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Partial Onset Seizures Phase 2, Phase 3 Continuous Endpoint NCT00975715

Efficacy, Safety and Tolerability of TRI476 (Oxcarbazepine) in Children With Inadequately Controlled Partial Onset Seizures: Complete Statistical Analysis

This randomized, double-blind, placebo-controlled trial evaluated adjunctive TRI476 in children with inadequately controlled partial onset seizures. The primary comparison was the registry-defined change in seizure frequency, with a separate reported comparison for participant response.

Trial start: 2009-09  ·  Enrollment: 99  ·  Sponsor: Novartis Pharmaceuticals
Scope of this record

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 Efficacy, Safety and Tolerability of TRI476 (Oxcarbazepine) in Children With Inadequately Controlled Partial Onset Seizures (NCT00975715), a randomized phase 2, phase 3 study. The primary outcome is Percent Change in Partial Onset Seizure Frequency Per 28 Days From Baseline to the Double-blind Phase, by Treatment Group.

99
Enrollment
Phase 2, Phase 3
2
Arms
In the primary outcome
-17.67
Mean difference
TRI476
-44.78–9.44
95% CI
Two-sided
FeatureRegistry value
ClinicalTrials.gov identifierNCT00975715
PhasePhase 2, Phase 3
ConditionPartial Onset Seizures
AllocationRandomized
Design modelParallel
MaskingDouble
Enrollment99
Arms in the primary outcome2
Lead sponsorNovartis Pharmaceuticals
Results postedYes

2. Clinical Question

The clinical question is whether adding TRI476 to participants’ existing antiepileptic treatment is associated with a different change in partial onset seizure frequency than adding placebo. The registry describes the intended population as children with inadequately controlled partial onset seizures, and the study as an evaluation of short-term efficacy, safety and tolerability.

Population

Children with inadequately controlled partial onset seizures. The primary outcome population is described as the Full Analysis set, including participants who received study drug.

Intervention

TRI476, identified in the title as oxcarbazepine, given as adjunctive therapy. Participants received TRI476 based on body weight, with titration up to the maintenance dose, alongside their traditional antiepileptic dosage.

Comparator

Placebo to TRI476, alongside participants’ traditional antiepileptic dosage. The placebo group’s dosing regimen was not adjusted.

Primary question

How did the registry-defined percent change in partial onset seizure frequency per 28 days from screening to the double-blind phase differ between the TRI476 and placebo groups?

The record describes random allocation, double masking and a parallel-group design. Its summary says participants were to receive the assigned treatment for 8 weeks. The posted results report group means and standard deviations for the primary measure, plus an unadjusted recalculation of the between-group mean difference and its confidence interval. These results describe the recorded comparison; they do not by themselves establish the cause of every observed change or address outcomes that were not numerically reported.

3. Trial Design

The registry identifies NCT00975715 as a randomized, double-blind, parallel-group study of TRI476 versus placebo in children with inadequately controlled partial onset seizures. The study is listed as Phase 2 and Phase 3. Novartis Pharmaceuticals is named as sponsor. The record gives a start date of 2009-09, primary completion of 2012-10 and a completed status.

Enrollment is recorded as 99. The brief summary describes a planned 1:1 allocation and treatment for 8 weeks. Participants assigned to TRI476 received weight-based treatment with titration up to a maintenance dose, in addition to their traditional antiepileptic dosage. Participants assigned to placebo received placebo to TRI476, with no adjustment to their dosing regimen, also alongside traditional antiepileptic treatment. Thus the intended contrast concerns adding TRI476 rather than replacing background treatment.

The primary outcome is reported for 47 participants in the TRI476 group and 51 in the placebo group. The primary outcome population is called the Full Analysis set and is defined in the record as participants who received study drug. The record does not report further detail about exclusions from that set, adherence, withdrawals, or how missing outcome measurements were handled.

Named secondary outcomes include partial seizure frequency by study period, participant response during the double-blind phase, change by seizure type, and Clinical Global Impression of Change at final assessment. Numerical results are posted for the response outcome, while the other named secondary outcomes do not have numerical results in the registry record. The registry record does not report the original sample-size justification, detailed randomization procedures, allocation concealment procedures, or a fuller 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.

