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 Repeat-Dose Pharmacokinetics Study of NRL-1 in Epilepsy Subjects (NCT02724423), a non-randomized phase 1 study. The primary outcome is Cmax of Diazepam After Single Intranasal Doses of NRL-1 (Diazepam Nasal Spray) Administered to Epilepsy Subjects During the Ictal or Peri-ictal Period.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02724423 |
| Phase | Phase 1 |
| Condition | Acute Repetitive Seizures |
| Allocation | Non-Randomized |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 57 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Neurelis, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
The study concerned epilepsy subjects in seizure-related and non-seizing conditions. The primary outcome description focuses on subjects in the ictal or peri-ictal state, defined as during or immediately following a seizure involving motor activity or altered awareness, and contrasts that condition with the normal, non-seizing state. The registry says 57 subjects received NRL-1 and were included in the safety analysis dataset. It reports 47 subjects per arm (82.5%) in the pharmacokinetic analysis dataset. These descriptions concern different analysis populations; the registry does not explain the apparent difference in their counts.
Intervention
Subjects received NRL-1, described as diazepam nasal spray, by a single intranasal dose. The dose was 5 mg, 10 mg, 15 mg, or 20 mg, determined according to body weight. The registry describes dosing under ictal or peri-ictal and inter-ictal conditions. It does not report the number of subjects receiving each dose or provide dose-specific outcome estimates.
Comparator
The relevant contrast is between pharmacokinetic observations in the seizure-related condition and those in the normal, non-seizing condition. The registry identifies ictal and inter-ictal settings, but this was not a randomized comparison. It therefore should not be read as a randomized, like-for-like contrast between independent treatment groups. The record does not give further detail about the order or timing of condition-specific observations.
Primary question
The primary outcome is the maximum observed plasma concentration of diazepam, or Cmax, after a single intranasal dose of NRL-1 in the ictal or peri-ictal setting. The stated clinical-pharmacology question is whether the seizure-related condition is associated with a different diazepam concentration profile than the normal, non-seizing condition. The registry outcome description says the epileptic condition had minimal impact on pharmacokinetics, but numerical estimates and statistical analyses are not reported in the registry record. The precision and evidential basis of that statement therefore cannot be assessed from the record.
3. Trial Design
This was a Phase 1, open-label, non-randomized, single-group study. The registry lists an enrollment of 57 and a completed status. The start date was 2016-06-30, and the primary completion date was 2019-04-10. Neurelis, Inc. is listed as the sponsor. The study is described as evaluating pharmacokinetics and safety in epilepsy subjects.
The intervention was NRL-1, identified as diazepam nasal spray. The brief study summary and arm descriptions state that a single intranasal dose was administered, with the dose selected according to body weight from 5 mg, 10 mg, 15 mg, or 20 mg. The title refers to a repeat-dose study, while the intervention descriptions specify a single dose. The registry does not explain this difference in wording. The two described settings are ictal, including peri-ictal, and inter-ictal. The record does not establish a randomized allocation between these conditions; it explicitly identifies the allocation as non-randomized.
Because the study was open-label and non-randomized, it was not a blinded randomized trial designed to estimate a treatment effect against a concurrent randomized control. Its purpose, as described, was pharmacokinetic and safety assessment. The condition contrast is relevant to the question of whether seizure-related circumstances coincide with different measured diazepam exposure, but condition comparisons can be affected by differences in the people, timing, or circumstances represented in each set of observations. The registry does not report enough design detail to assess these features.
The registry reports 57 subjects in the safety analysis dataset and 47 subjects per arm (82.5%) in the pharmacokinetic analysis dataset. The relationship between these counts, and how subjects contributed observations across settings, is not explained. The record lists two outcome measures: the primary Cmax outcome and a secondary AUC outcome. It reports zero analyses. Thus, the design and endpoint definitions can be described, but numerical outcome comparisons and their inferential support are not available in the registry record.
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 | NRL-1 |
|---|---|
| STARTED | 57 |
| COMPLETED | 54 |
| NOT COMPLETED | 3 |
Analysis population for the primary outcome, as defined in the registry: Of the 57 subjects who received NRL-1 and were included in the safety analysis dataset, there were 47 subjects per arm (82.5%) in the pharmacokinetic analysis dataset.
