Phase 1b Study of Tizanidine in Pediatric Patients With Cerebral Palsy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1b Study of Tizanidine in Pediatric Patients With Cerebral Palsy (NCT01405950), a non-randomized phase 1 study. The primary outcome is Pharmacokinetic (PK) Parameter AUC0-8 (Area Under the Concentration-time Curve From Time 0 to 8 Hours) of a Single Dose of Tizanidine at 4 Different Dose Levels in Children and Adolescents With Cerebral Palsy and Mild to Moderate Spasticity..

2. Clinical Question

3. Trial Design

The registry record describes a Phase 1b, single-dose, multicenter, open-label study. Its official title identifies four oral dose levels of tizanidine, and the study model is parallel. Allocation is listed as nonrandomized, and masking as none. These features describe how the study was organized; they do not establish that dose-level groups were comparable in all other respects.

The registry lists an enrollment of 10 and the status as terminated. The recorded start is 2011-05, and primary completion is recorded as 2012-03. The reason for termination is not reported in the registry record. The record names Acorda Therapeutics as sponsor.

The four intervention entries are Zanaflex Capsules. Arm labels are Dose Level 1, Dose Level 2, Dose Level 3, and Dose Level 4, but their descriptions are blank. In particular, the actual dose associated with each label and the way participants came to receive a particular level are not reported in the registry record. The enrollment figure should not be taken to mean that every enrolled participant contributed data to every endpoint; endpoint-specific participant counts are not reported.

The study was framed around pharmacokinetics, safety and tolerability, and pharmacodynamics. The primary outcome was pharmacokinetic, and Cmax was listed as a secondary outcome. The registry lists two outcome measures and zero analyses. That is a statement about what the record contains, not evidence that no analyses were conducted outside the registry. A statistical analysis plan, including prespecified methods for comparing dose levels, is not reported 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetics Population

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.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetic (PK) Parameter AUC0-8 (Area Under the Concentration-time Curve From Time 0 to 8 Hours) of a Single Dose of Tizanidine at 4 Different Dose Levels in Children and Adolescents With Cerebral Palsy and Mild to Moderate Spasticity., measured over Baseline and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours.

The primary endpoint, AUC0-8, represents the area under the concentration-time curve from time 0 to 8 hours after a single tizanidine dose. In general, the area under such a curve is used as a summary of drug exposure across a specified time interval, bringing concentration measurements over time into one pharmacokinetic measure. It is distinct from a measurement at one time point.

The record lists the unit as hour*nanogram/mililiter and identifies the endpoint as a mean, with standard error as the dispersion measure. The stated assessment schedule includes baseline and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours. Baseline is described as immediately before the standardized meal and before tizanidine administration; the other listed times are after administration. The description says PK parameters will be derived using WinNonlin Pro, version 5.0.1 or later.

Pharmacokinetic measures are used to describe how drug concentrations change over time. AUC0-8 was selected as the primary measure, while Cmax was listed as a secondary measure. Numerical AUC0-8 estimates, standard errors, and participant counts for the endpoint are not reported in the registry record. The endpoint description therefore identifies what was intended to be measured, but does not establish the observed exposure at any dose level.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean describe?

For a continuous measure such as AUC0-8, the mean is a summary of the measured values in a group. It provides a central estimate, but by itself does not show how much individual measurements vary or how accurately the group mean is estimated. The registry specifies that the primary endpoint is a mean. It does not report the endpoint means themselves, so their size and pattern cannot be interpreted.

What does the standard error describe?

In general, a standard error describes the sampling uncertainty of an estimated statistic, such as a mean. It is not the same as the spread of individual observations: standard deviation describes variation among observations, whereas standard error concerns the precision of an estimate. The registry identifies standard error as the dispersion measure for AUC0-8, but provides no numerical standard errors. Precision therefore cannot be judged from the registry record.

How should a confidence interval be read?

In general, a confidence interval gives a range of values compatible with an estimate under a stated statistical procedure. Its width conveys precision: a narrower interval indicates more precise estimation than a wider interval, all else equal. A confidence interval is not a guarantee that the true value lies inside the particular interval. No confidence intervals for the primary or secondary pharmacokinetic outcomes are reported in the registry record.

What is a dose-level comparison?

A comparison between dose levels asks how the measured outcome differs across groups assigned to those levels. The study is listed as nonrandomized, and the arm descriptions do not state how participants were assigned. In general, nonrandomized groups can differ in characteristics that also relate to the measured outcome. A simple contrast would not by itself separate a dose association from such differences. The registry record does not report an adjusted model, a prespecified contrast, or another analysis method for evaluating dose-level differences.

The study model is listed as parallel, meaning the registry describes separate groups rather than a crossover structure. The record does not give additional detail about the timing or conduct of group assignment. The labels for four dose levels should not be mistaken for four documented numerical dose values: the actual doses are not reported in the registry record.

What do the scheduled measurements contribute?

