Trial Outcomes & Findings for A Drug-drug Interaction Study With Risdiplam Multiple Dose and Midazolam in Healthy Participants (NCT NCT03988907)
NCT ID: NCT03988907
Last Updated: 2020-10-19
Results Overview
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.
COMPLETED
PHASE1
35 participants
Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
2020-10-19
Participant Flow
Participant milestones
| Measure |
Part 1
Participants received a dose of 5 milligram (mg) risdiplam once daily (QD) for 14 consecutive days. Participants were fasted overnight (at least 8 hours) prior to dosing on Day 1 and refrained from consuming water from 1 hour pre-dose until 2 hours post-dose.
|
Part 2
All study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with 8 mg risdiplam began. The precise dose was 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 8 mg risdiplam). On Day 16, participants received 8 mg risdiplam. Participants were fasted overnight (at least 8 hours) prior to dosing on Day 1, 3, and 15 and refrained from consuming water from 1 hour pre-dose until 2 hours post-dose.
|
|---|---|---|
|
Overall Study
STARTED
|
8
|
27
|
|
Overall Study
COMPLETED
|
8
|
26
|
|
Overall Study
NOT COMPLETED
|
0
|
1
|
Reasons for withdrawal
| Measure |
Part 1
Participants received a dose of 5 milligram (mg) risdiplam once daily (QD) for 14 consecutive days. Participants were fasted overnight (at least 8 hours) prior to dosing on Day 1 and refrained from consuming water from 1 hour pre-dose until 2 hours post-dose.
|
Part 2
All study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with 8 mg risdiplam began. The precise dose was 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 8 mg risdiplam). On Day 16, participants received 8 mg risdiplam. Participants were fasted overnight (at least 8 hours) prior to dosing on Day 1, 3, and 15 and refrained from consuming water from 1 hour pre-dose until 2 hours post-dose.
|
|---|---|---|
|
Overall Study
Unable to complete visit
|
0
|
1
|
Baseline Characteristics
A Drug-drug Interaction Study With Risdiplam Multiple Dose and Midazolam in Healthy Participants
Baseline characteristics by cohort
| Measure |
Part 1
n=8 Participants
Participants received a dose of 5 milligram (mg) risdiplam once daily (QD) for 14 consecutive days. Participants were fasted overnight (at least 8 hours) prior to dosing on Day 1 and refrained from consuming water from 1 hour pre-dose until 2 hours post-dose.
|
Part 2
n=27 Participants
All study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with 8 mg risdiplam began. The precise dose was 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 8 mg risdiplam). On Day 16, participants received 8 mg risdiplam. Participants were fasted overnight (at least 8 hours) prior to dosing on Day 1, 3, and 15 and refrained from consuming water from 1 hour pre-dose until 2 hours post-dose.
|
Total
n=35 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
41 Years
STANDARD_DEVIATION 10.2 • n=93 Participants
|
42 Years
STANDARD_DEVIATION 10.1 • n=4 Participants
|
42 Years
STANDARD_DEVIATION 10.0 • n=27 Participants
|
|
Sex: Female, Male
Female
|
4 Participants
n=93 Participants
|
11 Participants
n=4 Participants
|
15 Participants
n=27 Participants
|
|
Sex: Female, Male
Male
|
4 Participants
n=93 Participants
|
16 Participants
n=4 Participants
|
20 Participants
n=27 Participants
|
|
Race/Ethnicity, Customized
Hispanic or Latino
|
1 Participants
n=93 Participants
|
5 Participants
n=4 Participants
|
6 Participants
n=27 Participants
|
|
Race/Ethnicity, Customized
Not Hispanic or Latino
|
7 Participants
n=93 Participants
|
22 Participants
n=4 Participants
|
29 Participants
n=27 Participants
|
|
Race/Ethnicity, Customized
Asian
|
1 Participants
n=93 Participants
|
0 Participants
n=4 Participants
|
1 Participants
n=27 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
4 Participants
n=93 Participants
|
15 Participants
n=4 Participants
|
19 Participants
n=27 Participants
|
|
Race/Ethnicity, Customized
White
|
3 Participants
n=93 Participants
|
11 Participants
n=4 Participants
|
14 Participants
n=27 Participants
|
|
Race/Ethnicity, Customized
Other
|
0 Participants
n=93 Participants
|
1 Participants
n=4 Participants
|
1 Participants
n=27 Participants
|
PRIMARY outcome
Timeframe: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=12 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=11 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and in Combination With Risdiplam
Day 1 midazolam alone
|
22.6 h*ng/mL
Geometric Coefficient of Variation 64.7
|
—
|
|
Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and in Combination With Risdiplam
Day 15 midazolam + risdiplam
|
—
|
25.1 h*ng/mL
Geometric Coefficient of Variation 41.3
|
PRIMARY outcome
Timeframe: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=27 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=26 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
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
Day 1 midazolam alone
|
19.9 h*ng/mL
Geometric Coefficient of Variation 49.0
|
—
|
|
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
Day 15 midazolam + risdiplam
|
—
|
22.0 h*ng/mL
Geometric Coefficient of Variation 47.7
|
PRIMARY outcome
Timeframe: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=27 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=26 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 2: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone and in Combination With Risdiplam
Day 15 midazolam + risdiplam
|
—
|
8.96 ng/mL
Geometric Coefficient of Variation 40.4
|
|
Part 2: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone and in Combination With Risdiplam
Day 1 midazolam alone
|
7.65 ng/mL
Geometric Coefficient of Variation 48.5
|
—
|
PRIMARY outcome
Timeframe: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=17 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=15 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 2: AUCinf of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
Day 1 midazolam alone
|
8.66 h*ng/mL
Geometric Coefficient of Variation 34.1
|
—
|
|
Part 2: AUCinf of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
Day 15 midazolam + risdiplam
|
—
|
9.41 h*ng/mL
Geometric Coefficient of Variation 33.6
|
PRIMARY outcome
Timeframe: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=27 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=26 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 2: AUClast of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
Day 1 midazolam alone
|
7.75 h*ng/mL
Geometric Coefficient of Variation 39.8
|
—
|
|
Part 2: AUClast of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
Day 15 midazolam + risdiplam
|
—
|
9.43 h*ng/mL
Geometric Coefficient of Variation 34.4
|
PRIMARY outcome
Timeframe: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=27 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=26 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 2: Cmax of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
Day 1 midazolam alone
|
3.18 ng/mL
Geometric Coefficient of Variation 45.2
|
—
|
|
Part 2: Cmax of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam
Day 15 midazolam + risdiplam
|
—
|
4.10 ng/mL
Geometric Coefficient of Variation 38.3
|
SECONDARY outcome
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 postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=8 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=8 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
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
Day 1
|
404 h*ng/mL
Geometric Coefficient of Variation 15.8
|
78.4 h*ng/mL
Geometric Coefficient of Variation 16.2
|
|
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
Day 14
|
1250 h*ng/mL
Geometric Coefficient of Variation 24.6
|
349 h*ng/mL
Geometric Coefficient of Variation 23.8
|
SECONDARY outcome
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 postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=8 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=8 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 1
|
399 h*ng/mL
Geometric Coefficient of Variation 16.2
|
78.2 h*ng/mL
Geometric Coefficient of Variation 16.3
|
|
Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 14
|
3160 h*ng/mL
Geometric Coefficient of Variation 33.3
|
929 h*ng/mL
Geometric Coefficient of Variation 31.9
|
SECONDARY outcome
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 postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=8 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=8 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 14
|
78.6 ng/mL
Geometric Coefficient of Variation 23.7
|
19.1 ng/mL
Geometric Coefficient of Variation 20.7
|
|
Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 1
|
25.9 ng/mL
Geometric Coefficient of Variation 13.2
|
4.33 ng/mL
Geometric Coefficient of Variation 23.4
|
SECONDARY outcome
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 postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=27 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=27 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 3
|
613 h*ng/mL
Geometric Coefficient of Variation 24.5
|
131 h*ng/mL
Geometric Coefficient of Variation 32.2
|
|
Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 16
|
1730 h*ng/mL
Geometric Coefficient of Variation 21.3
|
504 h*ng/mL
Geometric Coefficient of Variation 31.6
|
SECONDARY outcome
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 postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample. PK parameters were determined based on available data.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=27 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=27 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 3
|
597 h*ng/mL
Geometric Coefficient of Variation 24.6
|
130 h*ng/mL
Geometric Coefficient of Variation 32.5
|
|
Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 16
|
4280 h*ng/mL
Geometric Coefficient of Variation 26.5
|
1350 h*ng/mL
Geometric Coefficient of Variation 35.6
|
SECONDARY outcome
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 postdosePopulation: The PK population consisted of all participants who had received at least 1 dose of study treatment (risdiplam or midazolam), and who had data from at least 1 postdose PK sample.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=27 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=27 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 3
|
42.6 ng/mL
Geometric Coefficient of Variation 30.8
|
7.33 ng/mL
Geometric Coefficient of Variation 32.9
|
|
Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
Day 16
|
113 ng/mL
Geometric Coefficient of Variation 21.5
|
30.5 ng/mL
Geometric Coefficient of Variation 32.5
|
SECONDARY outcome
Timeframe: Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early TerminationPopulation: The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not. In the 2 mg midazolam + 8 mg risdiplam QD (Test) arm, 1 participant withdrew from the study and was unable to attend visit, hence not included in the analysis.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=27 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=26 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 2: Percentage of Participants With Adverse Events After Midazolam Administration Alone and in Combination With Risdiplam
With at least one AE
|
7.4 Percentage of Participants
|
7.7 Percentage of Participants
|
|
Part 2: Percentage of Participants With Adverse Events After Midazolam Administration Alone and in Combination With Risdiplam
With at least one SAE
|
0.0 Percentage of Participants
|
0.0 Percentage of Participants
|
SECONDARY outcome
Timeframe: Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early TerminationPopulation: The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
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.
