Cerebral Perfusion Pressure Using Precedex and Other Sedatives: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cerebral Perfusion Pressure Using Precedex and Other Sedatives (NCT01169467), a randomized phase 3 study. The primary outcome is Variability of Intracranial Pressure (ICP).

2. Clinical Question

3. Trial Design

The registry identifies this as a randomized, triple-masked, parallel-group Phase 3 study sponsored by Duke University. It was marked completed. The recorded study start was 2009-10, and primary completion was 2013-11. Enrollment was 89. The registry does not describe the randomization sequence or allocation concealment, and the roles covered by triple masking are not reported in the registry record.

Participants were assigned to standard-of-care sedation plus Precedex or standard-of-care sedation alone. For the primary outcome, 34 participants were included in the combination group and 25 in the standard-of-care group. The outcome description says that everyone who completed the trial was included except fourteen subjects whose data were incomplete and could not be included in this analysis. The registry does not report further details about the missing measurements or the reasons for their absence.

The primary endpoint was variability of intracranial pressure from baseline to 24 hours. Three secondary outcomes are posted: sedative and analgesic use during 24 hours, cerebral perfusion pressure changes from baseline to 24 hours, and mean arterial blood pressure variability from baseline to 24 hours. Their analysis populations differ by outcome, as reflected in the posted group counts. The registry record does not report the original sample-size justification, the planned statistical analysis, or whether interim analyses were conducted. Randomization and masking describe aspects of the design, but do not by themselves establish how these details were handled.

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

Analysis population for the primary outcome, as defined in the registry: Everyone who completed the trial was included except for fourteen subjects had incomplete data and could not be included in this analysis.

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 Variability of Intracranial Pressure (ICP), measured over Baseline to 24 hours.

The primary endpoint is variability of intracranial pressure (ICP), reported in mmHg. The registry describes variability as the standard deviation of all ICP measurements within 24 hours, with the outcome timeframe stated as baseline to 24 hours. This is a summary of how spread out the repeated measurements were during the stated period; it is not the average ICP level itself. Lower or higher variability should not be interpreted as a clinical benefit or harm on its own without additional clinical context.

The outcome results report a group mean and standard error for each arm. In this setting, the group mean summarizes the participant-level variability values, while the standard error indicates the precision of the estimated group mean. The comparison is therefore about average variability between the randomized groups, rather than a direct comparison of every individual ICP reading.

Continuous monitoring can produce repeated measurements, and reducing those measurements to a variability summary gives researchers a way to compare how stable the recorded ICP was across groups. That general statistical rationale does not establish that this measure captures every clinically relevant feature of ICP. The registry does not report further justification for choosing this endpoint, details of measurement frequency, or a threshold defining a clinically important difference.

7. Results Posted in the Registry

• Standard-of-Care: mean 5.61 versus 5.66 on control; difference -0.05 (95% CI -1.81 to 1.71), standardized effect d = -0.01; z-test p = 0.956.

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.

Amount of Sedative/Analgesic Used During Treatment in Patients With Secondary Brain Injury

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Standard-of-Care: mean 213.10 versus 155.40 on control; difference 57.70 (95% CI -11.17 to 126.57), standardized effect d = 0.36; z-test p = 0.101.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Standard-of-Care and the control. The interval gives the range of effects that remain compatible with the data.

Cerebral Perfusion Pressure Changes in Patients With Secondary Brain Injury

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Standard-of-Care: mean 12.30 versus 11.50 on control; difference 0.80 (95% CI -1.10 to 2.70), standardized effect d = 0.22; z-test p = 0.410.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Standard-of-Care and the control. The interval gives the range of effects that remain compatible with the data.

Mean Arterial Blood Pressure (MAP) Variability in Patients With Secondary Brain Injury

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Standard-of-Care: mean 13.80 versus 12.30 on control; difference 1.50 (95% CI -1.66 to 4.66), standardized effect d = 0.25; z-test p = 0.353.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Standard-of-Care and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover three related but distinct areas: sedative and analgesic use, cerebral perfusion pressure, and mean arterial blood pressure variability. Taken together, they broaden the description beyond the primary ICP variability measure, but they do not replace or directly validate it. A pattern across several measures can be informative for understanding the measured outcomes, yet the outcomes may differ in scale, variability, available participants, and clinical interpretation.

The secondary comparisons have estimates in different directions and uncertainty intervals that include zero. The registry reports unadjusted p-values for these comparisons, and the record does not describe a multiplicity adjustment or identify a confirmatory hierarchy for the secondary outcomes. When several results are considered, an isolated estimate or p-value deserves less weight than a result supported by a prespecified analysis that accounts for the full testing plan. The absence of a reported adjustment does not prove one was not used in another analysis, but it is not described in the registry record.

