Cosyntropin Versus Epidural Blood Patch (EBP) for Treatment of Treatment of Post Dural Puncture Headache: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cosyntropin Versus Epidural Blood Patch (EBP) for Treatment of Treatment of Post Dural Puncture Headache (NCT02394457), a randomized phase 4 study. The primary outcome is Headache Pain Score.

2. Clinical Question

The registry describes a Phase 4 randomized, double-masked crossover trial with enrollment of 29. Its stated hypothesis concerns whether cosyntropin is at least as effective as current conservative therapy and/or epidural blood patch, while the posted primary comparison is between the cosyntropin and epidural blood patch groups. These descriptions do not, by themselves, establish a formal equivalence or non-inferiority design. The trial’s posted primary result is a comparison of group means at one day post procedure; it should be read as evidence about that endpoint and time point, not as a complete account of every possible treatment outcome or later follow-up.

3. Trial Design

The registry identifies this as a Phase 4 randomized, double-masked, crossover trial. Enrollment is recorded as 29, and the status is completed. The recorded start is 2010-08 and primary completion is 2014-04. The sponsor is United States Naval Medical Center, San Diego. These registry entries describe the registry entry, but do not establish details of conduct that are not recorded there.

Participants were described as being randomly assigned to epidural blood patch with intravenous fluid therapy or intravenous cosyntropin with intravenous fluid therapy. The cosyntropin group is recorded as receiving 500 mcg in 1000cc Normal Saline. The other group is described as receiving epidural blood patch and saline. The registry also states that participants in the cosyntropin arm could request crossover to epidural blood patch after a 24 hour assessment period. The number who crossed over, the timing of any crossover, and how such participants were handled in the analysis are not reported in the registry record.

The word “crossover” can refer to a design in which participants receive more than one intervention over time, but the posted group summaries are presented as two treatment groups and do not describe a paired, within-participant comparison. The sequence allocation, washout arrangements, and any analysis accounting for repeated observations are not reported in the registry record. The method used to maintain masking is also not reported.

The primary endpoint is a mean headache pain score one day post procedure. The registry lists functioning score as a secondary outcome and reports one set of comparative functioning results at the same time point. The posted record does not describe the sample-size justification, the trial’s original statistical analysis plan, the prespecified analysis population, or whether the posted summaries follow the original plan. The design features that are documented therefore support a description of randomization, masking, and a planned crossover option, but do not answer all questions about implementation or analysis.

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

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 Headache Pain Score, measured over 1 day post procedure.

The primary endpoint is headache pain score one day after the procedure. It is recorded as a mean on a numerical scale from 0, no pain, to 10, worst pain, with standard deviation as the measure of spread. The scale gives a numerical summary of symptom intensity at a defined follow-up point. Comparing group means allows readers to describe the average recorded pain score in each group and the difference between those averages.

A one-day assessment captures pain at a specific early follow-up time. It does not, on its own, describe how pain changed from before treatment, how long any change lasted, or what happened at later follow-up points. The trial description mentions pain scores before the procedure, at emergency department discharge, and on post-procedural days 1, 3, and 7. The posted primary result is specifically for day 1; results for the other time points are not reported in the registry record.

The scale’s stated endpoints give the direction of interpretation: lower scores indicate less reported pain, while higher scores indicate more. A group mean is an average and does not show the full distribution of individual scores. The standard deviation conveys how much observed scores varied within each group, but it does not give the range of responses or the number of participants who improved by a particular amount. The registry does not report a threshold for a clinically important change, so statistical comparisons should not be taken as a direct measure of clinical importance.

7. Results Posted in the Registry

• Epidural Blood Patch Group B: mean 2.33 versus 6.67 on control; difference -4.34 (95% CI -8.45 to -0.23), standardized effect d = -0.74; z-test p = 0.038.

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.

