This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Drug-drug Interaction Study With Risdiplam Multiple Dose and Midazolam in Healthy Participants (NCT03988907), a non-randomized phase 1 study. The primary outcome is Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and in Combination With Risdiplam.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03988907 |
| Phase | Phase 1 |
| Condition | Spinal Muscular Atrophy |
| Allocation | Non-Randomized |
| Design model | Sequential |
| Masking | None (open label) |
| Enrollment | 35 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Hoffmann-La Roche |
| Results posted | Yes |
2. Clinical Question
Population
The study enrolled healthy adult male and female participants. The registry record lists spinal muscular atrophy as a condition, but the study summary describes the participants as healthy; it does not say that they had spinal muscular atrophy. The pharmacokinetic population included participants who received at least one dose of risdiplam or midazolam and had at least one postdose pharmacokinetic sample.
Intervention
Part 1 investigated multiple daily doses of risdiplam. Participants were scheduled to receive 5 mg once daily for 14 consecutive days. Part 2 used a sequence in which participants received risdiplam once daily and a single dose of midazolam on two occasions: alone on Day 1 and alongside risdiplam on Day 15. The detailed sequence for the primary endpoint specifies 8 mg risdiplam once daily during the treatment period.
Comparator
For the primary pharmacokinetic question, midazolam administered alone on Day 1 is compared with midazolam administered in combination with risdiplam on Day 15. This is a within-study, sequential comparison, not a randomized comparison between independent groups. The record describes the study as non-randomized and open-label.
Primary question
The primary endpoint is the area under the midazolam concentration-time curve extrapolated from time zero to infinity (AUCinf), measured after midazolam alone and after midazolam with risdiplam. It addresses whether the midazolam exposure measured in the study differs between these two treatment conditions. Numerical estimates of AUCinf for the two conditions and their comparison are not reported in the registry record.
3. Trial Design
This was a Phase I, 2-part, open-label, non-randomized, sequential study. It enrolled 35 participants and is listed as completed. The registry record gives a study start date of 2019-06-18 and a primary completion date of 2019-09-29. The study summary describes the participants as healthy adults.
Part 1 examined safety, tolerability, and pharmacokinetics during multiple dosing of risdiplam. The described regimen was 5 mg once daily for 14 consecutive days. Part 2 investigated the effect of risdiplam on midazolam pharmacokinetics. Participants received 2 mg oral midazolam on Day 1. Risdiplam treatment began on Day 3, and midazolam was given again on Day 15, one hour after the thirteenth risdiplam dose. The primary endpoint description specifies 8 mg risdiplam once daily from Days 3 to 16, with midazolam given on Day 15 alongside risdiplam. This is the dose sequence described for the primary pharmacokinetic assessment; the registry says the Part 2 dose was based on Part 1 results.