The secondary results are best read alongside the primary finding as additional descriptive evidence from this trial. They cannot establish that the treatment groups were equivalent on these measures, and their uncertainty limits definitive conclusions. The registry does not report further inferential analyses for the secondary outcomes or state how these results were intended to affect interpretation of the primary endpoint.

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

• Amount of Sedative/Analgesic Used During Treatment in Patients With Secondary Brain Injury
• Cerebral Perfusion Pressure Changes in Patients With Secondary Brain Injury
• Mean Arterial Blood Pressure (MAP) Variability in Patients With Secondary Brain Injury

9. Statistical Interpretation

10. Statistical Methods Explained

The outcomes are continuous measures, so the registry reports a mean for each group and a mean difference between groups. For the primary outcome, each participant's ICP variability is described as the standard deviation of measurements within 24 hours. The reported group mean is then a summary across participants. This is different from reporting a single ICP reading or the average ICP level during the period.

What does the standard error describe?

A standard error describes the sampling precision of an estimated quantity, such as a group mean. In general, it reflects how much an estimate would vary across repeated samples under a statistical model. It is not the same as the standard deviation of individual observations. That distinction matters because the primary endpoint itself is a standard deviation within each participant, while the spread statistic displayed alongside the group mean is labeled as a standard error. For the primary groups, the posted standard errors are 0.63 and 0.64 mmHg.

How should the mean difference be read?

The mean difference expresses the contrast between the two group means in the outcome's units. In the primary comparison, the standard-of-care group mean is 5.61 mmHg and the standard-of-care plus Precedex group mean is 5.66 mmHg; the posted difference is -0.05 mmHg. The direction follows the contrast used in the registry's results. A value near zero indicates that the estimated group means are close, but interpretation also depends on uncertainty and the clinical meaning of the measure. A difference is not automatically important merely because it is nonzero.

What does a confidence interval add?

A confidence interval gives a range of values compatible with the data and the statistical procedure used. In general, a 95% confidence interval describes the long-run performance of the method across repeated studies, rather than assigning a 95% probability to this particular interval containing a fixed true value. The primary interval extends from -1.81 to 1.71 mmHg. It includes zero, so the data do not distinguish the estimate from no group difference using that interval as the uncertainty summary. The width also shows why the small point estimate should not be mistaken for a precise estimate of zero.

What does the p-value say?

The unadjusted p-value for the primary comparison is 0.956. In general, a p-value measures how surprising data at least as discrepant as those observed would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of an effect. A large p-value is not proof of no difference or equivalence. The registry does not report an equivalence margin or a prespecified threshold for a clinically important difference.

The secondary comparisons also report means, mean differences, confidence intervals, and unadjusted p-values. Since the registry does not report a multiplicity adjustment, these p-values do not account for the fact that several outcomes were examined. General statistical practice treats a collection of unadjusted secondary tests cautiously because multiple opportunities to observe a low p-value can increase the chance of a chance finding. No particular correction can be inferred from the record.

Why does over-dispersion matter in general?

For some outcome types, the variability in the data can exceed what a simple statistical model expects. This is called over-dispersion. It can make standard errors too small and confidence intervals too narrow if the model fails to account for the extra variability. The posted primary outcome is continuous, and the registry describes a mean-based comparison; it does not report an over-dispersion assessment or a model of this kind. This general concept should not be read as a finding about this trial.

The registry does not report the full statistical analysis plan, model diagnostics, covariate adjustments, handling of missing measurements, or interim analyses. Consequently, the posted summary statistics allow a basic reading of group means and uncertainty, but not a full audit of the analysis choices. The record does not state how the trial's original sample size was justified.

11. Confidence Intervals and Precision

The primary mean difference is -0.05 mmHg, and its 95% confidence interval ranges from -1.81 to 1.71 mmHg. The interval includes zero and values on both sides of zero. This means the posted estimate is compatible with no difference as well as with differences in either direction under the interval's statistical assumptions. Its range is much broader than the point estimate, so the result is not a precise estimate of a small difference.

Confidence intervals communicate uncertainty in a way that a p-value alone cannot. The p-value of 0.956 is unadjusted and does not show the size or precision of the estimate. The interval helps show the range of group contrasts consistent with the data and method, but it cannot tell whether any particular value within that range is clinically important. The registry does not report a clinically important difference threshold.