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 | NRL-1 |
|---|---|---|
| Participants analysed | 57 | |
| Age, Categorical: <=18 years | Participants | 20 |
| Age, Categorical: Between 18 and 65 years | Participants | 37 |
| Age, Categorical: >=65 years | Participants | 0 |
| Age, Continuous | years | 28.1 (SD 15.33) |
| Sex: Female, Male: Female | Participants | 31 |
| Sex: Female, Male: Male | Participants | 26 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 1 |
| Race (NIH/OMB): Black or African American | Participants | 5 |
| Race (NIH/OMB): White | Participants | 46 |
| Race (NIH/OMB): More than one race | Participants | 5 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Region of Enrollment: United States | participants | 57 |
6. Primary Endpoint
The registry lists the primary outcome as Cmax of Diazepam After Single Intranasal Doses of NRL-1 (Diazepam Nasal Spray) Administered to Epilepsy Subjects During the Ictal or Peri-ictal Period, measured over Blood samples were obtained at 0, 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, and 6 hours after dosing. If feasible, samples were drawn at 8 and 12 hours post-dose but were excluded from PK analysis..
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Geometric Coefficient of Variation |
| Unit | ng/mL |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is Cmax of diazepam after a single intranasal dose of NRL-1, measured in ng/mL. Cmax is the maximum concentration observed in the sampled blood measurements. It is used in pharmacokinetic assessment because it describes the peak concentration reached during the observed sampling period; it does not by itself describe the full concentration-time profile or total exposure.
The registry specifies a geometric mean and geometric coefficient of variation as the summary measures. In general, a geometric mean is useful for measurements that are positive and may vary multiplicatively or have a right-skewed distribution. A geometric coefficient of variation describes relative variability on a multiplicative scale; it is not the same as a confidence interval and does not itself quantify the uncertainty in the estimated mean. These are general statistical interpretations of the named measures.
Blood samples were scheduled at 0, 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, and 6 hours after dosing. Samples at 8 and 12 hours could be drawn if feasible, but were excluded from pharmacokinetic analysis. The stated primary endpoint description concerns Cmax in the ictal or peri-ictal state, compared with the normal, non-seizing state. The actual geometric means, variability estimates, and any uncertainty intervals are not reported in the registry record, so the magnitude and precision of the contrast cannot be evaluated.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies a pharmacokinetic question: whether diazepam exposure after intranasal NRL-1 differs in a seizure-related setting from exposure in the normal, non-seizing setting. It describes Cmax as the primary outcome and AUC as a secondary outcome. The endpoint description states that the epileptic condition had minimal impact on diazepam nasal spray pharmacokinetics. That statement is part of the registry’s narrative, not a numerical result that can be independently evaluated from the reported information.
No Cmax or AUC estimates, variability values, confidence intervals, or test results are reported in the registry record. The record also reports zero analyses. Consequently, it is not possible to determine the size of any observed condition contrast, how variable the measurements were, or how precisely the contrast was estimated. A narrative characterization such as “minimal impact” does not indicate whether the estimate was close to no difference, whether a range of clinically relevant values remained compatible with the data, or whether a prespecified criterion was met. The registry does not report such a criterion.
The stated summaries are geometric means and geometric coefficients of variation. In general, variation in pharmacokinetic measurements can be substantial, and a point estimate alone does not show the uncertainty around it. Confidence intervals, when reported, convey a range of values compatible with the data under the model and assumptions used. No confidence interval is reported. The absence of an interval is not evidence that the estimate is precise or imprecise; it means precision cannot be judged from the registry record.
The comparison is not randomized. This matters because a difference between observations in ictal or peri-ictal and inter-ictal or normal conditions could reflect more than the condition itself. Differences in subject characteristics, observation timing, dose, or other circumstances could contribute. Conversely, a lack of an apparent difference could be difficult to interpret without knowing the analysis approach and the extent of missing or excluded data. These are general considerations for non-randomized condition comparisons, not claims that any particular bias occurred in this study.
The reported analysis populations also warrant care. The record states that 57 subjects were included in the safety analysis dataset and that 47 subjects per arm (82.5%) were in the pharmacokinetic analysis dataset. The registry does not clarify how these counts relate to each other or how the condition-specific analyses were formed. Without that information and without numerical endpoint results, readers should treat the narrative conclusion as an unquantified registry statement rather than a result whose magnitude, uncertainty, or robustness can be assessed.