The endpoint description lists baseline and measurements at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours. In general, observations at multiple times can characterize a concentration-time profile, while AUC0-8 summarizes exposure over its specified interval. The registry says PK parameters will be derived using WinNonlin Pro, version 5.0.1 or later. It does not report concentration values, the resulting AUC0-8 estimates, or details about how incomplete profiles were handled.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variability is greater than a statistical model assumes. If a model underestimates variability, standard errors may be too small and intervals may be too narrow. Appropriate methods depend on the outcome and model. The record does not identify an inferential model for the continuous pharmacokinetic endpoint, so it is not possible to assess whether over-dispersion was considered or relevant to a particular analysis.

What do the planning illustrations mean?

General sample-size planning can use assumptions about a significance level, allocation, a target effect, and a statistical approximation. The planning assumptions described for this record are a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect expressed as a stated fraction of an observed effect. Such illustrations are planning scenarios, not observed power and not evidence that the trial was designed or analyzed using those assumptions. The record does not report the trial's own sample-size justification, and the nonrandomized design is not the equal-allocation randomized comparison described by those illustrative assumptions.

For a continuous outcome, sample-size illustrations may be expressed as participants per arm for a stated power and target effect. In general, changing the target effect changes the required sample size, as does changing assumptions about variability or allocation. The registry record does not provide a trial-specific statistical plan or report observed endpoint estimates from which to assess the performance of a planning scenario. Any such illustration should therefore be kept separate from the study's reported results.

The registry identifies a Pharmacokinetics Population, but does not define it further or report how many participants contributed to AUC0-8 or Cmax. It is also not reported whether analyses were adjusted, whether participants were excluded from endpoint analyses, or whether missing measurements were imputed. Without those details and the numerical outcomes, the precision and robustness of any pharmacokinetic estimate cannot be evaluated.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Dose Level 1", "Dose Level 2")
n   <- c(7, 2)
m   <- c(5.6, 6.11)
sp  <- c(1.79, 1.29)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Dose Level 1  7  5.600  4.736  1.220  9.980
CARM  Dose Level 2  2  6.110  1.824  -10.281  22.501

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary pharmacokinetic outcome, AUC0-8, and a secondary outcome, Cmax. When a study examines multiple outcomes or multiple comparisons, there can be more than one opportunity to identify a result as statistically notable. In general, a multiplicity strategy may specify which outcomes are confirmatory, how comparisons are ordered, or whether significance thresholds are adjusted. A multiplicity plan is not reported in the registry record. No p-values or analysis results are listed, so the record does not permit an assessment of how multiplicity was handled.

The primary endpoint description gives a measurement schedule and identifies the Pharmacokinetics Population. It does not report endpoint-specific counts, the number of missing concentration measurements, or how incomplete profiles were handled. A missing-data method, including any imputation approach or sensitivity analysis, is not reported in the registry record. The availability of scheduled time points does not establish that every participant had a complete set of measurements.

The record gives an overall enrollment of 10, but does not state how many participants were included in each pharmacokinetic analysis. Adverse-event risk counts are reported for Dose Level 1 and Dose Level 2 only. Counts for Dose Level 3 and Dose Level 4 are not reported in the registry record. The stated Pharmacokinetics Population should not be assumed to have the same membership as the groups used for safety summaries.

The record lists zero analyses. That does not establish that no analysis took place; it means that analyses are not listed in the registry record. Prespecified analysis methods, adjustments for baseline characteristics, handling of missing outcomes, and any interim analyses are not reported in the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event record lists serious events and other events separately for Dose Level 1 and Dose Level 2. For Dose Level 1, 0 of 8 at risk had a serious event recorded, while 1 of 8 at risk had an other event recorded. For Dose Level 2, 0 of 2 at risk had a serious event recorded, while 2 of 2 at risk had other events recorded. These are the registry's counts for the listed groups, not a comparison adjusted for differences between groups.

The record does not list adverse-event group counts for Dose Level 3 or Dose Level 4. It does not provide the event terms for the other events in these groups, and no top serious-event terms are listed. Deaths are not reported in the registry record. The record also does not provide event timing, duration, severity details, relatedness assessments, or information on whether one participant could contribute more than one event. Those details should not be inferred from the counts.

In general, safety counts in a small study describe the recorded events and the group at risk; they do not, by themselves, establish a comparative risk estimate. The nonrandomized allocation further limits like-for-like comparison. The posted figures should therefore be read as descriptive registry entries, not as proof of safety or harm.

13. What the Result Does, and Does Not, Mean

This registry record describes a single-dose, open-label, nonrandomized Phase 1b study of tizanidine at four oral dose levels in pediatric subjects with mild to moderate spasticity due to cerebral palsy. Its primary endpoint was AUC0-8, a measure of concentration-time exposure, and Cmax was listed as a secondary outcome. The record also contains limited adverse-event counts for two dose levels.