The secondary outcome intervals also include zero: for sedative and analgesic use, the interval is -11.17 to 126.6 mg/ml; for cerebral perfusion pressure, it is -1.105 to 2.705 mmHg; and for mean arterial blood pressure variability, it is -1.664 to 4.664 mmHg. Each interval pertains to its own outcome and analysis population. These ranges should not be compared as though their units or clinical meanings were the same.

Precision depends on the amount and variability of the analyzed data, as well as on the analysis method. The primary outcome includes 34 participants in one arm and 25 in the other, with fourteen subjects excluded because their data were incomplete. The registry does not provide additional missing-data analyses. That limits assessment of how the omitted data might affect the uncertainty or the estimated difference.

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.

The sample-size figures are planning illustrations based on the observed effect, not the trial's original design assumptions. The registry's original sample-size justification is not reported in the registry record. These figures are participants per arm for 80% power and participants per arm for 90% power, rather than total participants or total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect.

The 80% power column describes the number of participants per arm that the planning calculation estimates would be needed to have an 80% chance of detecting the specified effect under those assumptions, if the effect and model assumptions were correct. The 90% power column uses a higher target chance of detecting that effect and therefore requires more participants per arm. These are prospective planning quantities, not evidence about the probability that this completed trial detected an effect.

The rows consider planning for 100%, 75%, and 50% of the observed effect. A smaller effect is harder to distinguish from random variation, so the illustration requires more participants for smaller target effects. The curve conveys the same general relationship between the assumed effect and the required sample size; it should be read as a planning aid, not as a new analysis of trial outcomes. The figures are not observed power.

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 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 = -0.050; pooled standard deviation σ = 3.482.
2. n = 2 × (1.96 + 0.842)² × 3.482² / -0.050² = 76,129.4, rounded up to 76,130 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 <- -0.0499999999999998                      # observed difference in means
sigma <- 3.48198824025343                     # 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(1169467)
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 = 76,130 (80% power), 101,916 (90% power)
 75% of observed effect: n per arm = 135,342 (80% power), 181,184 (90% power)
 50% of observed effect: n per arm = 304,518 (80% power), 407,663 (90% power)
power.t.test: 76130.3 
Simulated power at n = 76,130 per arm: 0.803 (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, comparisons, or analyses are examined. In general, conducting multiple tests without an adjustment can raise the chance that at least one result appears unusual by chance alone. The registry lists one primary outcome and three secondary outcomes, but does not report a multiplicity strategy, a hierarchy among outcomes, or a distinction between confirmatory and exploratory secondary tests. The posted secondary p-values are unadjusted. Their interpretation should therefore remain cautious, especially if attention is focused on one result among several.

Missing primary outcome data are explicitly noted: fourteen subjects had incomplete data and could not be included in the primary analysis. The primary outcome group counts are 34 and 25. The registry does not report why data were incomplete, whether missingness was related to participant characteristics or outcomes, or whether an imputation or sensitivity analysis was performed. Without those details, it is not possible to assess from the record whether the analyzed participants represent all randomized participants for this endpoint.

The available group counts also vary across the secondary outcomes. The record does not explain the differences in outcome-specific availability or state whether all participants with available data were analyzed according to their randomized group. The primary outcome population is described as people who completed the trial, with the incomplete-data exclusion noted; a fuller analysis-population definition is not reported in the registry record.

The registry does not report the full statistical analysis plan, any interim analyses, or the trial's original sample-size justification. These omissions limit the ability to assess whether the posted outcome definitions and analyses match the original plan, or whether any decisions were made in response to accumulating data. They do not establish that such procedures were absent; they mean that the registry record does not report them.

15. 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

Serious events with the highest arm-level rate: death (withdrawal of life support) (2.3%).

The registry lists serious adverse events for 44 participants at risk in the standard-of-care plus Precedex group and 40 at risk in the standard-of-care group. It reports one participant affected by a serious adverse event in the combination group and none in the standard-of-care group. For other adverse events, the affected counts are zero in both groups, with the same at-risk group counts listed.

The registry lists Death (Withdrawal of Life Support) as a top serious adverse event term at 2.3%. The record does not specify the arm associated with that term in the listed summary. Death counts by group are not reported in the registry record. The serious adverse event counts and term should be read as registry safety reporting, not as proof that the intervention caused or prevented an event.

These figures are descriptive. The registry does not provide enough detail to assess event timing, severity beyond the serious classification, relatedness to treatment, or comparative uncertainty. A count of zero in the posted category does not demonstrate that an event is impossible or that there is no safety risk.