9. Statistical Methods Explained
The registry identifies the study as Phase 1, open-label, non-randomized, and single-group. Those design labels describe how the study was organized; they do not reveal the statistical model used to analyze the pharmacokinetic outcomes. The registry does not report the analysis method for Cmax or AUC, any covariate adjustment, or a formal hypothesis test. Since no analyses are reported, there is no stated inferential procedure to interpret.
What does Cmax summarize?
Cmax is the highest measured concentration in the observed concentration-time profile. It is a peak-exposure summary, rather than a measure of total exposure across the observation period. As a general concept, a peak measure can depend on both the underlying concentration profile and the times at which samples are collected. The registry lists planned blood sampling from the predose time through 6 hours after dosing, with later samples at 8 and 12 hours excluded from pharmacokinetic analysis even if feasible. This sampling schedule defines the measurements available for the stated outcome; it does not establish which sample was the peak for any subject or condition.
The record names the geometric mean and geometric coefficient of variation. In general, geometric summaries are often used for positive concentration measurements that are skewed or whose variability is better represented proportionally than additively. A geometric mean summarizes a central tendency on a multiplicative scale. A geometric coefficient of variation describes relative spread on that scale. It should not be interpreted as a confidence interval, a standard error, or a test of whether the condition contrast is statistically distinguishable from no difference. The registry does not state the exact calculation or model used.
Why does a confidence interval matter?
In general, a confidence interval communicates uncertainty in an estimated quantity under specified statistical assumptions. Its width reflects how much information the analysis provides together with variability and model structure. A narrow interval can indicate greater precision than a wide interval, but interpretation also depends on the outcome scale and the question being asked. A confidence interval is not a guarantee that the true value lies within its bounds, nor does an interval alone establish whether a difference matters scientifically. No confidence intervals for Cmax or AUC are reported in the registry record, so the precision of the stated conclusion cannot be assessed.
A statistical test, if reported, would address compatibility between the observed data and a specified null hypothesis under a chosen method. A p-value would not quantify the size of a difference, the probability that the null hypothesis is true, or the importance of an observed difference. The record gives no p-values or test descriptions. Therefore, no conclusion about statistical significance can be drawn from the registry entry.
What does non-randomized mean for the contrast?
Random allocation, when used, helps balance measured and unmeasured characteristics between comparison groups on average. This study is explicitly non-randomized, so that protection does not apply to its condition contrast. As a general matter, observations made under different conditions may also differ in timing, participant composition, dose, or other factors. A statistical adjustment can sometimes address recorded covariates, but the registry does not report whether any adjustment was used. It would be inappropriate to assume a particular design or model beyond the labels and descriptions in the record.
The registry describes ictal or peri-ictal and inter-ictal settings, and the primary outcome description refers to comparison with a normal, non-seizing state. It does not report the sequence of conditions, whether the same subjects contributed data under each condition, or how repeated measurements were handled. These details matter statistically. If observations from the same person are related, a suitable analysis may need to account for that correlation; treating related observations as independent can misstate uncertainty. This is a general methodological point, not a claim about the analysis performed.
Why can over-dispersion matter?
In general, over-dispersion occurs when the variability in observed data exceeds what a statistical model assumes. If the model underestimates variability, standard errors may be too small and confidence intervals too narrow. If the model accommodates the observed variability appropriately, uncertainty estimates can be more reliable. Concentration measurements may vary across people and sampling circumstances, but the registry does not report a model, a dispersion assessment, or diagnostics. The named geometric coefficient of variation describes relative variability; it does not establish whether a particular model adequately represented it.
The registry’s sample-size assumptions describe a planning illustration using a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. These are planning assumptions, not evidence about the study’s actual design calculations. No sample-size justification for the trial is reported in the registry record, and no numerical planning results are stated in the record. Such illustrations should not be treated as observed power. In general, post hoc power calculations based on an observed effect do not replace estimates with confidence intervals and can be difficult to interpret.
Overall, the statistical methods that were actually used for the primary and secondary endpoints are not reported in the registry record. The endpoint names and summary measures identify what was intended to be measured, but they are not enough to reconstruct the analysis. In particular, no estimates, uncertainty intervals, model specifications, missing-data handling, or hypothesis tests are available for evaluating the reported narrative conclusion.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists two outcome measures: primary Cmax and secondary AUC. It does not report a statistical analysis for either outcome, and it gives no multiplicity procedure or testing hierarchy. When several outcomes or contrasts are examined, general statistical practice may account for the increased chance of finding an apparently notable result by chance. Whether that adjustment is necessary, and how it should be done, depends on the analysis plan and inferential goals. Neither is described in the registry record, so no multiplicity adjustment should be assumed.