Functioning Score

• 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 deviations.
• Result:
  • Epidural Blood Patch Group B: mean 2.00 versus 6.53 on control; difference -4.53 (95% CI -6.21 to -2.85), standardized effect d = -2.09; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Epidural Blood Patch Group B than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry identifies Functioning Score as a secondary outcome and posts one set of comparative results at one day post procedure. The direction of the group comparison is aligned with the primary pain result: the epidural blood patch group has a lower reported mean than the cosyntropin group. This provides a related measure of function at the same follow-up, rather than an independent replication of the pain endpoint.

The registry lists Functioning Score more than once among its secondary outcomes, but does not provide distinct posted results for each listing. It also refers to additional follow-up times in the trial description. Results for other secondary measures or those other time points are not reported in the registry record. The overall pattern across all planned secondary endpoints therefore cannot be assessed from the available results.

Secondary findings can help describe whether outcomes beyond the primary measure move in a similar direction, but they are usually less conclusive than a prespecified primary comparison. There may be multiple secondary outcomes, time points, or analyses, and the registry does not report whether a multiplicity procedure was planned or applied. Without that information, an unadjusted secondary p-value should be interpreted cautiously rather than as definitive corroboration.

The registry does not report a hierarchy among secondary outcomes, a secondary analysis plan, or the number of participants contributing to each secondary measurement beyond the posted group summaries. It also does not report how missing measurements or crossover were treated. These limitations prevent a complete assessment of consistency, completeness, and inferential strength across secondary outcomes. The posted secondary result is best read as supportive descriptive information, with less weight than the primary result and with uncertainty about the broader set of planned outcomes.

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

• Functioning Score
• Functioning Score
• Functioning Score

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: it is a numerical score measured on a scale, rather than a count of events or a yes-or-no outcome. The registry reports the mean and standard deviation for each group. The mean describes the group’s average score. The standard deviation describes the spread of individual scores around that average. Neither statistic alone gives the complete distribution of participant responses.

The posted comparison is a mean difference between the epidural blood patch and cosyntropin groups. Its sign depends on the order of subtraction. In this comparison, the epidural blood patch mean is set against the cosyntropin mean, so a negative difference corresponds to a lower mean in the epidural blood patch group. Interpreting the sign requires knowing that order; a negative value does not inherently mean a worse result. For the pain scale in this trial, lower values correspond to less pain.

A confidence interval describes a range of values reasonably compatible with the data and the statistical model used to produce it. In repeated use of the same procedure, intervals constructed this way would capture the underlying quantity at the stated rate, under the model’s assumptions. An interval is not a guarantee that the true value lies inside it, nor is it a range containing a stated proportion of individual participants. The registry posts a confidence interval for the mean difference, but the specific method used to calculate it is not reported in the registry record.

The reported p-value is unadjusted. In general, a p-value measures how surprising data at least as incompatible with a null hypothesis would be if that null hypothesis and the analysis assumptions were true. It is not the probability that the null hypothesis is true, nor the probability that the observed finding arose “by chance.” A p-value also does not establish clinical importance. Interpretation should consider the estimated difference and its confidence interval, not the p-value alone. The registry does not identify the exact test or model used for the posted p-value.

The trial is described as randomized and double-masked. Random allocation is generally intended to make treatment groups comparable, on average, with respect to measured and unmeasured baseline characteristics. Masking is generally intended to reduce influences on care, measurement, or reporting that could arise from knowledge of the assigned treatment. These design labels do not reveal how allocation was implemented or how masking was maintained; those details are not reported in the registry record.

The crossover designation and the option for participants in the cosyntropin arm to request epidural blood patch are important when interpreting the summaries. In a conventional crossover analysis, the same participants can contribute measurements under more than one treatment, and within-participant comparisons may be relevant. The posted outcome information instead gives group means and sample sizes by treatment group. It does not report participant-level paired results, crossover counts, treatment sequences, or a model accounting for repeated measurements. It is therefore not possible to establish from the registry record whether the posted comparison uses a crossover-aware method or how crossover was addressed.

Over-dispersion is a general concern when data vary more than a chosen statistical model expects. For a continuous scale, the distribution may be skewed, bounded, or affected by a small number of unusual observations. These features can affect standard errors and confidence intervals if a method assumes a different distribution. The registry reports standard deviations but does not report diagnostic checks, distributional assumptions, robust methods, or sensitivity analyses. This is not evidence that a particular assumption was violated; it means those checks cannot be assessed from the registry record.