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

The result addresses a focused statistical question: how the mean of participant-level ICP variability over the stated 24-hour period compared between two randomized groups. The posted primary estimate is -0.05 mmHg, with a 95% confidence interval from -1.81 to 1.71 mmHg. The estimate is close to zero, but the interval is broad enough to include differences in either direction. The findings therefore describe an uncertain group contrast; they do not establish equivalence or rule out differences of clinical importance.

The primary analysis excluded fourteen subjects because their data were incomplete. The record does not explain the missingness or report sensitivity analyses. This limits confidence in extending the estimate from analyzed participants to all enrolled participants. The randomized design is relevant to the group comparison, but interpretation also depends on the quality and completeness of outcome data and the methods used to analyze them.

The secondary results add information about other measured outcomes but are also uncertain, and their p-values are unadjusted. They should not be treated as independent confirmation of the primary result or as a basis for broad conclusions about the treatment. The registry does not report a threshold for clinical importance, the original sample-size rationale, or the detailed analysis plan.

These statistical findings do not, by themselves, determine how the treatment should be used. They describe the posted outcome estimates and their precision. Clinical decisions require evidence and context beyond the information in this registry record, and no treatment recommendation follows from these results alone.

17. Why This Trial Matters Statistically

This trial is statistically instructive because its primary point estimate is close to zero while its confidence interval remains wide enough to include a range of group differences. It illustrates why a small estimated difference and a large p-value do not prove that two groups are equivalent. The interval, the outcome definition, and the study population all matter when interpreting a null-looking result.

It also highlights the distinction between variability within a participant and uncertainty in a group mean. ICP variability is defined using the standard deviation of measurements within a 24-hour period, whereas the standard error describes precision of the group mean. Keeping those quantities distinct helps avoid mistaking a measure of outcome variation for a measure of estimation uncertainty.

The registry notes incomplete primary data and outcome-specific differences in group counts. Missing data can affect both the precision and the interpretation of a comparison, so a transparent account of exclusions and sensitivity analyses is important. Here, the reason for incomplete measurements and the handling of missingness are not reported in the registry record.

Finally, the multiple secondary outcomes show why multiplicity matters. Unadjusted secondary p-values may be useful as descriptive evidence, but they are less decisive when the testing plan and multiplicity strategy are not reported. The sample-size illustrations also reinforce that planning depends on the effect one aims to detect: smaller effects require more participants under the stated assumptions. These lessons apply generally to reading registry results, without making claims beyond the measurements and analyses posted for this trial.

18. 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 primary analysis excluded fourteen subjects with incomplete data, and the registry does not describe the reasons or provide a missing-data sensitivity analysis. This is a trial-specific limitation because the primary comparison applies to the analyzed outcome data, not automatically to every enrolled participant. The registry also does not report why the secondary-outcome group counts vary.

The primary endpoint is described as the standard deviation of all ICP measurements within 24 hours, but the record does not provide details about measurement frequency, the exact calculation procedure beyond that description, or a threshold for a clinically important difference. Without such context, the size of the mean difference is difficult to translate into clinical importance.

The record identifies randomization and triple masking but does not describe the allocation process or which people were masked. It also does not report the full analysis plan, adjustment for multiplicity, interim analyses, original sample-size justification, or sensitivity analyses. These details are important for assessing how the results were planned and how robust they may be to analytic choices.

The secondary comparisons are accompanied by unadjusted p-values, and the record does not report a multiplicity procedure. The safety summary is also limited: it gives affected and at-risk counts, but does not provide event timing, treatment relatedness, or group-specific death counts. Finally, the registry's planning illustrations use observed effects and specified assumptions; they do not recover the trial's original design rationale or resolve the uncertainty in the observed effects.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Cerebral Perfusion Pressure Using Precedex and Other Sedatives — NCT01169467.
• Registry record last updated 2015-11-02; status last verified 2015-10.
• Results first posted 2015-11-02.
• 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.

22. Record Summary

The registry describes a completed, randomized, triple-masked, parallel-group Phase 3 trial with enrollment of 89. It compared standard-of-care sedation plus Precedex with standard-of-care sedation alone. The primary outcome was variability of ICP from baseline to 24 hours, described as the standard deviation of measurements within 24 hours. The primary analysis excluded fourteen subjects with incomplete data.

The posted primary mean difference was -0.05 mmHg, with a 95% confidence interval from -1.81 to 1.71 and an unadjusted p-value of 0.956. Three secondary outcomes are posted, along with descriptive serious and other adverse event counts. The registry does not report the original sample-size justification, full analysis plan, missing-data sensitivity analyses, or multiplicity procedure.