Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury (NCT03496545), a randomized phase 1, phase 2 study. The primary outcome is Temperature Burden.

2. Clinical Question

The trial’s purpose was to evaluate the antipyretic effect of bromocriptine in critically ill patients with acute neurologic injury and fever from infectious and non-infectious causes. The registry describes treatment initiation within 1 hour after a temperature reading of at least 38.3ºC. The principal comparison is therefore between adding bromocriptine to acetaminophen and using acetaminophen alone, with the temperature outcome assessed over 48 hours.

The reported primary outcome is a continuous measure, expressed in degrees Celsius, and summarized as a mean with a standard deviation. The registry record does not define the measurement schedule or provide additional detail on how the burden above 37°C was aggregated. That limits how specifically the endpoint can be interpreted beyond its stated definition. The question concerns the measured temperature outcome in this trial; it does not by itself answer broader questions about neurologic recovery, other clinical outcomes, or the effects of treatment in populations beyond those described in the registry.

3. Trial Design

The record describes a randomized, parallel-group trial sponsored by the University of California, San Francisco. It is listed as Phase 1 and Phase 2, with an enrollment of 47. The study is marked completed. The recorded start date is 2018-11-30 and the primary completion date is 2019-11-02. The official title characterizes the study as open-label with a blinded endpoint. The masking entry is single; which study roles were masked is not reported in the registry record.

One group received acetaminophen 650 mg every 4 hours for 48 hours. The other received bromocriptine 5 mg and acetaminophen 650 mg every 4 hours for 48 hours. Both regimens could be delivered by mouth, nasogastric tube, or feeding tube. Treatment was initiated within 1 hour after a temperature reading of at least 38.3ºC. The registry labels acetaminophen as standard of care in its arm description.

The primary outcome was mean total body temperature burden above 37°C over 48 hours while the patient received the assigned medication or medications. The record also lists secondary outcomes concerning symptomatic hypotension, nausea and headache; total time with temperature at least 38.3ºC; and total time to a first temperature below 37.5ºC. The registry lists four outcome measures overall, but detailed posted results for all secondary outcomes are not available in the outcome information summarized in the record.

The number randomized to each group is not given as a randomization count. The reported primary outcome includes 20 participants in the acetaminophen group and 24 in the bromocriptine-and-acetaminophen group. Whether these numbers represent all randomized participants, a particular analysis population, or participants with observed outcome data is not reported in the registry record. The allocation procedure, concealment method, and original sample-size justification are also not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

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 Temperature Burden, measured over over 48 hours.

The primary endpoint is described as mean total body temperature burden above 37°C over 48 hours, measured in degrees Celsius. It is summarized by a mean and standard deviation for each treatment group. The stated timeframe is the 48-hour period during which participants received the assigned medication regimen.

A continuous temperature measure preserves more information about the observed values than a simple indicator of whether a participant crossed a threshold. A group mean provides a concise summary of the central level, while the standard deviation describes variation among participants. Comparing the group means estimates the average difference in the recorded measure. The confidence interval around that difference helps show how much uncertainty remains in the estimate.

Temperature is relevant to the study’s stated aim because the trial evaluates an antipyretic effect in febrile critically ill patients with acute neurologic disease. The registry’s endpoint definition refers to burden above 37°C, while the outcome values are reported in degrees Celsius. Additional operational detail about the calculation of burden, the frequency of temperature measurements, and the handling of readings during the 48-hour period is not reported in the registry record. Those details would help clarify precisely what changes in the summary measure represent.

The endpoint is a temperature outcome, not a direct measure of neurologic function, survival, or overall recovery. A difference in this endpoint should therefore be interpreted only as a comparison of the recorded temperature measure in the trial groups, not as proof of a difference in other clinical outcomes.

7. Results Posted in the Registry

• Bromocriptine and Acetaminophen: mean 37.70 versus 37.80 on control; difference -0.10 (95% CI -0.43 to 0.23), standardized effect d = -0.18; z-test p = 0.546.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a continuous primary outcome summarized by group means and standard deviations. The comparison is a mean difference: the combination-group mean minus the acetaminophen-group mean. With this direction, a negative estimate means the observed mean was lower in the combination group, while a positive estimate would mean it was higher. The estimated difference is -0.1°C.

What does a mean and standard deviation describe?

The mean is a summary of the group’s average recorded outcome. The standard deviation describes how dispersed individual observations are around that group average. It is not the uncertainty in the estimated mean itself. That uncertainty depends on the amount of information in the group as well as the variation among observations. The registry gives standard deviations of 0.5°C and 0.6°C for the two groups, alongside the respective reported outcome counts.

