Efficacy and Tolerability of Topiramate in Treatment of Bipolar Mania and Alcohol Use in Adolescents and Young Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Tolerability of Topiramate in Treatment of Bipolar Mania and Alcohol Use in Adolescents and Young Adults (NCT00550394), a randomized phase 4 study. The primary outcome is Drinks Per Day.

2. Clinical Question

3. Trial Design

The registry identifies this as a randomized, triple-masked, parallel-group Phase 4 trial. It was sponsored by the University of Cincinnati, had a recorded enrollment of 56, and is listed as completed. The record gives a start of 2008-04 and a primary completion of 2010-06. These dates describe the registry timeline; they do not establish when every participant entered or completed follow-up.

The parallel-group design assigned participants to one of two medication combinations: quetiapine plus topiramate or quetiapine plus placebo. Random allocation is intended, in general, to make treatment groups comparable at the point of assignment, on average. Masking is intended to limit the influence of treatment knowledge on participant experience, care, and outcome assessment. The registry calls the study triple-masked but does not report which specific groups of people were masked or how masking was maintained.

The primary outcome results list 21 participants in the quetiapine-plus-placebo group and 18 in the quetiapine-plus-topiramate group. These are the group sizes attached to the posted outcome summaries. The relationship between those outcome counts and the recorded enrollment of 56 is not reported in the registry record; the counts should not be treated as a complete account of enrollment or participant flow.

The registry identifies four outcome measures and no posted secondary results. It reports no trial analyses in its analysis record. The displayed between-group comparison is a recalculated, unadjusted comparison from the posted group summaries, rather than a sponsor-reported analysis. The original protocol, the trial’s statistical analysis plan, the allocation procedure, and the trial’s own sample-size assumptions are 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.

Before assignment: 56 study participants were consented for study participation, of which 17 were screen fails.

Overall Study

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 Drinks Per Day, measured over baseline to 12 weeks or endpoint (up to 11 weeks).

The primary endpoint is the change in self-reported drinks per day. The record defines drinks per day as drinks consumed divided by the number of days during the relevant study period. It describes the change as covering baseline to 12 weeks or endpoint (up to 11 weeks). This is a continuous measure: each participant can have a value on a numeric scale, and the group results are expressed as means with standard deviations.

In general, a change score is used to describe how an outcome differs from its starting level over a specified period. A negative change in drinks per day indicates a lower reported value relative to baseline, under the stated change definition. The group means are -1.4 for quetiapine plus placebo and -2.4 for quetiapine plus topiramate. These are within-group summaries; the randomized comparison of interest is the difference between the groups, not whether either group’s mean change is individually different from zero.

Self-report makes the endpoint directly dependent on participants’ reports of alcohol consumption. The registry record does not describe the instrument or method used to collect those reports, nor does it report validation or missing-data procedures. The endpoint addresses alcohol use as measured by this specific average-per-day summary; it does not, by itself, represent every dimension of alcohol use or the trial’s separate interest in bipolar mania symptoms.

7. Results Posted in the Registry

• Quetiapine + Topiramate: mean -2.40 versus -1.40 on control; difference -1.00 (95% CI -3.55 to 1.55), standardized effect d = -0.26; z-test p = 0.443.

8. Statistical Interpretation

9. Statistical Methods Explained

The posted comparison is a recalculated, unadjusted comparison of two group means. It uses the reported mean change, standard deviation, and outcome group size for each treatment group. The result describes the difference in average change in drinks per day between the groups, with the comparison oriented as quetiapine plus topiramate relative to quetiapine plus placebo. A negative difference means the topiramate group’s mean change is lower on the outcome scale; it does not, on its own, establish that the groups differ reliably.

What does a mean describe?

For a continuous outcome, a mean is the arithmetic average of the observed values in a group. It gives a compact description of the group’s central value, but it does not show how values are distributed among participants. The standard deviation describes the degree of spread around the mean. A larger standard deviation indicates more dispersion in the observed values, not necessarily a larger or more important treatment effect. Here the reported standard deviations are 2.3 for quetiapine plus placebo and 5.1 for quetiapine plus topiramate.

Group means can move in the same direction while the difference between groups remains uncertain. A within-group change answers how the group average changed relative to baseline. The randomized treatment contrast asks whether average change differed between the assigned groups. The contrast is therefore the key estimate for the comparative question, while the two group means provide context for it.

What does the confidence interval express?