Blood samples for pharmacokinetic analysis were collected at predose and multiple postdose times on Day 1 and Day 15. The listed sampling times extend to 24 hours after dosing. The sequential arrangement permits comparison of midazolam pharmacokinetic measurements in the same study context under the two treatment conditions. It is not a randomized, parallel-group comparison, and the registry explicitly cautions that the arms are not a like-for-like control comparison. The record does not report details of a protocol rationale for the sequence, allocation procedures beyond non-randomization, or a statistical analysis plan.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Overall Study
| Stage | Part 1 | Part 2 |
|---|---|---|
| STARTED | 8 | 27 |
| COMPLETED | 8 | 26 |
| NOT COMPLETED | 0 | 1 |
Reasons for not completing this period:
| Reason | Part 1 | Part 2 |
|---|---|---|
| Unable to complete visit | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: 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.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | Part 1 | Part 2 | Total |
|---|---|---|---|---|
| Participants analysed | 8 | 27 | 35 | |
| Age, Continuous | Years | 41 (SD 10.2) | 42 (SD 10.1) | 42 (SD 10.0) |
| Sex: Female, Male: Female | Participants | 4 | 11 | 15 |
| Sex: Female, Male: Male | Participants | 4 | 16 | 20 |
| Race/Ethnicity, Customized: Hispanic or Latino | Participants | 1 | 5 | 6 |
| Race/Ethnicity, Customized: Not Hispanic or Latino | Participants | 7 | 22 | 29 |
| Race/Ethnicity, Customized: Asian | Participants | 1 | 0 | 1 |
| Race/Ethnicity, Customized: Black or African American | Participants | 4 | 15 | 19 |
| Race/Ethnicity, Customized: White | Participants | 3 | 11 | 14 |
| Race/Ethnicity, Customized: Other | Participants | 0 | 1 | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Part 2: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Midazolam Alone and in Combination With Risdiplam, measured over Day 1 and Day 15: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | h*ng/mL |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is midazolam AUCinf, the area under the concentration-time curve from time zero extrapolated to infinity. AUC represents overall drug exposure over time, while the extrapolation extends the estimate beyond the last observed concentration using the pharmacokinetic data. The endpoint was measured after a single 2 mg oral dose of midazolam alone on Day 1 and after a single 2 mg oral dose with risdiplam on Day 15. The registry describes the endpoint in h*ng/mL and reports the intended summary measure as a geometric mean with geometric coefficient of variation as its dispersion measure.
As a general pharmacokinetic concept, AUC is used to characterize exposure rather than the concentration at one isolated time point. Comparing AUC under the two conditions can describe how exposure differs when midazolam is administered with another drug. A geometric summary is commonly used for positive pharmacokinetic measurements that may be skewed: it summarizes values on a multiplicative scale rather than treating equal absolute changes as equivalent across the full measurement range. The geometric coefficient of variation describes relative variability on that scale.
The registry record identifies the endpoint, sampling schedule, population definition, and summary measure, but numerical AUCinf estimates and a numerical comparison are not reported in the registry record. Consequently, the direction and magnitude of any difference, and its statistical precision, cannot be described from the record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The primary endpoint is designed to compare midazolam exposure after a dose given alone with exposure after a dose given during risdiplam treatment. The record describes the sampling schedule and the planned geometric summary, but it does not report the resulting AUCinf values, a treatment comparison, a confidence interval, or a p-value. Therefore, the posted results do not establish from the information in the registry record whether the measured exposure was higher, lower, or similar between the two conditions, or how precisely any difference was estimated.
The comparison is sequential and non-randomized. Midazolam alone was administered on Day 1, while midazolam with risdiplam was administered on Day 15 after risdiplam treatment had begun. Thus, the two measurements are associated with different study days and treatment circumstances. A within-participant comparison can reduce some sources of between-participant variation, but the registry does not describe an analysis that adjusts for time-related changes or other possible influences. The record also does not report the statistical model or the handling of within-participant correlation.
The endpoint is summarized using a geometric mean and geometric coefficient of variation. These describe the distribution and relative variability of the pharmacokinetic measurements, but they do not by themselves show the size or uncertainty of the comparison between conditions. A confidence interval, if reported, would describe the range of values compatible with the data and the analysis under its assumptions; no confidence interval for the primary comparison is reported in the registry record.
The study is Phase I and focuses on pharmacokinetics, safety, and tolerability in healthy participants. The primary endpoint therefore concerns measured midazolam exposure in this study setting. It is not a direct measure of clinical benefit, and the registry does not report outcomes in people with spinal muscular atrophy. The record lists the condition but describes enrollment of healthy participants, so the findings cannot be generalized to patients from this record alone.
The safety results list serious adverse events and other adverse events separately by study part. Serious events and deaths are recorded as zero in both parts, while other adverse events are recorded for some participants. Those counts describe events recorded in the registry and should not be interpreted as proof that no unrecorded or unobserved risks occurred. The registry does not provide the detailed event terms in the information.