Before assignment: Participants kept same dosage of their traditional antiepileptics prior to screening and throughout the study. They received TRI476 or placebo in a 1:1 ratio. TRI476 dose was increased gradually, based on body weight during the titration period (day 0- 14). The tolerated dose was given during the maintenance period (up to day 56).

Titration Period

StageTRI476Placebo
STARTED4851
COMPLETED4151
NOT COMPLETED70

Reasons for not completing this period:

ReasonTRI476Placebo
Adverse Event60
Protocol Violation10

Maintenance Period

StageTRI476Placebo
STARTED4151
COMPLETED3950
NOT COMPLETED21

Reasons for not completing this period:

ReasonTRI476Placebo
Adverse Event21

Analysis population for the primary outcome, as defined in the registry: The Full Analysis set included all participants who received study drug.

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.

CharacteristicUnitTRI476PlaceboTotal
Participants analysed485199
Age, Continuousyears9.8 (SD 2.91)9.2 (SD 2.83)9.5 (SD 2.87)
Sex: Female, Male: FemaleParticipants222446
Sex: Female, Male: MaleParticipants262753

6. Primary Endpoint

The registry lists the primary outcome as Percent Change in Partial Onset Seizure Frequency Per 28 Days From Baseline to the Double-blind Phase, by Treatment Group, measured over screening and 28 days.

ElementRegistry entry
Result typeMean
Measure of spreadStandard Deviation
Unitpercentage change per 28 days
Endpoint classificationContinuous Endpoint

The primary endpoint is the percent change in partial onset seizure frequency per 28 days from the screening phase to the double-blind phase, reported by treatment group. Seizure frequency is expressed per 28 days by dividing the number of partial onset seizures in a phase by the number of days in that phase and multiplying by 28, according to the registry definition. Standardizing frequency to a common period can make group summaries more comparable when observation periods differ.

The record defines the percent-change calculation as the double-blind-phase frequency minus the screening-phase frequency, divided by the double-blind-phase frequency, then multiplied by 100. This is the stated registry formula and is not the familiar form that uses baseline frequency as the denominator. Interpretation should therefore follow the record’s specific definition rather than silently substituting another formula. Under the reported convention, negative values indicate a lower frequency in the double-blind phase relative to screening, while positive values indicate a higher frequency.

The outcome is summarized as a mean with standard deviation. A mean describes the group’s average recorded change, while the standard deviation describes variability among participants. Seizure-frequency outcomes can vary considerably between participants, so the spread matters alongside the average. The endpoint is used to compare the groups’ recorded changes during the double-blind treatment period; it does not alone describe all aspects of seizure burden, safety, or longer-term outcomes.

7. Results Posted in the Registry

Mean difference: TRI476

-17.67

95% CI: -44.78 to 9.44

Recalculated from the posted summary statistics

Primary outcome by arm, with 95% confidence intervals
Primary outcome by arm with 95% confidence intervals-26.6-13.20.213.727.140.5TRI476 (n=47)Placebo (n=51)percentage change per 28 days (95% CI)
Treatment effect versus the control arm
Forest plot of mean difference vs control (95% CI)TRI476-49-37-24-111.2014mean difference vs control (95% CI)

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Secondary outcomeTypeEffect measureEstimate (95% CI)Planning size, 80% power
Percent of Participants With Response During Double-blind Phase, by Treatment GroupBinary EndpointRisk difference+19.5 pts (6.3 to 32.7)48 per arm

Percent of Participants With Response During Double-blind Phase, by Treatment Group

Treatment effect versus the control arm
Forest plot of risk difference (percentage points) vs control (95% CI)TRI476-2.624.9713202835risk difference (percentage points) vs control (95% CI)

The registry lists several secondary outcomes, covering seizure frequency over study periods, participant response, change by seizure type, and clinical impression of change. Among these, numerical comparative results are reported for participant response. Numerical results for the other named measures are not reported in the registry record, so an overall pattern across every secondary outcome cannot be established from the posted results.