In general, a confidence interval describes the range of estimates compatible with the data under the method’s assumptions, and it conveys precision as well as direction. A narrower interval indicates greater precision; a wider interval indicates greater uncertainty. The 95% confidence interval for the recalculated mean difference is -3.553 to 1.553. Since that range crosses zero, the summary is compatible with no mean difference as well as differences in either direction. The interval should not be interpreted as a range containing a known proportion of individual participants’ outcomes.

What does the p-value address?

The unadjusted p-value is 0.443. In general, a p-value measures how unusual data at least as inconsistent with a specified null hypothesis would be if that hypothesis and the analysis assumptions held. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of an effect. The registry record does not report a sponsor-conducted analysis or a prespecified analysis plan for this result. The recalculated p-value should therefore be understood as a summary-based, unadjusted calculation, rather than as confirmation of the trial’s planned inferential procedure.

Why can variability affect precision?

General statistical principle: more variability in an outcome makes it harder to estimate a group mean and the difference between group means precisely, all else being equal. This is why the group standard deviations matter alongside the means and group sizes. The topiramate group has a larger reported standard deviation than the placebo group. The comparison’s confidence interval reflects uncertainty in the estimated contrast, but the registry record does not report model diagnostics or alternative variance assumptions. No adjusted estimate is posted.

The record identifies the primary measure as a mean with standard deviation, which is consistent with describing a continuous outcome. It does not report details such as the exact model used for the trial’s own analysis, adjustment for baseline values, handling of repeated measurements, or treatment of missing data. Those choices can affect estimation and inference; without them, the recalculated result should not be presented as the trial’s complete statistical analysis.

What is not established by this calculation?

The recalculation is not evidence that the original investigators used this method, and it does not reproduce an unreported sponsor analysis. It is limited to the summary statistics posted for the endpoint. It cannot recover individual-level patterns, examine whether the outcome distribution was skewed, check assumptions, or assess the effect of missing outcomes. The registry record lists zero analyses and no secondary results, so further analytic detail is not reported. In general, a full interpretation of a randomized trial also depends on its prespecified outcomes, analysis population, protocol, and handling of data; those details are not reported in the registry record.

10. Confidence Intervals and Precision

The recalculated mean difference is -1.0 drinks per day, with a 95% confidence interval from -3.553 to 1.553. The interval is wide relative to the point estimate and crosses zero. That means the result is not precise enough to determine from this summary whether the underlying average difference favors quetiapine plus topiramate, favors quetiapine plus placebo, or is close to zero.

In general, a confidence interval conveys the uncertainty of an estimate under the assumptions of its calculation. It is not a statement that every plausible value is equally likely, and it does not describe the range of individual participant responses. The interval concerns the between-group mean difference in change in drinks per day. Its endpoints include values on both sides of zero, so the point estimate should not be treated as a settled estimate of direction or magnitude.

The p-value of 0.443 is consistent with the interval’s uncertainty, but it does not resolve it. A result that does not cross a conventional significance threshold is not proof of no difference, and this record does not report an equivalence margin or an equivalence analysis. The standard deviations of 2.3 and 5.1 also show that the participant-level values vary within both groups, with greater observed spread in the topiramate group.

Precision is also affected by what is not reported. The registry record does not explain how the outcome group sizes relate to recorded enrollment, whether all randomized participants contributed outcome data, or how missing observations were handled. Without those details or individual-level data, the interval cannot address possible effects of missingness or alternative analysis choices. The available interval is best read as an uncertain summary-based estimate, not as a complete account of the trial’s inferential uncertainty.

11. 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.

The planning figures are participants per arm, not total events. They are illustrations based on the observed effect, not the trial’s own design assumptions. The stated planning 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.

For planning for 100% of the observed effect, the figures are 233 participants per arm for 80% power and 312 participants per arm for 90% power. For planning for 75% of the observed effect, they are 414 participants per arm for 80% power and 554 participants per arm for 90% power. For planning for 50% of the observed effect, they are 930 participants per arm for 80% power and 1,245 participants per arm for 90% power.

In general, power is the probability that a specified analysis would detect an effect of a chosen size under its assumptions if that effect were the true one. The 80% and 90% columns describe different planning targets: the 90% target aims for a higher chance of detection and therefore requires more participants for the same assumed effect. Smaller effects are harder to distinguish from random variation, so planning to detect a smaller fraction of the observed effect requires more participants. These figures are planning illustrations, not observed power.

