Spinal Muscular AtrophyPhase 1NCT03988907

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

A Phase 1 study testing Risdiplam and Midazolam in people with Spinal Muscular Atrophy, run by Hoffmann-La Roche at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for: Spinal Muscular Atrophy
What is being tested?: Risdiplam and Midazolam
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 35 participants
Where: 1 siteUnited States
Study dates: 18 Jun 2019to 29 Sep 2019
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 55 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

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

Who cannot join

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

Show all 12Show fewer

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

Trial locations and contacts

1 site in 1 country.

United States1 site

Covance Research Unit - Dallas
Dallas, Texas, 75247

Other trials in United States

About this study

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

Conditions: Spinal Muscular Atrophy
Being tested: Risdiplam, Midazolam
Medical subject headings: Muscular Atrophy, Spinal

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

RisdiplamDrug
Part 1: a dose of 5 milligram (mg) risdiplam QD ; Part 2: precise dose will be based on Part 1 results
MidazolamDrug
single dose administration of 2 mg midazolam

Study groups in NCT03988907
Study group	Role	What they receive
Part 1	Experimental	Participants will receive a dose of 5 milligram (mg) risdiplam once daily (QD) for 14 consecutive days Receives: Drug: Risdiplam
Part 2	Experimental	All study participants will receive a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with risdiplam will begin. The precise dose will be based on the results of Part 1, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam) Receives: Drug: Risdiplam; Drug: Midazolam

What is being measured

The primary outcome is the main question the study is designed to answer.

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

Secondary outcomes (8)

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

18 Jun 201929 Sep 2019

First posted18 Jun 2019
Study start18 Jun 2019
Primary completion29 Sep 2019
Study completion29 Sep 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Spinal Muscular AtrophyStudies of the same condition, open and under way.
More trials run by Hoffmann-La RocheThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Enrolment: 35 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03988907
Sponsor's protocol ID: BP41361
Status last verified: Sep 2020
First submitted: 14 Jun 2019
Last updated: 19 Oct 2020
Results posted: Yes, on ClinicalTrials.gov
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research\_and\_development/who\_we\_are\_how\_we\_work/clinical\_trials/our\_commitment\_to\_data\_sharing.htm).

Publications

Cleary Y, Kletzl H, Grimsey P, Heinig K, Ogungbenro K, Silber Baumann HE, Frey N, Aarons L, Galetin A, Gertz M. Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children. Clin Pharmacokinet. 2023 Jun;62(6):891-904. doi: 10.1007/s40262-023-01241-7. Epub 2023 May 6.
PubMed 37148485

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 19 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase I, 2-Part, Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of Risdiplam and the Effect of Risdiplam on the Pharmacokinetics of Midazolam Following Oral Administration in Healthy Participants
ClinicalTrials.gov ID: NCT03988907
Acronym / sponsor ID: BP41361
Conditions: Spinal Muscular Atrophy
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 35 participants (actual)
Lead sponsor: Hoffmann-La RocheIndustry (pharma, biotech, devices)
Study start: 18 Jun 2019 (actual)
Primary completion: 29 Sep 2019 (actual)
Study completion: 29 Sep 2019 (actual)
First posted: 18 Jun 2019 (actual)
Results: Posted 19 Oct 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Part 1	Experimental	Drug: RisdiplamParticipants will receive a dose of 5 milligram (mg) risdiplam once daily (QD) for 14 consecutive days
Part 2	Experimental	Drug: Risdiplam, Drug: MidazolamAll study participants will receive a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with risdiplam will begin. The precise dose will be based on the results of Part 1, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam)

Who may qualify

Ages: 18 to 55 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (4 listed)

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

Key exclusion criteria (12 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
RisdiplamPart 1: a dose of 5 milligram (mg) risdiplam QD ; Part 2: precise dose will be based on Part 1 results	Drug	Part 1, Part 2
Midazolamsingle dose administration of 2 mg midazolam	Drug	Part 2

Primary outcome

Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and 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
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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.