The reported response comparison points in a direction different in strength from the primary continuous comparison: its unadjusted recalculated risk-difference interval excludes no difference, while the primary mean-difference interval includes no difference. These findings are not contradictory by definition. Response classifies participants according to a threshold, whereas the primary endpoint summarizes continuous changes in frequency. Dichotomizing an outcome can produce a different comparison from analyzing its continuous values, and the outcomes need not have identical sensitivity or precision.

Secondary outcomes are usually interpreted with more caution because multiple outcomes create multiple opportunities for apparently noteworthy findings. If no adjustment or prespecified hierarchy is reported, an unadjusted p-value does not account for that broader set of comparisons. The registry record does not report a multiplicity procedure or a prespecified order governing the secondary analyses. The response result is therefore useful as supporting information, but it cannot independently settle the primary question or be treated as confirmatory without regard to the analysis plan and multiplicity.

The listed secondary outcomes may offer complementary perspectives on frequency, response, seizure type and clinical impression. However, absent numerical results prevent assessment of whether those perspectives were consistent with one another. The record lists 4 secondary outcomes and reports no analyses in its analyses listing. A lack of posted numerical results should not be interpreted as evidence that an outcome showed no difference; it means the result is not reported in the registry record.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

9. Statistical Interpretation

Clinical Biostats interpretation

The primary group means were -2.85 for TRI476 and 14.82 for placebo. The unadjusted recalculated mean difference, defined as TRI476 minus placebo, was -17.67 percentage points, with a 95% confidence interval from -44.78 to 9.443 and an unadjusted p-value of 0.201. The point estimate is in the direction of a lower registry-defined percent change in the TRI476 group, but the interval includes no difference and also allows estimates in the opposite direction. The posted primary comparison therefore does not precisely distinguish the groups using this unadjusted calculation.

The standard deviations were 63.55 for TRI476 and 73.33 for placebo, substantially wider than the separation between the group means. That pattern indicates considerable participant-level variability relative to the average group contrast. It also helps explain why the confidence interval around the difference is broad: the mean estimates are uncertain, rather than being precise estimates of a narrow range of possible differences.

The separate response outcome has a different pattern. The registry reports response in 23.4% of participants receiving TRI476 and 3.9% receiving placebo. The unadjusted recalculated risk difference is 0.195, with a 95% confidence interval from 0.063 to 0.327 and an unadjusted p-value of 0.005. That interval is above no difference, but this is a secondary comparison and should not be treated as interchangeable with the primary continuous endpoint. The registry record does not report adjusted analyses for this outcome or a multiplicity procedure governing interpretation of secondary results.

These are comparisons of randomized groups, but the numerical estimates posted for the comparisons are unadjusted recalculations from summary statistics. They are not a substitute for a sponsor-reported analysis where such an analysis exists. The record reports no discrepancy flag. The primary result and the response result address distinct summaries of seizure outcomes, and their different patterns do not mean that one cancels out the other. They instead underline the importance of the endpoint definition, statistical uncertainty, and the status of each comparison as primary or secondary.

The registry also names additional secondary measures, including seizure frequency by study period, seizure type, and clinical impression of change. Numerical results for those measures are not reported in the registry record. The results should consequently be read as a limited account of the trial’s posted efficacy outcomes, not as a complete description of every planned or collected measure. The short treatment period and lack of reported longer-term results further restrict what can be inferred about outcomes beyond the study period.

10. Statistical Methods Explained

The primary measure is continuous: each participant contributes a percent-change value, and the registry reports a group mean and standard deviation. A mean difference compares the average value in one group with the average in the other. Here, the reported recalculation uses TRI476 minus placebo, so a negative estimate points toward a lower mean value in the TRI476 group under the registry’s outcome definition. It does not mean that every participant had a lower value.

What does the standard deviation describe?

A standard deviation describes how dispersed participant values are around the group mean. It is not the uncertainty of the mean difference and is not a confidence interval. The reported standard deviations, 63.55 for TRI476 and 73.33 for placebo, indicate substantial variation in the individual outcome values. When individual responses vary, a group average can conceal very different experiences among participants. That is why the mean should be read alongside the spread and the uncertainty around the between-group estimate.

What does a mean difference represent?

The recalculated mean difference is -17.67 percentage points. It summarizes the separation between the two group averages on the registry-defined scale. A difference in means retains the original measurement scale, which can make it easier to relate the estimate to the endpoint than a standardized effect measure. It remains a summary contrast: it does not describe the distribution of all participant-level values, and it does not establish why an individual’s seizure frequency changed.

