timeFrame: 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
measure: Part 2: Percentage of Participants With Adverse Events After Midazolam Administration Alone and in Combination With Risdiplam
timeFrame: Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination
measure: Part 1 and Part 2: Percentage of Participants With Adverse Events After Administration of Multiple Doses of Risdiplam
timeFrame: Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination
Other outcomes:
Locations:
city: Dallas
country: United States
facility: Covance Research Unit - Dallas
state: Texas
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: