Spinal Muscular Atrophy
Conditions
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.
Interventions
DRUGRisdiplam
Part 1: a dose of 5 milligram (mg) risdiplam QD ; Part 2: precise dose will be based on Part 1 results
DRUGMidazolam
single dose administration of 2 mg midazolam
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose | 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. |
| 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 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose | 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. |
| Part 2: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone and 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 | 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. |
| Part 2: AUCinf of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and 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 | 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. |
| Part 2: AUClast of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and 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 | 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. |
| Part 2: Cmax of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Percentage of Participants With Adverse Events After Midazolam Administration Alone and in Combination With Risdiplam | Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination | 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. |
| 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: 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 | 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. |
| Part 1 and Part 2: Percentage of Participants With Adverse Events After Administration of Multiple Doses of Risdiplam | Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination | 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. |
| Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | 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 | 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. |
| Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | 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 | 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. |
| Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | 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 | 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. |
| Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | 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 | 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. |
| Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 8 |
| 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. | 27 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Unable to complete visit | 0 | 1 |
Baseline characteristics
| Characteristic | Part 2 | Part 1 | Total |
|---|---|---|---|
| Age, Continuous | 42 Years STANDARD_DEVIATION 10.1 | 41 Years STANDARD_DEVIATION 10.2 | 42 Years STANDARD_DEVIATION 10 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 15 Participants | 4 Participants | 19 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 22 Participants | 7 Participants | 29 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 3 Participants | 14 Participants |
| Sex: Female, Male Female | 11 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 16 Participants | 4 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 27 |
| other Total, other adverse events | 2 / 8 | 15 / 27 |
| serious Total, serious adverse events | 0 / 8 | 0 / 27 |
Outcome results
Primary
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.
Time frame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 |
90% CI: [0.93, 1.26]
Primary
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.
Time frame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 |
90% CI: [1.02, 1.2]
Primary
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.
Time frame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 |
90% CI: [0.99, 1.27]
Primary
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.
Time frame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 |
90% CI: [1.11, 1.3]
Primary
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.
Time frame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 |
90% CI: [1.14, 1.41]
Primary
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.
Time frame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 |
90% CI: [1.06, 1.28]
Secondary
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.
Time frame: Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 1 and Part 2: Percentage of Participants With Adverse Events After Administration of Multiple Doses of Risdiplam | With at least one AE | 51.9 Percentage of Participants |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 |
Secondary
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 | 78.4 h*ng/mL | Geometric Coefficient of Variation 16.2 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 | 349 h*ng/mL | Geometric Coefficient of Variation 23.8 |
Secondary
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 1 | 399 h*ng/mL | Geometric Coefficient of Variation 16.2 |
| 2 mg Midazolam (Reference) | Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 14 | 3160 h*ng/mL | Geometric Coefficient of Variation 33.3 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 1 | 78.2 h*ng/mL | Geometric Coefficient of Variation 16.3 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 14 | 929 h*ng/mL | Geometric Coefficient of Variation 31.9 |
Secondary
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 1 | 25.9 ng/mL | Geometric Coefficient of Variation 13.2 |
| 2 mg Midazolam (Reference) | Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 14 | 78.6 ng/mL | Geometric Coefficient of Variation 23.7 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 1 | 4.33 ng/mL | Geometric Coefficient of Variation 23.4 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 14 | 19.1 ng/mL | Geometric Coefficient of Variation 20.7 |
Secondary
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 3 | 597 h*ng/mL | Geometric Coefficient of Variation 24.6 |
| 2 mg Midazolam (Reference) | Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 16 | 4280 h*ng/mL | Geometric Coefficient of Variation 26.5 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 3 | 130 h*ng/mL | Geometric Coefficient of Variation 32.5 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 16 | 1350 h*ng/mL | Geometric Coefficient of Variation 35.6 |
Secondary
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 3 | 613 h*ng/mL | Geometric Coefficient of Variation 24.5 |
| 2 mg Midazolam (Reference) | Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 16 | 1730 h*ng/mL | Geometric Coefficient of Variation 21.3 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 3 | 131 h*ng/mL | Geometric Coefficient of Variation 32.2 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 16 | 504 h*ng/mL | Geometric Coefficient of Variation 31.6 |
Secondary
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 2 mg Midazolam (Reference) | Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 3 | 42.6 ng/mL | Geometric Coefficient of Variation 30.8 |
| 2 mg Midazolam (Reference) | Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 16 | 113 ng/mL | Geometric Coefficient of Variation 21.5 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 3 | 7.33 ng/mL | Geometric Coefficient of Variation 32.9 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses | Day 16 | 30.5 ng/mL | Geometric Coefficient of Variation 32.5 |
Secondary
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.
Time frame: Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam (Reference) | 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 |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | Part 2: Percentage of Participants With Adverse Events After Midazolam Administration Alone and in Combination With Risdiplam | With at least one AE | 7.7 Percentage of Participants |
| 2 mg Midazolam + 8 mg Risdiplam QD (Test) | 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 |