How should the confidence interval be read?

A confidence interval expresses uncertainty around an estimate under the assumptions of the calculation. The interval from -44.78 to 9.443 is wide and includes no difference. It therefore indicates that the posted summary statistics are compatible with a range of possible group contrasts, including a contrast in either direction. The interval does not assign a probability to the true effect being inside its endpoints, and its width does not indicate that all values in the interval are equally plausible. The interval should be considered with the point estimate and the design, not reduced to a pass-or-fail label.

What does the p-value add?

The unadjusted p-value of 0.201 is a measure of how unusual results at least as inconsistent with a no-difference model would be under the model’s assumptions. It is not the probability that there is no effect, nor does it measure the size or clinical importance of a difference. A p-value does not capture the full range of plausible effects; the confidence interval is more informative about precision. The registry does not report an adjusted primary analysis, and the recalculation is explicitly unadjusted.

How does the response comparison differ?

Response is a binary outcome: participants are classified as responders or non-responders under the study’s definition. The reported group percentages are 23.4% and 3.9%. The recalculated risk difference is the absolute difference between the group response proportions, expressed on the proportion scale. Its confidence interval, from 0.063 to 0.327, does not include no difference, and the unadjusted p-value is 0.005. This comparison describes the response endpoint, not the continuous primary endpoint, and its statistical evidence should be interpreted in light of its secondary status and the absence of a reported multiplicity adjustment.

For binary outcomes, the risk difference is an absolute contrast in proportions. Other measures, such as a risk ratio or odds ratio, describe relative contrasts and can give a different impression of magnitude, especially when outcomes are uncommon. The record includes recalculated relative measures for response, but the confidence interval for the risk difference offers a direct absolute-scale interpretation. None of these measures removes uncertainty or resolves the question of whether the outcome definition captures all relevant aspects of seizure control.

What analysis details are unavailable?

The registry lists the primary outcome as a mean with standard deviation and identifies the Full Analysis set as participants who received study drug. It does not report the exact statistical model used for the sponsor’s primary analysis, covariate adjustment, handling of missing outcome data, transformations, sensitivity analyses, or interim analyses. Those details should not be inferred from the summary statistics. General statistical practice may use models or transformations when continuous outcomes are skewed or over-dispersed, but the record does not say whether any such approach was used in this trial. Over-dispersion, in general, means that variability is larger than assumed by a particular model; an unsuitable variance assumption can make standard errors and confidence intervals unreliable.

The recalculated comparisons are simple unadjusted summaries from the posted group statistics. They are useful for understanding the direction, scale, and rough precision of the contrast, but they do not reproduce undocumented features of a sponsor analysis. Statistical interpretation should therefore distinguish the registry’s descriptive outcome summaries from the additional unadjusted calculations and avoid attributing methods to the trial that are not reported in the registry record.

11. Confidence Intervals and Precision

The primary mean difference is -17.67 percentage points, with a 95% confidence interval from -44.78 to 9.443. The interval is wide, extending across no difference and including values on either side of it. This means the summary statistics do not pin down the size or direction of the group contrast with high precision. The point estimate alone gives only one value from a broader range of estimates compatible with the calculation.

The variation within groups is also important. Standard deviations were 63.55 in the TRI476 group and 73.33 in the placebo group, compared with group means of -2.85 and 14.82. The observed individual-level spread is large relative to the mean separation. This does not establish that the measure is unsuitable, but it makes clear why the group averages should not be treated as representative of every participant’s outcome.

For the response comparison, the risk difference is 0.195, with a 95% confidence interval from 0.063 to 0.327. This interval is entirely above no difference under the unadjusted calculation, but its width still leaves uncertainty about the magnitude of the contrast. It is a secondary result and is not a replacement for the primary endpoint’s less precise estimate.