Multiplicity arises when several outcomes, time points, or comparisons are examined. Even if each analysis is considered separately, looking across many tests can make it more likely that at least one result appears statistically notable. Methods for addressing multiplicity can include prespecifying a primary comparison, adjusting thresholds, or treating secondary outcomes as exploratory. The registry identifies a primary endpoint and lists secondary outcomes, while the trial description mentions multiple follow-up times. Whether a multiplicity plan was specified or applied is not reported in the registry record, so the posted unadjusted p-values should be read with that limitation in mind.

The registry lists no reported analyses in the analysis field. This does not erase the numerical results posted for the primary and secondary outcomes, but it means detailed information about the statistical procedures is not recorded there. The analysis population, handling of missing measurements, covariate adjustment, and treatment of protocol deviations are not reported in the registry record. The reported summaries should therefore be distinguished from a fully documented analysis plan.

Sample-size illustrations based on observed effects are not the same as the trial’s original sample-size justification. The record gives planning assumptions for the illustrations, but the original design assumptions and rationale are not reported in the registry record. Such calculations describe how sample size would vary under stated planning conditions; they do not describe the probability that this completed trial detected an effect.

11. Confidence Intervals and Precision

For the primary comparison, the posted mean difference is -4.34 units, and its 95% confidence interval extends from -8.446 to -0.234. The entire interval is on the negative side of zero, consistent with a lower average pain score in the epidural blood patch group under the stated subtraction order. At the same time, the interval spans a range of possible effect sizes, so the estimate is not highly precise about the magnitude of the difference.

Precision is about uncertainty in an estimate, not whether a result is important. A narrow interval would indicate that the estimate is more tightly constrained under the analysis assumptions; a wider interval indicates greater uncertainty. The observed interval should be considered alongside the group means and standard deviations, and alongside the fact that the posted groups are small. The registry does not provide a prespecified clinically important difference against which to judge the interval.

The confidence interval is not a prediction interval for individual outcomes. Participants can have scores that differ substantially from the group average, and the interval does not say where any particular participant’s score would fall. The standard deviations describe variation within the groups, while the confidence interval describes uncertainty in the estimated group difference. These answer different statistical questions.

The exact confidence-interval procedure and its assumptions are not reported in the registry record. Nor does the record explain how potential crossover or missing observations were incorporated. The precision described by the posted interval is therefore conditional on the analysis that produced it, whose details cannot be evaluated from the registry entry alone. The interval helps quantify uncertainty, but does not resolve uncertainties about the analysis population, outcome completeness, or interpretation across multiple outcomes.

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 table and curve are planning illustrations, not records of who enrolled or completed the trial. The figures are participants per arm, not total event counts: this is a continuous-outcome comparison, and the registry’s planning assumptions specify participants per arm for these calculations. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

The illustrations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. Thus, the scenarios consider planning for 100%, 75%, or 50% of the observed effect. Smaller target effects require more participants to distinguish them from random variation under the same assumptions.

The 80% power column gives the planned number of participants per arm for a design that would have an 80% chance of detecting the stated effect under the assumptions if that effect were the true one. The 90% power column gives the corresponding per-arm planning number for a 90% chance. Greater planned power generally requires a larger sample for the same target effect. These are design calculations, not evidence that the completed study had a particular probability of finding a result.

This is not observed power. The calculations use the observed effect as their starting point, and the resulting planning numbers should not be read as a retrospective measure of the trial’s success or as confirmation that the original design used these assumptions. They illustrate how required sample size changes when the target effect and desired power change.