Outcome measures
| Measure |
2 mg Midazolam (Reference)
n=8 Participants
Participants received a single oral dose of 2 mg of midazolam on Day 1 of the treatment sequence. Participants were fasted overnight (at least 8 hours) prior to dosing on and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
2 mg Midazolam + 8 mg Risdiplam QD (Test)
n=27 Participants
Participants received 8 mg risdiplam QD orally for 14 consecutive days (Day 3 to Day 14), and on Day 15 participants received a single oral dose of 2 mg of midazolam again. Participants were fasted overnight (at least 8 hours) prior to dosing on Days 3, and 15 and refrained from consuming water from 1 hour predose until 2 hours postdose, excluding the amount of water consumed at dosing.
|
|---|---|---|
|
Part 1 and Part 2: Percentage of Participants With Adverse Events After Administration of Multiple Doses of Risdiplam
With at least one AE
|
25.0 Percentage of Participants
|
51.9 Percentage of Participants
|
|
Part 1 and Part 2: Percentage of Participants With Adverse Events After Administration of Multiple Doses of Risdiplam
With at least one SAE
|
0.0 Percentage of Participants
|
0.0 Percentage of Participants
|
Adverse Events
Part 1
Part 2
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Part 1
n=8 participants at risk
Participants received a dose of 5 milligram (mg) risdiplam once daily (QD) for 14 consecutive days. Participants were fasted overnight (at least 8 hours) prior to dosing on Day 1 and refrained from consuming water from 1 hour pre-dose until 2 hours post-dose.
|
Part 2
n=27 participants at risk
All study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with 8 mg risdiplam began. The precise dose was 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 8 mg risdiplam). On Day 16, participants received 8 mg risdiplam. Participants were fasted overnight (at least 8 hours) prior to dosing on Day 1, 3, and 15 and refrained from consuming water from 1 hour pre-dose until 2 hours post-dose.
|
|---|---|---|
|
Cardiac disorders
Extrasystoles
|
12.5%
1/8 • Number of events 1 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
0.00%
0/27 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
|
Gastrointestinal disorders
Abdominal pain
|
12.5%
1/8 • Number of events 1 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
3.7%
1/27 • Number of events 1 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
|
Gastrointestinal disorders
Nausea
|
12.5%
1/8 • Number of events 1 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
3.7%
1/27 • Number of events 1 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
0.00%
0/8 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
7.4%
2/27 • Number of events 2 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
|
Nervous system disorders
Headache
|
0.00%
0/8 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
18.5%
5/27 • Number of events 6 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
|
Respiratory, thoracic and mediastinal disorders
Rhinitis allergic
|
0.00%
0/8 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
7.4%
2/27 • Number of events 2 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
|
Respiratory, thoracic and mediastinal disorders
Sneezing
|
0.00%
0/8 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
7.4%
2/27 • Number of events 2 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
|
Respiratory, thoracic and mediastinal disorders
Upper-airway cough syndrome
|
0.00%
0/8 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
7.4%
2/27 • Number of events 2 • Part 1: Day -1; Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination Part 2: Day -1; Day 1 to Day 22 and up to 10+/-2 Days Post Final Dose or Early Termination
The Safety population consisted of all participants who received at least 1 dose of the study treatment (risdiplam or midazolam), whether prematurely withdrawn from the study or not.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
- Publication restrictions are in place
Restriction type: OTHER