The record says 57 subjects received NRL-1 and were included in the safety analysis dataset. It reports 47 subjects per arm (82.5%) in the pharmacokinetic analysis dataset. It does not explain why the pharmacokinetic analysis population is described this way, how subjects contributed to each condition, or which observations were excluded and why. The scheduled blood samples at 8 and 12 hours, if feasible, were excluded from pharmacokinetic analysis. This is an explicit analysis detail, but the registry does not report the availability of those samples or the handling of missing measurements at other times.
Missing-data methods can affect results when the amount or pattern of missingness is related to outcome values or study conditions. In general, complete-case analysis, imputation, and model-based approaches make different assumptions; the appropriate interpretation depends on what was missing and why. The registry record does not report which approach was used, whether any data were imputed, or whether sensitivity analyses were conducted. It also does not report interim analyses or a detailed statistical analysis plan. These aspects are therefore not reported in the registry record and cannot be assessed.
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 |
|---|---|---|---|
| NRL-1 | 1 | 57 | 1.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| NRL-1 | 0 of 57 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 3% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| NRL-1 | 9 of 57 |
Most frequent serious adverse event terms
| Event term | Organ system | NRL-1 |
|---|---|---|
| Recurrent seizures | Nervous system disorders | 1 of 57 |
| Static encephalopathy | Nervous system disorders | 1 of 57 |
Most frequent non-serious adverse event terms
| Event term | Organ system | NRL-1 |
|---|---|---|
| Dysgeusia | Nervous system disorders | 3 of 57 |
| Nasopharyngitis | Infections and infestations | 2 of 57 |
| Nasal Discomfort | Respiratory, thoracic and mediastinal disorders | 2 of 57 |
| Seizure | Nervous system disorders | 2 of 57 |
Serious events with the highest arm-level rate: recurrent seizures (1.8%), static encephalopathy (1.8%).
The registry reports a single NRL-1 safety group, with 57 subjects at risk for serious adverse events and 1 affected. It separately lists 57 at risk and 9 affected in the other adverse-event category. The record reports 0 deaths. These are descriptive counts in the registry; they do not establish that NRL-1 caused the events or that an event was unrelated to treatment.
The listed serious adverse-event terms are recurrent seizures and static encephalopathy, each reported as 1.8%. These percentages are presented as registry values and are not recalculated. The record does not provide event narratives, timing, severity details beyond the serious-event classification, or an assessment of causal relationship. Nor does the listed information show whether any person experienced more than one event. Counts of affected subjects and event terms should not be treated as interchangeable.
In general, adverse-event summaries depend on how events are defined, collected, coded, and attributed. A count in a study group is a description of what was recorded during the study, not a comparison with an untreated control. Because this was a non-randomized, single-group study, the safety figures do not provide a like-for-like comparative estimate. The registry record does not report additional safety analyses that would support a stronger interpretation.
12. What the Result Does, and Does Not, Mean
The registry establishes that this completed Phase 1 study evaluated pharmacokinetics and safety of NRL-1 in epilepsy subjects. It identifies the primary outcome as diazepam Cmax after a single intranasal dose and describes sampling through 6 hours for pharmacokinetic analysis. It also lists AUC as a secondary outcome. The registry narrative says that the epileptic condition had minimal impact on diazepam nasal spray pharmacokinetics.
That narrative should be distinguished from a quantitative result. The record does not report Cmax or AUC estimates, variability values, confidence intervals, or statistical tests. It therefore does not allow a reader to judge how large the condition contrast was, how uncertain it was, or whether the data were compatible with a range of possible differences. The word “minimal” is not accompanied by a numerical definition or a prespecified threshold in the registry record.
The study does not constitute a randomized treatment comparison. Its condition contrast may be informative for pharmacokinetic context, but non-random allocation and absent details about condition order, participant contributions, and analysis methods limit what can be inferred from the record. The results do not establish a causal effect of seizure state on exposure, and the available information does not permit a detailed assessment of the generalizability of the pharmacokinetic findings.
The safety counts describe recorded events in the NRL-1 group. They are not a comparison with a control group and should not be interpreted as proof that treatment caused or prevented any event. The registry lists serious-event terms and reports no deaths, but does not provide the clinical details or causal assessments needed for a fuller account.