8 secondary outcomes

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
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
Part 1: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
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
Part 1: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
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
Part 2: AUCtau of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
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
Part 2: AUClast of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
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
Part 2: Cmax of Risdiplam and M1 Risdiplam Following Multiple Oral Doses
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
Part 2: Percentage of Participants With Adverse Events After Midazolam Administration Alone and in Combination With Risdiplam
Time frame: Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination
Part 1 and Part 2: Percentage of Participants With Adverse Events After Administration of Multiple Doses of Risdiplam
Time frame: Day 1 to Day 20 and up to 10+/-2 Days Post Final Dose or Early Termination

Results and safety

Results posted to the registry on 19 Oct 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Part 1	8	8
Part 2	27	26

Primary outcome: Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and 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. Geometric mean (Geometric Coefficient of Variation). Unit: h*ng/mL

Measure	2 mg Midazolam (Reference) n = 12	2 mg Midazolam + 8 mg Risdiplam QD (Test) n = 11
Day 1 midazolam alone	22.6 (64.7)	–
Day 15 midazolam + risdiplam	–	25.1 (41.3)

2 mg Midazolam (Reference) vs 2 mg Midazolam + 8 mg Risdiplam QD (Test): Ratio of Geometric Least Squares Means: 1.08 (90% CI 0.93 to 1.26)

Population analysed: 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.

Primary outcome: 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

Time frame: Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose. Geometric mean (Geometric Coefficient of Variation). Unit: h*ng/mL

Measure	2 mg Midazolam (Reference) n = 27	2 mg Midazolam + 8 mg Risdiplam QD (Test) n = 26
Day 1 midazolam alone	19.9 (49.0)	–
Day 15 midazolam + risdiplam	–	22.0 (47.7)

2 mg Midazolam (Reference) vs 2 mg Midazolam + 8 mg Risdiplam QD (Test): Ratio of Geometric Least Squares Means: 1.11 (90% CI 1.02 to 1.20)

Primary outcome: Part 2: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone and 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. Geometric mean (Geometric Coefficient of Variation). Unit: ng/mL

Measure	2 mg Midazolam (Reference) n = 27	2 mg Midazolam + 8 mg Risdiplam QD (Test) n = 26
Day 1 midazolam alone	7.65 (48.5)	–
Day 15 midazolam + risdiplam	–	8.96 (40.4)

2 mg Midazolam (Reference) vs 2 mg Midazolam + 8 mg Risdiplam QD (Test): Ratio of Geometric Least Squares Means: 1.16 (90% CI 1.06 to 1.28)

Primary outcome: Part 2: AUCinf of Midazolam Metabolite (1-Hydroxy Midazolam) Alone and 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. Geometric mean (Geometric Coefficient of Variation). Unit: h*ng/mL

Measure	2 mg Midazolam (Reference) n = 17	2 mg Midazolam + 8 mg Risdiplam QD (Test) n = 15
Day 1 midazolam alone	8.66 (34.1)	–
Day 15 midazolam + risdiplam	–	9.41 (33.6)

2 mg Midazolam (Reference) vs 2 mg Midazolam + 8 mg Risdiplam QD (Test): Ratio of Geometric Least Squares Means: 1.12 (90% CI 0.99 to 1.27)

8 secondary outcomes are reported in the full results.

Adverse events

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. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Part 1	0 of 8 (0%)	2 of 8 (25%)	0 of 8
Part 2	0 of 27 (0%)	15 of 27 (55.6%)	0 of 27

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 37148485Cleary Y, Kletzl H, Grimsey P, Heinig K, Ogungbenro K, Silber Baumann HE, Frey N, Aarons L, Galetin A, Gertz M. Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children. Clin Pharmacokinet. 2023 Jun;62(6):891-904. doi: 10.1007/s40262-023-01241-7. Epub 2023 May 6.
Individual participant dataSharing planned: No. Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Clinical Trials study director

Hoffmann-La Roche

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Risdiplam and Midazolam in people with Spinal Muscular Atrophy, run by Hoffmann-La Roche at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and 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). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03988907, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2020.