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 = -4.340; pooled standard deviation σ = 5.852.
2. n = 2 × (1.96 + 0.842)² × 5.852² / -4.340² = 28.5, rounded up to 29 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 <- -4.34                      # observed difference in means
sigma <- 5.85150079368204                     # 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(2394457)
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 = 29 (80% power), 39 (90% power)
 75% of observed effect: n per arm = 51 (80% power), 68 (90% power)
 50% of observed effect: n per arm = 115 (80% power), 153 (90% power)
power.t.test: 29.5 
Simulated power at n = 29 per arm: 0.796 (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

The registry identifies a primary endpoint and lists secondary outcomes, while the trial description refers to pain and functional assessments at several follow-up points. Examining multiple endpoints and time points can increase the chance that at least one comparison appears statistically notable when each is assessed separately. A prespecified multiplicity strategy can help define which findings are confirmatory and how the interpretation of multiple tests should be controlled. Whether such a strategy was used is not reported in the registry record.

The posted p-value for the primary comparison is unadjusted, and the secondary comparison is also reported with an unadjusted p-value. No adjustment procedure, testing hierarchy, or designation of exploratory analyses is reported in the registry record. The posted results should therefore be interpreted as individual comparisons, not as evidence that the full family of outcomes has been evaluated with a controlled overall error rate.

Missing-data handling is not reported in the registry record. The record does not state how many observations were missing at each endpoint or follow-up, how missing values were handled, or whether any sensitivity analysis was performed. The reported sample sizes for the posted primary comparison are 15 and 13; the record does not explain whether those counts represent all randomized participants, participants with observed outcomes, or another analysis population.

The trial is described as crossover, with an option for participants in the cosyntropin arm to request epidural blood patch after a 24 hour assessment period. The number of crossovers and their treatment in the analysis are not reported. The registry also does not state whether analyses followed initial assignment, treatment received, or a different population definition. These omissions matter because crossover and missing observations can affect which participants contribute to a group comparison and what that comparison represents.

Detailed statistical methods, including any covariate adjustment, are not reported in the registry record. Without a documented analysis population, missing-data strategy, and multiplicity plan, the posted estimates remain interpretable as registry results, but cannot be fully assessed against a prespecified statistical framework.

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 0% reporting threshold.

The registry reports zero serious adverse events among 15 participants at risk in the intravenous cosyntropin group and among 13 participants at risk in the epidural blood patch group. It also reports zero other adverse events among the same respective at-risk group sizes. No serious adverse-event terms are listed.

These figures mean that no serious or other adverse events are recorded as affecting participants in the posted groups. They do not establish that no adverse events occurred outside the categories or observation period captured in the record, and they do not describe the type, severity, timing, or duration of events beyond the posted counts. The record does not report deaths. The absence of reported events in these group summaries should not be treated as proof that either intervention is free of risk.

Adverse-event counts are descriptive and should be read in light of the number of participants at risk and the completeness of reporting. The registry does not provide additional detail about the safety surveillance period or event-collection procedures. The posted figures therefore summarize what was recorded, without resolving whether rare events or events outside the recorded categories could occur.

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

The posted primary result describes lower average headache pain scores in the epidural blood patch group than in the intravenous cosyntropin group one day after the procedure. The estimated mean difference is accompanied by a confidence interval that remains below zero but covers a broad range. The result conveys both a direction in the group averages and uncertainty about the size of the difference.

This comparison does not show what happened to every participant. Group means can conceal varied responses, and the registry does not report individual-level data or the proportion of participants reaching a particular score. The result also addresses one endpoint at one follow-up time. Although the trial description mentions other pain assessments and functioning measures, complete results for those assessments are not reported in the registry record.

The numerical finding is not, by itself, proof of clinical importance. The registry does not state a threshold for a clinically important pain-score difference, and a p-value does not supply such a threshold. Statistical evidence about a group difference and its practical meaning are related but distinct questions. The posted confidence interval helps describe statistical uncertainty, but does not establish how participants valued the outcomes or whether the difference would matter in a particular setting.

Nor does the result establish formal equivalence, non-inferiority, or a definitive ranking of treatments. The trial description states a hypothesis about cosyntropin being at least as effective as conservative therapy and/or epidural blood patch, but the registry does not report a non-inferiority margin or a prespecified equivalence criterion. A comparison that has an unadjusted p-value below a conventional threshold is not a substitute for those design elements.