The trial’s original sample-size justification, target effect, and planning assumptions are not reported in the registry record. These illustrations use the posted observed effect as their reference, and should not be read as evidence that the trial was designed around those assumptions.

12. 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 z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

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 = -1.000; pooled standard deviation σ = 3.848.
2. n = 2 × (1.96 + 0.842)² × 3.848² / -1.000² = 232.5, rounded up to 233 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 <- -1                      # observed difference in means
sigma <- 3.84837628097877                     # 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(550394)
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 = 233 (80% power), 312 (90% power)
 75% of observed effect: n per arm = 414 (80% power), 554 (90% power)
 50% of observed effect: n per arm = 930 (80% power), 1,245 (90% power)
power.t.test: 233.4 
Simulated power at n = 233 per arm: 0.802 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry record identifies four outcome measures but reports no posted secondary results. The primary result addressed concerns change in self-reported drinks per day. Results for other outcomes, including the study’s stated interest in bipolar mania symptoms, are not reported in the registry record. Without those results, the endpoint discussed cannot provide a complete account of all outcomes the study may have assessed.

Multiplicity arises in general when multiple outcomes, time points, groups, or statistical tests are considered. If many tests are conducted, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for that possibility. The registry record does not report a multiplicity adjustment, a hierarchy of outcomes, or a prespecified plan for interpreting multiple tests. It is therefore not possible to determine how the posted primary endpoint fits into the trial’s full testing strategy.

The record lists zero analyses. It does not provide a statistical analysis plan, details of analysis populations, or a statement identifying whether participants were analyzed according to randomized assignment. The relationship between the overall enrollment of 56 and the primary outcome group sizes of 21 and 18 is not explained. The record also does not report participant flow, reasons for missing outcomes, imputation methods, or sensitivity analyses.

These are reporting gaps rather than proof that a particular method was or was not used. In general, analysis populations and missing-data procedures matter because conclusions can depend on who contributes data and on assumptions about unobserved outcomes. Since those details are not reported in the registry record, the recalculated result should be kept distinct from any unreported trial analysis, and it cannot establish whether missingness or multiplicity influenced the investigators’ conclusions.

14. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: suicidal ideation (33.3%), suicide attempt (4.8%).

The serious adverse event figures are reported by group. In the quetiapine-and-placebo group, 8 participants were affected among 21 at risk; in the quetiapine-and-topiramate group, 2 were affected among 18 at risk. These are counts, not estimates of a causal treatment effect. The record also lists other adverse events affecting 4 participants among 21 at risk in the placebo group and 11 among 18 at risk in the topiramate group. The registry does not provide a comparative statistical analysis of these counts.

The serious adverse event terms listed include Suicidal ideation at 33.3% and Suicide Attempt at 4.8%. The record does not establish in these entries which group or groups those terms correspond to, so they should not be assigned to a treatment group. Death counts are not reported in the registry record. Missing death figures must not be interpreted as zero deaths.

In general, adverse event counts describe events recorded during a study and do not alone show whether treatment caused them. The registry record does not provide event timing, severity detail beyond the serious classification, exposure duration, or a full account of how events were assessed. These figures therefore describe posted safety reporting, not a definitive comparative safety analysis.

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

The primary outcome summaries show negative mean changes in drinks per day in both groups. The recalculated difference is -1.0 drinks per day for quetiapine plus topiramate compared with quetiapine plus placebo. The estimate points toward a greater decrease in the topiramate group, but the 95% confidence interval, -3.553 to 1.553, includes values in either direction and zero. The result is therefore uncertain in both direction and size.

The unadjusted p-value of 0.443 does not establish that the treatments are equivalent, nor does it prove that there is no difference. Equivalence requires a defined margin and suitable analysis, which are not reported in the registry record. The estimate and interval describe a specific continuous endpoint based on self-reported drinks per day; they do not answer every question about alcohol use or bipolar mania.

These posted data do not establish whether either medication combination changes mania symptoms, because results for that outcome are not reported in the registry record. They also do not establish overall benefit or harm. The safety entries show affected-participant counts and listed serious adverse event terms, but the record does not provide a group-specific mapping for those terms or a comparative safety analysis. The death counts are not reported.