A difference between group means condenses the comparison into the original measurement scale. Here that scale is degrees Celsius, making the estimate interpretable as a temperature difference. The estimate does not describe every participant’s response: individual outcomes can vary around each group mean. Nor does the difference, by itself, describe whether the measure is clinically important; that judgment would require a suitable clinical context and a stated threshold for importance, neither of which is reported in the registry record.

How should the confidence interval be read?

A confidence interval expresses the uncertainty in an estimated effect under the statistical method used. The reported 95% interval for the mean difference is -0.425°C to 0.225°C. In general, a confidence interval is generated by a procedure that, over repeated studies under its assumptions, would cover the true effect at the stated rate. It is not a range containing every individual participant’s outcome, and it is not a probability statement that the true effect lies in this particular interval.

Because this interval includes zero, the posted result does not distinguish clearly between a lower mean in the combination group, no mean difference, and a higher mean within the interval’s limits. The interval’s endpoints also communicate scale: they show the range of effects that remain reasonably compatible with the data and the method, rather than only giving a yes-or-no significance decision. The registry does not identify an interval method or state whether the comparison was adjusted for other variables.

What does the p-value add?

The unadjusted p-value is 0.546. A p-value measures how unusual results at least as incompatible with a specified null model would be if that model and the analysis assumptions were correct. It does not measure the size or clinical importance of the estimated difference. It is also not the chance that the finding arose “by chance” in a broad, assumption-free sense. Since the registry labels this value unadjusted, it should not be interpreted as accounting for multiple outcome or analysis choices.

A p-value and a confidence interval answer related but different questions. The p-value gives a measure of compatibility with a null value under a test; the interval conveys the uncertainty and range of effect sizes. Neither replaces review of the design, outcome definition, missing data, and analysis population. A p-value that does not indicate a clear difference cannot establish equivalence, particularly without a prespecified equivalence margin.

Why do allocation and masking matter?

Random allocation is intended to make treatment groups comparable on average with respect to measured and unmeasured factors, although chance imbalances can still occur. The registry identifies the trial as randomized and parallel-group. The method used to generate the allocation sequence and conceal assignments before enrollment is not reported in the registry record. Those details are relevant because predictable or unconcealed allocation can undermine the protection randomization is meant to provide.

The official title describes an open-label trial with a blinded endpoint, while the masking entry says single. Open-label treatment means the description does not characterize treatment as fully masked. Blinding an endpoint assessor can reduce some opportunities for assessment to be influenced by treatment knowledge, but the identity of the masked role and the procedures used are not reported in the registry record. Temperature readings may appear objective, yet how and when readings are taken, recorded, or selected can still matter.

What can be concluded from the posted analysis?

The registry lists zero analyses in the outcome-analysis information. The displayed group summaries and unadjusted comparison therefore do not come with a detailed analysis description in the record. Covariate adjustment, handling of repeated temperature measurements, model choice, assumptions checks, and prespecified analysis details are not reported in the registry record. General statistical interpretation should remain conditional on the methods used and the quality and completeness of the underlying measurements.

General statistical considerations also include variation beyond what a simple mean-and-standard-deviation summary can represent. For a continuous outcome, a mean comparison is most straightforward when the summary is meaningful for the outcome distribution and the analysis adequately accounts for the design. If observations are especially skewed, contain influential values, or are repeatedly measured in ways that are not independent, other modeling choices may be relevant. Whether any such features occurred or were addressed is not reported in the registry record. The posted summaries support a cautious description of the observed group means and their stated uncertainty, not reconstruction of an unreported analysis plan.

10. Confidence Intervals and Precision

The estimated mean difference is -0.1°C, with a 95% confidence interval from -0.425°C to 0.225°C. This interval is the main guide to precision: it shows that the estimate is uncertain enough to remain compatible with a difference in either direction, as well as with zero. The point estimate alone would conceal that uncertainty.

Precision refers to how narrowly the data locate an effect, given the design and statistical method. The interval is not a prediction range for individual temperatures, and it does not mean that all plausible values are equally likely. It describes uncertainty around the group-level mean difference under the assumptions of the analysis. The method used to calculate the interval is not reported in the registry record.

The outcome counts are 20 for acetaminophen and 24 for the combination group. The registry does not state whether these counts include everyone randomized or only participants with usable primary outcome data. It also does not report the amount or pattern of missing outcome information. Both the amount of usable data and the variation in the measurements can affect precision, so the counts alone do not explain the width of the interval.

The interval includes values below and above zero, and the registry gives an unadjusted p-value of 0.546. These features indicate that the estimated direction and magnitude are not tightly determined by the posted comparison. The record does not report a clinically important difference threshold, so the interval cannot be classified as excluding effects considered important by the study team. It is most informative to retain the estimate and its full interval together, rather than treating the point estimate or p-value as a complete account of the result.