9. Statistical Methods Explained
Statistical interpretation begins with the design. This is a non-randomized, sequential study, not a randomized comparison of parallel treatment groups. Participants in Part 2 received midazolam alone on Day 1 and later received midazolam while taking risdiplam. The treatment conditions are therefore observed at different times in the sequence. General statistical reasoning treats such comparisons differently from randomized parallel-group comparisons: treatment condition and study time may be intertwined, and the registry record does not state how any such effects were handled analytically.
What does AUCinf represent?
AUCinf is the area under a drug concentration-time curve from dosing through the observed sampling period, with the remaining portion extrapolated to infinity. In general, the area summarizes concentration over time and is used as a measure of systemic exposure. The extrapolated portion depends on the observed concentrations and the method used to characterize the terminal decline. The registry identifies AUCinf as the primary endpoint and lists blood sampling at predose and specified times through 24 hours after dosing. It does not report the numerical concentration data, the extrapolated fraction, or the calculation details beyond the endpoint definition.
Why use geometric summaries?
Pharmacokinetic measures are positive and can vary proportionally. In general, a geometric mean summarizes values after taking logarithms, then expressing the average back on the original scale. This makes multiplicative differences more natural to describe than differences in raw units when values are right-skewed. The geometric coefficient of variation describes relative dispersion for such measurements. Neither summary alone gives the treatment contrast or its precision. The registry does not report the geometric means, geometric coefficients of variation, or a numerical comparison for the primary endpoint.
What would a confidence interval tell the reader?
In general, a confidence interval describes uncertainty around an estimated quantity under the assumptions of the statistical method. For a comparison of pharmacokinetic exposure, the interval would help show which values of the treatment contrast are compatible with the data and model. Its width reflects precision, which depends on factors such as variability and the amount of usable data. A confidence interval is not a guarantee that the true value lies within its bounds, and it does not by itself address bias from the study design. No primary endpoint confidence interval is reported in the registry record, so precision cannot be assessed from the posted information.
How should variability be understood?
Variation among pharmacokinetic measurements can arise from differences between participants and from variation within a participant or in measurement. For positive, skewed data, relative variability may be more informative than absolute spread. The geometric coefficient of variation is the dispersion measure named for the primary endpoint. General statistical methods may also account for repeated measurements on the same participant, but the registry does not describe whether the analysis used such a model, how observations were paired, or how correlation was represented. Those details are not reported in the registry record.
What does the sample-size illustration mean?
The planning illustration is described as based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. Such calculations are prospective planning illustrations under assumptions; they are not observed power and do not demonstrate that the study had a particular probability of finding an effect. The record does not state that these assumptions were the trial's original design assumptions, and a sample-size justification for the study is not reported in the registry record. The numerical observed effect and the resulting planning values are not reported in the registry information used for this explanation.
More generally, the normal approximation is a simplifying statistical approach. Whether it is appropriate depends on the data structure, distribution, and analysis target. Equal allocation between two arms is an assumption for the illustration, but the clinical study itself is described as sequential and non-randomized. The planning assumptions should therefore not be mistaken for the actual allocation or conduct of this trial.
What analyses can be inferred?
The record lists 14 outcome measures and 6 analyses, but it does not provide enough detail to reconstruct the statistical analysis. It identifies the primary endpoint's summary measure, unit, sampling schedule, and pharmacokinetic population. It does not report a model specification, a treatment-effect scale, a confidence interval method, a missing-data procedure, or a multiplicity adjustment. Those methods should not be inferred from the endpoint name or from general conventions in pharmacokinetic studies.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 14 outcome measures and 6 analyses. The primary endpoint is the Part 2 AUCinf of midazolam alone and in combination with risdiplam. Secondary outcomes include other pharmacokinetic measures for risdiplam and its metabolite, as well as adverse-event outcomes. The record does not report a multiplicity strategy, such as a hierarchy of hypotheses, an adjustment to control the chance of false-positive findings across multiple tests, or an explanation that secondary analyses are descriptive. A multiplicity plan is therefore not reported in the registry record.