Confidence intervals describe statistical uncertainty under the calculation’s assumptions. They do not account automatically for missing data, multiplicity, measurement limitations, or biases not represented in the calculation. Since the registry does not report detailed missing-data methods or a multiplicity plan, the stated intervals should not be interpreted as resolving those issues. Precision is one part of interpretation, alongside endpoint relevance, study design and completeness of reporting.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

Effect to detectParticipants per arm, 80% powerParticipants per arm, 90% power
100% of the observed effect239319
75% of the observed effect424567
50% of the observed effect9531,275
Sample size needed versus the size of the effect to detect
Sample size needed versus size of effect to detect2005001,0002,00040%60%80%100%80% power90% powersize of effect to detect, as % of the effect observed (log vertical scale: participants per arm)
Treat these figures cautiously. The observed difference is imprecise: its confidence interval includes no difference at all. A sample size built on a noisy estimate can be far too small or too large, so the smaller-effect rows are the more cautious guide.
Method and assumptions. Two-sided α = 0.05, 1:1 allocation, two-sample comparison of means with the pooled standard deviation. Calculated for the comparison: TRI476.

The planning figures are participants per arm, rather than total events. They are illustrative calculations based on the observed effect, not the trial’s original design justification. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The original trial’s sample-size assumptions and justification are not reported in the registry record.

For the primary continuous comparison, planning for 100% of the observed effect gives 239 participants per arm for 80% power and 319 participants per arm for 90% power. Planning for 75% of the observed effect gives 424 participants per arm for 80% power and 567 participants per arm for 90% power. Planning for 50% of the observed effect gives 953 participants per arm for 80% power and 1,275 participants per arm for 90% power.

In plain terms, the 80% power column gives the estimated number of participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions, if that effect is real. The 90% column gives the corresponding estimate for a design with a 90% chance. A smaller effect is harder to distinguish from random variation, so the listed planning requirements rise as the assumed effect becomes smaller. These figures are planning illustrations, not observed power.

The values are based on the recalculated observed contrast and are not evidence that the original trial was designed around those assumptions. Observed effects from a study can be unstable, particularly when estimates are imprecise. A planning calculation based on them should not be treated as a recommended design without independent assumptions about the effect worth detecting, the outcome variability, and the analysis plan.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z1−α/2 = 1.960) and the desired power (z1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n = 2 (z1−α/2 + z1−β)2 σ2 / Δ2

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

  1. Observed difference Δ = -17.670; pooled standard deviation σ = 68.817.
  2. n = 2 × (1.96 + 0.842)2 × 68.8172 / -17.6702 = 238.1, rounded up to 239 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -17.67                      # observed difference in means
sigma <- 68.8172984086911                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(975715)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 239 (80% power), 319 (90% power)
 75% of observed effect: n per arm = 424 (80% power), 567 (90% power)
 50% of observed effect: n per arm = 953 (80% power), 1,275 (90% power)
power.t.test: 239.1 
Simulated power at n = 239 per arm: 0.791 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when several outcomes, time points, subgroups, or comparisons are examined. Even when each individual test uses a conventional significance threshold, considering many tests increases the chance that at least one will appear statistically notable by chance. Methods such as adjustment procedures or a prespecified hierarchy can address this issue, but the registry record does not report whether a multiplicity strategy was planned or used. The unadjusted secondary comparison should therefore be treated as exploratory or supportive rather than as a standalone confirmatory finding.

The record names several secondary measures and provides numerical results for the response outcome, but does not report numerical results for the other named measures. It also lists 0 analyses in its analysis listing. This does not establish that no analyses were performed; it means that analyses are not listed in that registry field. The detailed statistical plan, including any outcome hierarchy, interim analyses, subgroup analyses, or sensitivity analyses, is not reported in the registry record.

The Full Analysis set is defined as participants who received study drug. That definition identifies the reported primary population, but it does not clarify whether every randomized participant was included, how participants without evaluable endpoint data were treated, or whether the analysis followed an intention-to-treat principle. The record does not report reasons for missing measurements, missing-data methods, imputation, or sensitivity checks. Missingness can affect estimates if the availability of measurements is related to outcomes or treatment, so these details matter for interpreting the reported comparisons.

The group sizes for the primary outcome are 47 and 51, while enrollment is recorded as 99. The record does not explain the relationship between enrollment and the outcome denominators or report participant flow in sufficient detail to account for that difference. It would be inappropriate to infer the reasons from the available counts. Without flow and missing-data information, the reader cannot fully assess attrition or determine how robust the results are to alternative assumptions about unavailable outcomes.