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 use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect being planned for is the stated fraction of the observed effect. The original trial’s own sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under the planning assumptions, if that effect is real and the assumptions hold. The 90% power column gives the corresponding figure for a design with a 90% chance. These are planning probabilities for a hypothetical future design, not probabilities that the observed result is correct.

For planning at 100% of the observed effect, the figures are 488 participants per arm for 80% power and 652 participants per arm for 90% power. For planning at 75% of the observed effect, the figures are 866 participants per arm for 80% power and 1,160 participants per arm for 90% power. For planning at 50% of the observed effect, the figures are 1,949 participants per arm for 80% power and 2,608 participants per arm for 90% power. The smaller the effect targeted for detection, the more participants the illustration requires.

These calculations are not observed power. They are planning illustrations based on the observed effect, with the stated simplifying assumptions; they are not the trial’s original design rationale and do not establish what the study was capable of detecting under its actual conduct. A curve connecting planning values should be read as illustrating how required enrollment changes with the target effect, not as additional evidence about treatment outcomes.

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 = -0.100; pooled standard deviation σ = 0.557.
2. n = 2 × (1.96 + 0.842)² × 0.557² / -0.100² = 487.0, rounded up to 488 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 <- -0.0999999999999943                      # observed difference in means
sigma <- 0.556990211079239                     # 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(3496545)
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 = 488 (80% power), 652 (90% power)
 75% of observed effect: n per arm = 866 (80% power), 1,160 (90% power)
 50% of observed effect: n per arm = 1,949 (80% power), 2,608 (90% power)
power.t.test: 488 
Simulated power at n = 488 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 record lists three secondary outcomes: adverse events involving symptomatic hypotension, nausea and headache; total time with temperature at least 38.3ºC; and total time to a first temperature below 37.5ºC. It lists four outcome measures overall, but the number of posted analyses is zero. Numerical secondary outcome comparisons, analysis details, and the relationship between the listed outcomes and any planned hypotheses are not reported in the registry record.

Multiplicity is the issue that arises when several outcomes, time points, or analyses are considered. The more comparisons examined, the greater the opportunity for a nominally unusual result to occur even when there is no corresponding underlying effect. This is a general statistical concern, not a claim that a particular adjustment was required or used in this trial. The record does not report a multiplicity strategy, such as a hierarchy of outcomes or an adjustment to significance thresholds. The primary outcome’s p-value is explicitly unadjusted, so it should not be read as accounting for the other outcomes or analyses.

Missing-data handling is not reported in the registry record. The record does not state how many participants had unavailable primary outcome data, whether temperature readings were missing within otherwise observed follow-up, or what approach was used for such gaps. It also does not describe whether missingness was assessed by treatment group or whether sensitivity analyses were conducted. These details matter because conclusions can depend on who contributes data and on assumptions about outcomes that are not observed.

The analysis population is not reported in the registry record. The outcome counts are given, but the record does not clarify whether the summaries are based on all randomized participants, participants who received treatment, or participants with available endpoint measurements. The registry identifies randomization, but that alone does not establish how the reported comparison handled departures from assigned treatment or missing outcomes. Without these details, the reader cannot determine whether the primary comparison follows an intention-to-treat approach or another analysis population.

14. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hospitalization (3.8%).

For serious adverse events, the record lists 21 participants at risk in the acetaminophen group, with 0 affected, and 26 at risk in the bromocriptine-and-acetaminophen group, with 1 affected. Deaths are listed as 0 in the acetaminophen group and 1 in the combination group. These are counts recorded in the registry, not adjusted comparisons between groups.

The registry names hospitalization as a top serious adverse event term and gives 3.8%. The record does not specify in that entry which group or denominator the percentage refers to, so it should not be assigned to either treatment group based on the information stated there. Counts of participants at risk and affected are not interchangeable with event counts if a participant can experience more than one event; details about event handling are not reported in the registry record.

The registry also lists other adverse events, but those figures do not change the limitations of interpreting the serious-event counts. The groups are small, and the record does not provide a comparative statistical analysis of serious adverse events. A count of zero in one group does not establish absence of risk, and a count in one group does not by itself establish that treatment caused the event. The posted safety information is descriptive and should be interpreted with the stated denominators and reporting limitations in mind.

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

The posted primary outcome comparison estimates a mean difference of -0.1°C for bromocriptine plus acetaminophen relative to acetaminophen alone. The confidence interval, -0.425°C to 0.225°C, includes zero and permits effects in either direction. The unadjusted p-value is 0.546. Taken together, these statistics do not provide clear evidence of a difference in the reported mean temperature measure, but they do not establish that the two regimens are equivalent.