The pharmacokinetic population is defined as participants who received at least one dose of study treatment and had at least one postdose pharmacokinetic sample. Parameters were determined using available data. This identifies who could contribute to the pharmacokinetic analyses, but it does not describe how missing samples or incomplete profiles were handled, how many participants contributed to each endpoint, or how the extrapolated part of AUCinf was treated when data were incomplete. Those details are not reported in the registry record.
The record does not state whether an intention-to-treat analysis was planned or used. The study is non-randomized and its primary comparison is sequential, so the usual intention-to-treat framework for randomized trials cannot be assumed to apply in a particular way. Analysis populations for outcomes other than the stated pharmacokinetic population, including safety analyses, are not described in detail. Interim analyses and stopping rules are also not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Part 1 | 0 | 8 | 0.0% |
| Part 2 | 0 | 27 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Part 1 | 0 of 8 |
| Part 2 | 0 of 27 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Part 1 | 2 of 8 |
| Part 2 | 15 of 27 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Part 1 | Part 2 |
|---|---|---|---|
| Headache | Nervous system disorders | 0 of 8 | 5 of 27 |
| Abdominal pain | Gastrointestinal disorders | 1 of 8 | 1 of 27 |
| Nausea | Gastrointestinal disorders | 1 of 8 | 1 of 27 |
| Back pain | Musculoskeletal and connective tissue disorders | 0 of 8 | 2 of 27 |
| Rhinitis allergic | Respiratory, thoracic and mediastinal disorders | 0 of 8 | 2 of 27 |
| Sneezing | Respiratory, thoracic and mediastinal disorders | 0 of 8 | 2 of 27 |
| Upper-airway cough syndrome | Respiratory, thoracic and mediastinal disorders | 0 of 8 | 2 of 27 |
| Extrasystoles | Cardiac disorders | 1 of 8 | 0 of 27 |
In Part 1, the registry records 0 serious adverse events among 8 participants at risk and 2 participants with other adverse events among 8 at risk. In Part 2, it records 0 serious adverse events among 27 participants at risk and 15 participants with other adverse events among 27 at risk. Deaths are recorded as 0 in both parts. These are counts within each study part, not a randomized comparison between treatment groups.
The registry separates serious adverse events from other adverse events. A zero count for serious events means that none were recorded in the listed group; it does not establish that an event was impossible or that no risk exists. The other-adverse-event counts indicate that events were recorded for some participants, but the record information does not identify the event terms, severity, timing, or attribution. The group sizes and treatment sequences also differ, so these counts should not be read as a controlled estimate of comparative safety.
The record does not list serious-event terms in the information reported. It also does not provide detailed exposure-adjusted rates or a statistical comparison of safety outcomes. The counts are descriptive registry data and do not establish causation.
12. What the Result Does, and Does Not, Mean
The study addresses a focused pharmacokinetic question: how midazolam exposure measured by AUCinf compares when midazolam is administered alone and when it is administered with risdiplam. The registry identifies the endpoint, doses, sequence, sampling schedule, summary measure, and pharmacokinetic population. These details explain what the primary outcome was intended to measure.
However, numerical primary endpoint results are not reported in the registry record. Without the estimates for each condition and a comparison with its uncertainty, the direction, size, and precision of any difference cannot be described. No conclusion about a pharmacokinetic interaction can be drawn from the endpoint definition alone.
The study's non-randomized sequential design also matters. The midazolam-alone and combination measurements occurred on different days, and the second measurement followed risdiplam treatment. This design is not equivalent to random assignment to independent groups. The registry does not report an analysis model or adjustment details that would clarify how the sequence and repeated measurements were handled.
The study enrolled healthy participants, according to its summary. Its findings, if interpreted from a complete results record, would apply first to the measured pharmacokinetic and safety outcomes in this study population and setting. The record does not report patient outcomes in people with spinal muscular atrophy. The presence of that condition in the registry does not change the stated healthy-participant population.