These reporting gaps do not invalidate the posted estimates, but they limit assessment of how the trial handled multiple questions and incomplete data. The confidence intervals and p-values describe the stated unadjusted calculations; they do not account for unreported analysis choices.

15. Safety Results

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

ArmParticipants with serious adverse eventsParticipants at riskPercentage
TRI4761472.1%
Placebo1512.0%
Participants with at least one serious adverse event
Serious adverse events by armTRI4762.1%Placebo2.0%% of participants with at least one serious adverse event

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 3% reporting threshold.

ArmParticipants affected of at risk
TRI47638 of 47
Placebo27 of 51

Most frequent serious adverse event terms

Event termOrgan systemTRI476Placebo
BronchopneumoniaInfections and infestations0 of 471 of 51
SomnolenceNervous system disorders1 of 470 of 51

Most frequent non-serious adverse event terms

Event termOrgan systemTRI476Placebo
SomnolenceNervous system disorders20 of 475 of 51
NasopharyngitisInfections and infestations5 of 479 of 51
Upper respiratory tract infectionInfections and infestations4 of 475 of 51
VomitingGastrointestinal disorders5 of 473 of 51
RashSkin and subcutaneous tissue disorders4 of 472 of 51
NauseaGastrointestinal disorders2 of 473 of 51
InfluenzaInfections and infestations2 of 473 of 51
ConjunctivitisEye disorders2 of 472 of 51
PyrexiaGeneral disorders2 of 472 of 51
Upper respiratory tract inflammationRespiratory, thoracic and mediastinal disorders2 of 472 of 51

Serious events with the highest arm-level rate: somnolence (2.1%), bronchopneumonia (2.0%).

Do not overextend the safety comparison. Serious-adverse-event counts are safety observations, not efficacy outcomes, and should not be combined with the primary result into a single benefit-risk number.

The registry reports serious adverse events affecting 1 participant at risk in the TRI476 group and 1 participant at risk in the placebo group. The corresponding at-risk group sizes are 47 and 51. These counts describe the posted serious-event figures; they do not provide enough detail by themselves to compare event types, timing, duration, severity beyond the serious classification, or attribution to study treatment.

The record lists Somnolence at 2.1% and Bronchopneumonia at 2.0% among the top serious-event terms. It does not state in the provided serious-event summary which group those terms correspond to, so they should not be assigned to a treatment arm based on these entries. The record also reports other adverse events affecting 38 participants at risk in the TRI476 group and 27 at risk in the placebo group. These figures are counts, not a detailed account of event severity or clinical course.

Deaths are not reported in the registry record. Serious adverse event counts should be read as safety summaries within the recorded follow-up and population, not as complete evidence about all possible risks. The brief study duration was 8 weeks, and the registry does not provide detailed information about exposure, event narratives, discontinuations due to adverse events, or longer-term safety follow-up.

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

The posted primary estimate describes a lower mean registry-defined percent change in seizure frequency for TRI476 than placebo, but its confidence interval is broad and includes no difference. This means the available summary statistics leave substantial uncertainty about the size and direction of the primary contrast. The unadjusted p-value does not resolve that uncertainty, and should not be treated as a direct measure of clinical importance.

The response endpoint offers a separate, more favorable unadjusted comparison for TRI476. It is a secondary result, has its own outcome definition and is not equivalent to the primary continuous measure. The record does not report a multiplicity plan, and numerical findings for several other named secondary outcomes are absent. It is therefore important to distinguish a notable secondary comparison from a conclusive overall assessment across all outcomes.

The randomized, double-blind, placebo-controlled parallel design is intended to support a fair comparison between groups, while both groups continued traditional antiepileptic treatment. The results concern adjunctive TRI476 versus adjunctive placebo within this study’s participants and period. They do not establish what would happen in other populations, with other background treatments, or over longer follow-up. The registry describes treatment for 8 weeks, and longer-term outcomes are not reported in the registry record.