Interpretation is also limited by unreported details about crossover, missing observations, analysis populations, and the statistical analysis plan. The registry’s design label and crossover option make those details especially relevant to understanding what the posted group comparison estimates. The results should therefore be understood as the reported comparison at the specified time point, rather than a complete evaluation of all treatment experiences, longer-term outcomes, or every planned analysis.

17. Why This Trial Matters Statistically

This trial illustrates why statistical interpretation requires more than reading a p-value. The posted group means describe the observed averages, the mean difference gives the contrast and its direction, and the confidence interval shows uncertainty about the magnitude. Considering these together provides a fuller account than treating a threshold-crossing p-value as a complete conclusion.

It also highlights the distinction between an endpoint result and the broader trial question. The primary outcome is a pain score at a single follow-up time, while the trial description includes additional assessments and a crossover option. A single comparison cannot answer questions about later outcomes, function over time, or the effect of crossover unless those results and analytic details are also available.

The crossover designation makes clarity about analysis particularly important. Group summaries alone do not show whether participants who changed treatment were analyzed by initial assignment, actual treatment, or another approach. In crossover designs, within-participant information may be central, but the registry does not report whether such information contributed to the posted comparison. This is a reminder that design labels should be paired with enough analysis detail to determine what the estimate represents.

The sample-size illustrations provide a separate statistical lesson: planning requirements depend on the effect targeted and the desired power. They are not observed power and do not reveal the trial’s original design rationale. Keeping planning calculations distinct from the completed trial’s result helps prevent retrospective calculations from being mistaken for evidence about how well the study was designed or conducted.

Finally, the registry record shows how reporting completeness affects inference. The results contain useful group summaries, but the absence of documented analysis methods, multiplicity handling, missing-data procedures, and crossover accounting limits how thoroughly those estimates can be evaluated. Statistical transparency is needed to connect a numerical result to the precise population, estimand, and assumptions it represents.

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 registry record does not report participant characteristics or a detailed eligibility definition. The description notes that postdural puncture headache may follow intentional or unintentional dural puncture, but does not establish which participant circumstances were represented in the enrolled group. Generalizability to populations not characterized in the record cannot be assessed.

The trial is labeled crossover and permits crossover from cosyntropin to epidural blood patch after a 24 hour assessment period, but crossover counts, treatment sequence details, and analytic handling are not reported. The posted group means therefore do not reveal whether the analysis accounts for within-participant comparisons or treatment changes. The registry also does not explain whether the reported group sizes reflect all randomized participants or only those with available outcomes.

Although multiple pain and function time points are described, the posted primary result is for one day post procedure, and the record does not provide results for every stated assessment. The secondary outcome listings do not establish a complete set of distinct outcome results. The absence of a documented multiplicity plan makes it difficult to assess the inferential status of the unadjusted comparisons across outcomes and times.

The registry does not report the original sample-size justification, statistical analysis plan, missing-data methods, or detailed safety surveillance period. It also does not give a clinically important difference for the primary scale. These limitations are specific to the available record and should not be interpreted as evidence that the trial did or did not address these matters outside the registry entry.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Cosyntropin Versus Epidural Blood Patch (EBP) for Treatment of Treatment of Post Dural Puncture Headache — NCT02394457.
• Registry record last updated 2016-11-01; status last verified 2016-09.
• Results first posted 2016-11-01.
• 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 Phase 4 randomized, double-masked crossover trial comparing intravenous cosyntropin with epidural blood patch for postdural puncture headache. Enrollment is recorded as 29. The primary endpoint is mean headache pain score one day post procedure on a scale from 0, no pain, to 10, worst pain.

The posted group summaries show a lower mean pain score in the epidural blood patch group, with a mean difference of -4.34 and a 95% confidence interval from -8.446 to -0.234; the unadjusted p-value is 0.038. A secondary functioning result is also posted at one day post procedure. The registry records zero serious and zero other adverse events in each group, with no deaths reported.

Details about crossover, missing data, analysis populations, multiplicity, and the original sample-size rationale are not reported in the registry record. The posted comparisons should therefore be interpreted as results for the recorded outcomes and follow-up points, with those reporting limitations in mind.