NCT03988907

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

Completed Phase 1 Results posted Last updated 19 October 2020

What this trial tests

Phase 1 trial testing Risdiplam in Spinal Muscular Atrophy in 35 participants. Completed in 29 September 2019.

Timeline

18 June 2019

Primary endpoint
29 September 2019

29 September 2019

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	35
Start date	18 June 2019
Primary completion	29 September 2019
Estimated completion	29 September 2019
Sites	1 location across United States

Drugs / interventions tested

• Risdiplam (RISDIPLAM) — full drug profile →
• Midazolam (midazolam) — full drug profile →

Conditions studied

• Spinal Muscular Atrophy — all drugs for Spinal Muscular Atrophy →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

Adults 18 to 55, any sex, with Spinal Muscular Atrophy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and in Combination With Risdiplam Primary · 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 adminis

Day 1 midazolam alone

Group	Value	95% CI
2 mg Midazolam (Reference)	22.6	± 64.7

Day 15 midazolam + risdiplam

Group	Value	95% CI
2 mg Midazolam + 8 mg Risdiplam QD (Test)	25.1	± 41.3

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 Primary · 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 1 midazolam alone

Group	Value	95% CI
2 mg Midazolam (Reference)	19.9	± 49.0

Day 15 midazolam + risdiplam

Group	Value	95% CI
2 mg Midazolam + 8 mg Risdiplam QD (Test)	22.0	± 47.7

Part 2: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone and in Combination With Risdiplam Primary · 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 1 midazolam alone

Group	Value	95% CI
2 mg Midazolam (Reference)	7.65	± 48.5

Day 15 midazolam + risdiplam

Group	Value	95% CI
2 mg Midazolam + 8 mg Risdiplam QD (Test)	8.96	± 40.4

Part 2: AUCinf of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam Primary · 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 1 midazolam alone

Group	Value	95% CI
2 mg Midazolam (Reference)	8.66	± 34.1

Day 15 midazolam + risdiplam

Group	Value	95% CI
2 mg Midazolam + 8 mg Risdiplam QD (Test)	9.41	± 33.6

Part 2: AUClast of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam Primary · 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 1 midazolam alone

Group	Value	95% CI
2 mg Midazolam (Reference)	7.75	± 39.8

Day 15 midazolam + risdiplam

Group	Value	95% CI
2 mg Midazolam + 8 mg Risdiplam QD (Test)	9.43	± 34.4

Part 2: Cmax of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and in Combination With Risdiplam Primary · 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 1 midazolam alone

Group	Value	95% CI
2 mg Midazolam (Reference)	3.18	± 45.2

Day 15 midazolam + risdiplam

Group	Value	95% CI
2 mg Midazolam + 8 mg Risdiplam QD (Test)	4.10	± 38.3

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 Secondary · 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.

Day 1

Group	Value	95% CI
5 mg Risdiplam	404	± 15.8
M1 Risdiplam	78.4	± 16.2

Day 14

Group	Value	95% CI
5 mg Risdiplam	1250	± 24.6
M1 Risdiplam	349	± 23.8

Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses Secondary · 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.

Day 1

Group	Value	95% CI
5 mg Risdiplam	399	± 16.2
M1 Risdiplam	78.2	± 16.3

Day 14

Group	Value	95% CI
5 mg Risdiplam	3160	± 33.3
M1 Risdiplam	929	± 31.9

Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses Secondary · 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.

Day 1

Group	Value	95% CI
5 mg Risdiplam	25.9	± 13.2
M1 Risdiplam	4.33	± 23.4

Day 14

Group	Value	95% CI
5 mg Risdiplam	78.6	± 23.7
M1 Risdiplam	19.1	± 20.7

Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses Secondary · 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.

Day 3

Group	Value	95% CI
8 mg Risdiplam QD	613	± 24.5
M1 of Risdiplam	131	± 32.2

Day 16

Group	Value	95% CI
8 mg Risdiplam QD	1730	± 21.3
M1 of Risdiplam	504	± 31.6

Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses Secondary · 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.

Day 3

Group	Value	95% CI
8 mg Risdiplam QD	597	± 24.6
M1 of Risdiplam	130	± 32.5

Day 16

Group	Value	95% CI
8 mg Risdiplam QD	4280	± 26.5
M1 of Risdiplam	1350	± 35.6

Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses Secondary · 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.

Day 3

Group	Value	95% CI
8 mg Risdiplam QD	42.6	± 30.8
M1 of Risdiplam	7.33	± 32.9

Day 16

Group	Value	95% CI
8 mg Risdiplam QD	113	± 21.5
M1 of Risdiplam	30.5	± 32.5

Adverse events — posted to ClinicalTrials.gov

Time frame: 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. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part 1

Serious: 0/8 (0%)

Deaths: 0/8

Part 2

Serious: 0/27 (0%)

Deaths: 0/27

Other adverse events (8 terms — click to expand)

Reaction	System	Part 1	Part 2
Headache	Nervous system disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	—	—
Sneezing	Respiratory, thoracic and mediastinal disorders	—	—
Upper-airway cough syndrome	Respiratory, thoracic and mediastinal disorders	—	—
Extrasystoles	Cardiac disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—

Data from ClinicalTrials.gov NCT03988907 adverse events section.

Sponsor's own description

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.

Publications & conference data

5 peer-reviewed publications reference this trial (live from Europe PMC):

1. Model-Based Drug-Drug Interaction Extrapolation Strategy From Adults to Children: Risdiplam in Pediatric Patients With Spinal Muscular Atrophy.
   Cleary Y, Gertz M, Grimsey P, Günther A, et al · · 2021 · cited 35× · PMID 34347881 · DOI 10.1002/cpt.2384
2. Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children.
   Cleary Y, Kletzl H, Grimsey P, Heinig K, et al · · 2023 · cited 13× · PMID 37148485 · DOI 10.1007/s40262-023-01241-7
3. Pharmacological Therapies of Spinal Muscular Atrophy: A Narrative Review of Preclinical, Clinical-Experimental, and Real-World Evidence.
   Crisafulli S, Boccanegra B, Vitturi G, Trifirò G, et al · · 2023 · cited 11× · PMID 37891814 · DOI 10.3390/brainsci13101446
4. An updated review of the SMA clinical trial landscape in the United States: Findings from analysis of recruitment targets on ClinicalTrials.gov and a survey of SMA clinical trial sites on factors affecting site capacity and readiness.
   Sarr F, Peterson I, Glascock J, Curry M. · · 2026 · cited 1× · PMID 41658435 · DOI 10.1016/j.conctc.2026.101601
5. Pharmacokinetics of therapies approved for spinal muscular atrophy: A narrative review of current evidence.
   Sel EK, Gkrinia EMM, Roncato R, Vitezić D, et al · · 2025 · PMID 41299848 · DOI 10.1177/03000605251397777