In short, the registry documents the study question, endpoint definitions, sampling schedule, analysis population descriptions, and selected safety counts. It does not provide the numerical pharmacokinetic results or the statistical methods needed to evaluate the narrative claim about minimal impact. No treatment recommendation follows from these registry entries.
13. Why This Trial Matters Statistically
This study addresses a practical pharmacokinetic question: whether measured diazepam exposure differs between seizure-related and non-seizing conditions in epilepsy subjects. Pharmacokinetic assessments are often important when a treatment is administered in circumstances that may differ from those under which it is ordinarily studied. The registry’s focus on Cmax and AUC reflects two complementary summaries: peak concentration and overall exposure. Neither alone fully describes every aspect of a concentration-time profile.
Statistically, the study illustrates the distinction between an outcome definition and an estimable result. The registry specifies what was measured, the units, the named summary statistics, and the sampling times. But it does not report the actual estimates, their uncertainty, or the analytical method. Without those elements, readers cannot assess whether the condition contrast was small, whether it was estimated precisely, or how sensitive the conclusion may be to analytical choices.
The non-randomized, open-label design also makes it important to separate pharmacokinetic description from causal inference. Measurements in different conditions can be useful, but interpretation depends on how the observations were obtained and analyzed. The record does not explain the condition sequence, within-subject contribution, or adjustment strategy. These omissions are consequential for understanding variability and uncertainty, not merely reporting details.
The record also distinguishes safety and pharmacokinetic populations, reporting 57 subjects in the safety dataset and 47 subjects per arm (82.5%) in the pharmacokinetic dataset. That distinction reinforces why analysis populations should be clearly defined and linked to outcomes. Without an explanation of the counts or numerical endpoint results, the registry’s narrative conclusion cannot be independently appraised. The study is statistically relevant as an example of how registration information may document intended measurements while leaving key elements for evaluating precision and evidence unavailable.
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.
The most immediate limitation is that numerical primary and secondary outcome results are not reported in the registry record. The outcome description states that the epileptic condition had minimal impact on pharmacokinetics, but no Cmax or AUC values, geometric coefficients of variation, confidence intervals, or tests are available to quantify or evaluate that statement.
The registry does not describe the statistical analysis used for either outcome. It does not report model specifications, handling of repeated or paired observations, covariate adjustment, missing-data methods, or sensitivity analyses. The study is non-randomized and open-label, and the record does not state the sequence or timing of condition assessments. These limitations restrict interpretation of a condition contrast and its uncertainty.
The analysis population descriptions are also not fully reconciled. The record reports 57 subjects in the safety analysis dataset and 47 subjects per arm (82.5%) in the pharmacokinetic analysis dataset, without explaining the relationship between those counts or how subjects contributed under each condition. Dose-specific participation and results are not reported. Although the sample-size assumptions describe a planning illustration, the registry does not report the trial’s own sample-size justification.
There is also a wording difference: the study title refers to repeat-dose pharmacokinetics, while the brief summary and intervention descriptions state that subjects received a single intranasal dose. The registry does not explain this difference. Finally, blood samples at 8 and 12 hours were excluded from pharmacokinetic analysis even if feasible, and the record does not report whether such samples were collected. These features should be considered when interpreting what the registered information can establish.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Repeat-Dose Pharmacokinetics Study of NRL-1 in Epilepsy Subjects — NCT02724423.
- Registry record last updated 2021-10-05; status last verified 2021-08.
- Results first posted 2021-10-05.
- 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
NCT02724423 is a completed, Phase 1, open-label, non-randomized, single-group study sponsored by Neurelis, Inc. It enrolled 57 subjects and evaluated NRL-1, described as diazepam nasal spray, in epilepsy subjects. The registry describes a single intranasal dose of 5 mg, 10 mg, 15 mg, or 20 mg based on body weight, in ictal or peri-ictal and inter-ictal settings.
The primary outcome was diazepam Cmax, with AUC listed as a secondary outcome. Blood sampling was scheduled through 6 hours for pharmacokinetic analysis; later samples at 8 and 12 hours, if feasible, were excluded. The registry reports 57 subjects in the safety analysis dataset and 47 subjects per arm (82.5%) in the pharmacokinetic analysis dataset. It lists serious and other adverse-event counts and reports 0 deaths.
Numerical Cmax and AUC results, uncertainty estimates, and statistical analyses are not reported in the registry record. The registry’s narrative characterization of minimal pharmacokinetic impact therefore cannot be assessed for magnitude or precision from the recorded results.