The safety counts describe recorded events during the study, including zero serious adverse events and zero deaths in each part, as well as other adverse events in both parts. These descriptive counts are not a complete assessment of all possible risks and do not establish that risdiplam caused or prevented any event. The registry record does not report a comparative safety analysis or detailed event terms in the information reported.
13. Why This Trial Matters Statistically
This trial illustrates the distinction between an endpoint description and an endpoint result. The registry gives a clear pharmacokinetic target—midazolam AUCinf under two dosing conditions—and describes when samples were collected. But without numerical estimates and uncertainty measures, the main statistical comparison cannot be interpreted for direction, magnitude, or precision. A well-defined outcome does not substitute for posted results.
It also illustrates why design details are part of statistical interpretation. The comparison is sequential and non-randomized: midazolam alone was measured before the risdiplam treatment period, and the combination measurement followed that period. The record cautions that the arms are not a like-for-like control comparison. A reader should not treat the conditions as if they came from a randomized parallel-group trial.
The use of geometric means and geometric coefficients of variation reflects a common way to summarize positive pharmacokinetic measurements and their relative dispersion. Yet these summaries need to be accompanied by the actual estimates and a defined contrast to communicate what the study found. The registry identifies the summary approach but does not report the primary endpoint numbers.
Finally, the study's stated population and purpose constrain what the data could address. It was a Phase I study in healthy participants, focused on pharmacokinetics, safety, and tolerability. The listed condition does not make it a patient-outcome trial. The registry information therefore supports describing the planned question and design, while leaving the numerical primary result and its statistical uncertainty unresolved.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
Numerical results for the primary endpoint are not reported in the registry record. The record therefore does not permit an assessment of the observed AUCinf values, the estimated comparison, its confidence interval, or a p-value. It also does not report the numerical results for the listed secondary pharmacokinetic outcomes in the information used.
The study is open-label, non-randomized, and sequential. The primary comparison contrasts midazolam alone on Day 1 with midazolam administered during risdiplam treatment on Day 15. Because treatment condition and study time differ together, the design does not provide a randomized, concurrent control comparison. The registry does not describe an analysis intended to address potential time-related influences or repeated-measure correlation.
The population definition for pharmacokinetic analyses requires at least one dose and at least one postdose sample. The number of participants contributing to each endpoint, the completeness of concentration profiles, and the handling of missing or unusable samples are not reported in the registry record. The record also does not provide details of the extrapolated component of AUCinf or the statistical method used to compare conditions.
The summary describes healthy adult male and female participants, while the registry lists spinal muscular atrophy as a condition. The relationship between that listed condition and the study population is not explained beyond the healthy-participant description. The record does not report results for people with spinal muscular atrophy. Detailed adverse-event terms and a comparative safety analysis are also not reported in the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Drug-drug Interaction Study With Risdiplam Multiple Dose and Midazolam in Healthy Participants — NCT03988907.
- Registry record last updated 2020-10-19; status last verified 2020-09.
- Results first posted 2020-10-19.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
NCT03988907 is a completed Phase I, 2-part, open-label, non-randomized, sequential study sponsored by Hoffmann-La Roche. It enrolled 35 healthy participants and examined multiple-dose risdiplam, safety and tolerability, and the effect of risdiplam on midazolam pharmacokinetics. The registry lists spinal muscular atrophy as a condition, while the study summary describes healthy adult participants.
Part 1 used risdiplam 5 mg once daily for 14 consecutive days. Part 2 compared a single 2 mg dose of midazolam alone with a single 2 mg dose given during risdiplam treatment; the primary endpoint description specifies 8 mg risdiplam once daily in that sequence. The primary endpoint was midazolam AUCinf.
The record reports zero serious adverse events and zero deaths in both parts, with other adverse events recorded in each part. Numerical primary endpoint results, the statistical comparison, and details of multiplicity and missing-data methods are not reported in the registry record.