What the record does not establish is the observed value of AUC0-8 at any dose level, the size or precision of differences between levels, or the numerical Cmax results. The actual dose values and dose assignment procedures are not reported. Without these details, readers cannot assess the exposure pattern or determine whether any observed differences were statistically or clinically meaningful. A conclusion about effectiveness is not supported by the listed pharmacokinetic endpoint.

Nonrandomized allocation means that dose-level groups cannot be treated as randomized, like-for-like controls. Even if numerical group estimates were available, differences could be associated with participant or procedural differences as well as dose; the registry record does not report an adjustment strategy. The record also does not give a statistical analysis plan, endpoint-specific participant counts, missing-data methods, or the reason the study was terminated.

The safety entries are descriptive and are available only for Dose Level 1 and Dose Level 2. They do not establish comparative safety across all four levels. The registry's terminated status is a status, not an explanation of why the study ended, and should not be interpreted as evidence for a particular outcome.

Overall, the record establishes the study's stated design and intended measurements, but not the numerical pharmacokinetic findings needed to characterize exposure or its precision. It should be read as an incomplete account of results rather than as a basis for claims about treatment benefit, lack of benefit, or safety.

14. Why This Trial Matters Statistically

This study is statistically notable because it asks a pharmacokinetic question in a pediatric population using several dose levels, while the registry record leaves key elements needed for interpretation unreported. AUC0-8 is a defined summary of exposure across time, and Cmax offers a separate peak-concentration measure. Together, the listed outcomes illustrate how pharmacokinetic studies can characterize different aspects of concentration profiles.

The design details matter to interpretation. The study is described as open-label and nonrandomized, with a parallel model. In general, dose-level comparisons are more difficult to interpret when allocation is not randomized, because group characteristics may differ for reasons unrelated to dose. The record does not describe the allocation process or an adjustment strategy. This limits what can be inferred even if group outcomes are listed.

Reporting the endpoint definition and scheduled assessments is useful, but the absence of numerical AUC0-8 and Cmax results leaves the central statistical questions unanswered: what were the estimates, how variable were they, how many participants contributed, and how precise were the estimates? The record identifies a mean and standard error for the primary endpoint but provides neither values nor confidence intervals.

The adverse-event counts also show why denominators and group coverage matter. Entries are available for two dose levels, while corresponding counts for the other two are not reported. These descriptive entries should not be expanded into a comparison across all four levels. Likewise, the terminated status is informative as a record status but cannot explain study conduct or outcome in the absence of a stated reason.

The registry record is therefore useful for understanding the intended design and measurement framework, while also demonstrating the limits of interpreting results when endpoint estimates, analysis details, and participant accounting are absent.

15. 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 results for the primary endpoint are not reported in the registry record. The mean AUC0-8, its standard error, and endpoint-specific participant counts are absent. Numerical Cmax results are also not reported. As a result, neither the observed exposure nor its precision can be described from the record.

The actual doses associated with Dose Level 1 through Dose Level 4 are not reported, and the arm descriptions are blank. Allocation is listed as nonrandomized, but the assignment procedure is not described. This prevents readers from assessing how dose groups were formed and whether participant characteristics could differ across them. A statistical analysis plan, including any adjustment for group differences, is not reported in the registry record.

The record names a Pharmacokinetics Population but does not define membership or state how many participants contributed to each endpoint. Although the enrollment is listed as 10, endpoint-specific accounting and missing-measurement details are not reported. Methods for handling missing data, incomplete concentration profiles, and sensitivity analyses are also not reported in the registry record.

Safety information is limited in the record: adverse-event group counts are listed for Dose Level 1 and Dose Level 2, but not for Dose Level 3 or Dose Level 4. Event terms for other events and deaths are not reported in the registry record. The reason for the terminated status is also not reported.

Finally, the record lists zero analyses, but does not clarify whether analyses were conducted and not entered. These reporting gaps limit assessment of endpoint findings, statistical precision, multiplicity, and robustness. They do not establish that the study had no results or that a particular result occurred.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 1b Study of Tizanidine in Pediatric Patients With Cerebral Palsy — NCT01405950.
• Registry record last updated 2013-06-17; status last verified 2013-06.
• Results first posted 2013-05-13.
• 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.

19. Record Summary

The registry record describes a terminated, multicenter, open-label, nonrandomized Phase 1b study of single-dose tizanidine at four oral dose levels in pediatric subjects 2 to 16 years old with mild to moderate spasticity due to cerebral palsy. The study model is parallel; masking is listed as none. Enrollment is 10. The recorded start is 2011-05, and primary completion is 2012-03. Acorda Therapeutics is listed as sponsor.

AUC0-8 was the primary pharmacokinetic outcome, reported as a mean with standard error specified as the dispersion measure. Cmax was listed as a secondary outcome. Numerical results for both outcomes are not reported in the registry record, nor are endpoint-specific participant counts or an analysis plan. Adverse-event counts are listed for Dose Level 1 and Dose Level 2 only. The reason for termination is not reported in the registry record.