The statistical interpretation is limited by the unadjusted, recalculated nature of the comparison and by missing reporting about the original analysis plan, outcome populations, participant flow, and missing-data handling. The displayed outcome group sizes do not account for the recorded enrollment, and the registry record does not explain that difference. Thus, the result is informative as a summary of the posted endpoint data, but it is not a complete reconstruction of the trial’s planned analysis or all findings.

In general, a randomized comparison can support a causal interpretation when allocation, follow-up, outcome measurement, and analysis are adequately conducted and reported. The registry record contains limited detail about these features. Accordingly, the posted result should be read as an imprecise comparison in this trial record, not as a treatment recommendation or a definitive conclusion about clinical effects.

16. Why This Trial Matters Statistically

This trial illustrates why a difference in group means and the uncertainty around that difference need to be read together. The posted means are -1.4 and -2.4 drinks per day, and the recalculated contrast is -1.0. Looking only at the point estimate could make the comparison seem clear in direction. The confidence interval from -3.553 to 1.553 shows that the data summary is also compatible with differences favoring the comparator and with little or no difference.

It also illustrates the distinction between within-group change and a randomized between-group comparison. Both group means are negative, but that alone does not identify the effect of adding topiramate. The contrast between assigned groups is the relevant comparative estimate, and its precision is limited in the posted summary.

The spread of the outcome values matters as well. The standard deviation is 5.1 in the quetiapine-plus-topiramate group and 2.3 in the quetiapine-plus-placebo group. This difference in observed variability helps explain why group averages cannot be interpreted without considering uncertainty. General statistical principle: when outcome variability is substantial relative to the treatment contrast, estimates may be imprecise.

Finally, the record shows the importance of transparent reporting. Enrollment is listed as 56, while the primary outcome summaries have group sizes of 21 and 18. The relationship is not explained. The original statistical plan, analysis populations, missing-data methods, and secondary results are also not reported in the registry record. These gaps restrict interpretation even when a numerical comparison can be recalculated from posted summaries.

17. 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 available primary result is a recalculated, unadjusted comparison from group summary statistics, not a reported sponsor analysis. The registry record does not provide the original statistical analysis plan, adjusted estimates, model details, or an account of whether the calculation matches the investigators’ intended method. The comparison should therefore be treated as a descriptive statistical reconstruction of the posted summaries.

Overall enrollment is recorded as 56, while the outcome summaries report group sizes of 21 and 18. The registry record does not explain this discrepancy. It does not report a participant-flow account, reasons outcomes may be absent, or how missing data were addressed. The extent to which the posted groups represent randomized participants cannot be determined from the available record.

The primary endpoint is self-reported drinks per day. The record does not describe the reporting instrument, collection schedule, or validation procedures. Although the endpoint timeframe is stated as baseline to 12 weeks or endpoint (up to 11 weeks), details about how participant-specific endpoint timing was handled are not reported.

The registry record does not provide results for the study’s interest in mania symptoms, despite listing four outcome measures and no posted secondary results. Nor does it report a multiplicity plan or a full analysis population definition. Safety reporting is also limited: serious adverse event terms are listed without a group-specific mapping in the posted entries, and death counts are not reported. These limitations mean the posted summaries do not constitute a complete account of efficacy, analysis, or safety for the trial.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy and Tolerability of Topiramate in Treatment of Bipolar Mania and Alcohol Use in Adolescents and Young Adults — NCT00550394.
• Registry record last updated 2017-05-23; status last verified 2014-10.
• Results first posted 2017-05-23.
• 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.

21. Record Summary

This completed, randomized, triple-masked, parallel-group Phase 4 trial compared quetiapine plus topiramate with quetiapine plus placebo in adolescents and young adults with bipolar mania and alcohol use. The University of Cincinnati is listed as sponsor. The registry records enrollment of 56, a start of 2008-04, and primary completion of 2010-06.

The primary outcome was change in self-reported drinks per day, measured over baseline to 12 weeks or endpoint (up to 11 weeks). Posted group means were -1.4 for quetiapine plus placebo and -2.4 for quetiapine plus topiramate. The recalculated unadjusted mean difference was -1.0, with a 95% confidence interval from -3.553 to 1.553 and an unadjusted p-value of 0.443. This interval indicates substantial uncertainty about the direction and magnitude of the between-group difference.

The registry record does not report the original statistical plan, explain the relationship between enrollment and outcome group sizes, or provide secondary results. The posted comparison is therefore best read as an imprecise summary-based result rather than a complete account of the trial’s analyses.