The numerical summaries do not show how individual participants responded, how outcomes varied over time for each person, or whether changes were sustained. The primary endpoint’s registry formula also defines percent change using the double-blind-phase value as the denominator, so interpretation should adhere to that particular definition. Further, missing-data handling and detailed analysis methods are not reported, limiting independent assessment of the estimates.

These findings are statistical descriptions of posted trial results, not medical advice and not a complete account of benefits or harms. They do not, on their own, determine treatment choices or establish that a treatment works or does not work. A balanced reading considers the primary estimate, its uncertainty, the secondary response result, safety reporting, study duration, and gaps in the registry record.

17. Why This Trial Matters Statistically

This trial is statistically instructive because the primary outcome and the response outcome give different levels of apparent evidence. The primary endpoint is continuous and summarized as a mean difference, while response is binary and summarized using proportions and a risk difference. These analyses answer related but distinct questions. A secondary endpoint can appear more clearly separated even when the primary comparison remains imprecise, particularly when the endpoint definitions and statistical properties differ.

The primary estimate also illustrates why a point estimate should not be read in isolation. Its direction favors a lower mean value in the TRI476 group under the registry’s definition, but the confidence interval includes both no difference and estimates in the opposite direction. The wide standard deviations show considerable variation in participant outcomes. The interval and spread provide context that a single mean difference cannot convey.

The case also demonstrates the importance of checking how an endpoint is defined. The registry’s percent-change formula uses the double-blind-phase frequency in the denominator. Readers accustomed to a baseline-denominator formula should not assume that the same convention was used. A precise statistical description depends on the actual definition, not on the label alone.

Finally, the registry’s gaps matter for interpretation. Multiplicity procedures, missing-data handling, detailed analysis methods, original sample-size justification, and numerical results for several secondary measures are not reported. The planning illustrations based on the observed effect can help explain how smaller target effects require more participants, but they do not reconstruct the trial’s original design. Together, these features show why statistical significance, precision, endpoint construction, and reporting completeness need to be considered together.

18. Limitations

The primary comparison is imprecise: its confidence interval is wide and includes no difference. The group standard deviations are large relative to the separation between the means, indicating substantial variability in the recorded outcome. The posted summaries do not provide participant-level distributions, so the influence of unusual values or the shape of the outcome distribution cannot be assessed from the registry record.

The endpoint formula has a definition-specific feature: the double-blind-phase frequency is used as the denominator for percent change. That is the registry’s stated formula and should not be replaced with a more familiar convention. The record does not explain the rationale for this choice, and the formula’s implications for interpretation should be kept in mind when comparing the outcome with results defined differently elsewhere.

The registry record does not report detailed participant flow, the reasons for the difference between enrollment and the primary outcome denominators, or how missing measurements were handled. It also does not report the sponsor’s detailed statistical model, sensitivity analyses, subgroup results, multiplicity control, or the original sample-size justification. Numerical results are absent for several listed secondary outcomes. These omissions limit assessment of robustness, completeness, and the consistency of findings across outcomes.

The treatment period described in the summary is 8 weeks, so the posted efficacy and safety results concern a short-term period. Longer-term effectiveness and safety are not reported in the registry record. The serious adverse event summary provides limited counts and terms, without the narratives or group assignment for the listed top terms. These reporting limitations do not establish that an effect is present or absent, but they restrict the conclusions that can be drawn from this record alone.

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22. Record Summary

NCT00975715 is a completed randomized, double-blind, parallel-group study listed as Phase 2 and Phase 3. It evaluated weight-based TRI476 as adjunctive therapy against placebo in children with inadequately controlled partial onset seizures. The registry records enrollment of 99 and describes an 8-week treatment period alongside participants’ traditional antiepileptic treatment.

The primary endpoint was the registry-defined percent change in partial onset seizure frequency per 28 days. The unadjusted recalculated mean difference was -17.67 percentage points, with a 95% confidence interval from -44.78 to 9.443 and an unadjusted p-value of 0.201. The secondary response comparison favored TRI476 on its reported unadjusted risk-difference estimate, but secondary interpretation is limited by absent multiplicity information and missing numerical results for other named outcomes.

The record does not report the original sample-size justification, detailed missing-data methods, a full statistical analysis plan, or longer-term results. Safety summaries report 1 serious adverse event in each group; deaths are not reported in the registry record.

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