The result does not show whether any difference would be clinically important. No clinical importance threshold or equivalence margin is reported in the registry record. The temperature endpoint also does not directly measure neurologic recovery, functional status, or other outcomes that may matter to patients. The registry lists secondary outcomes, but their numerical results are not reported in the outcome information summarized in the record.

The result should not be expanded into a claim that bromocriptine does or does not work. The estimate is limited to the specified group comparison, the 48-hour temperature outcome, and the participants contributing to the posted summaries. The record does not clarify the analysis population, missing-data approach, or all details of measurement and analysis. Those uncertainties constrain how confidently the result can be generalized or interpreted.

The study is described as randomized, which is a useful design feature for comparing groups, and as open-label with a blinded endpoint. However, the allocation procedures and masking roles are not reported in the registry record. The trial’s enrollment and observed outcome counts are limited, and the precision interval remains broad enough to include effects on both sides of zero. The appropriate reading is therefore a cautious one: the posted estimate is close to zero, while the data do not precisely determine the direction or size of the underlying difference.

16. Why This Trial Matters Statistically

This trial illustrates why an estimated effect, its uncertainty, and the analysis context should be considered together. The mean difference of -0.1°C is a concise point estimate, but it does not capture the full range of values compatible with the data. The confidence interval extends from -0.425°C to 0.225°C and includes zero. A reader who relies only on the point estimate could overlook that the direction and magnitude remain uncertain.

It also illustrates the difference between failure to demonstrate a clear difference and evidence of equivalence. The unadjusted p-value is 0.546, but the registry does not report an equivalence margin or a design intended to test equivalence. Statistical non-significance alone cannot settle whether two regimens are sufficiently similar for a particular purpose.

The record’s limited analysis detail is also statistically important. The registry identifies randomization and a blinded endpoint in the official title, yet the allocation process, masking roles, analysis population, missing-data methods, and multiplicity strategy are not reported in the registry record. These design and analysis features affect how the estimate should be understood and how robust it may be.

Finally, the planning illustrations make clear that detecting smaller effects generally requires more participants under the stated assumptions. They are not a retrospective measure of the trial’s power, nor evidence that a future study would necessarily reproduce the observed estimate. Separating planning calculations from observed results helps prevent an uncertain estimate from being treated as a reliable target effect. The statistical lesson is to interpret the magnitude, precision, design, and reporting completeness as parts of one evidence assessment.

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 registry record leaves important design and reporting details unspecified. The method for sequence generation, allocation concealment, and the identity of the masked role are not reported in the registry record. The official title describes an open-label trial with a blinded endpoint, but the procedures used to maintain endpoint blinding are not described.

The reported primary outcome is defined as mean total body temperature burden above 37°C over 48 hours, but the registry does not give the temperature measurement schedule, the aggregation formula, or details about missing readings. The analysis population is not reported in the registry record, and the meaning of the outcome counts in relation to enrollment is not clarified. Missing-data methods, sensitivity analyses, and any covariate adjustment are also not reported.

The record lists three secondary outcomes but gives zero posted analyses. It does not report a strategy for handling multiple outcomes or analyses. The original sample-size justification, design assumptions, and any interim analyses are not reported in the registry record. The planning illustration is based on the observed effect and should not be mistaken for the original trial calculation.

Safety counts are descriptive, and the hospitalization percentage is not assigned to a group in the listed entry. The record does not provide a comparative statistical analysis of serious adverse events. These limitations do not invalidate the posted summaries, but they restrict what can be concluded about the robustness, generalizability, and clinical meaning of the estimates.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury — NCT03496545.
• Registry record last updated 2021-06-24; status last verified 2021-06.
• Results first posted 2021-06-24.
• 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

NCT03496545 is a completed randomized parallel-group trial sponsored by the University of California, San Francisco. It is listed as Phase 1 and Phase 2, with enrollment of 47. The official title describes an open-label, blinded-endpoint study in febrile critically ill adults with acute neurologic disease.

The comparison was bromocriptine plus acetaminophen versus acetaminophen alone. The primary outcome was mean temperature burden above 37°C over 48 hours. Reported group means were 37.7°C and 37.8°C, respectively, with an estimated mean difference of -0.1°C and a 95% confidence interval from -0.425°C to 0.225°C. The unadjusted p-value was 0.546.

The interval includes zero and allows differences in either direction. The registry lists secondary outcomes and adverse-event counts, but analysis-population details, missing-data methods, and several design and analysis procedures are not reported in the registry record.