This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Clinical, Pharmacological and Molecular Effects of IV and Oral Acetaminophen in Adults With aSAH (NCT02549716), a randomized phase 4 study. The primary outcome is Bioavailability of Acetaminophen in Cerebral Spinal Fluid (CSF) and Blood.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02549716 |
| Phase | Phase 4 |
| Condition | Subarachnoid Hemorrhage, Stroke |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Enrollment | 3 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Milton S. Hershey Medical Center |
| Results posted | Yes |
2. Clinical Question
Population
Adults with aneurysmal subarachnoid hemorrhage (aSAH) were the intended study population. The registry also lists subarachnoid hemorrhage and stroke as conditions. The record does not provide participant characteristics or describe which clinical features determined eligibility beyond the population stated in the study title and summary.
Intervention
One group was assigned intravenous acetaminophen with an oral placebo. The IV formulation is described as OFIRMEV, with a concentration of 1000mg/100ml (10mg/ml) and a total dose of 1 gram. The study also describes sampling after first administration and during subsequent dosing.
Comparator
The comparison group was assigned oral acetaminophen with an IV saline placebo. The oral formulation is described as two 500mg tablets, or 1 gram of acetaminophen. The parallel-group design compares these assigned routes rather than describing a crossover between routes.
Primary question
The primary question was whether acetaminophen bioavailability in cerebrospinal fluid (CSF) and blood differs between IV and oral administration. The study also planned to compare temperature and inflammatory cytokine levels. Because the primary outcome was not analyzed after early termination, the record does not establish the direction or size of any difference.
3. Trial Design
The registry describes a randomized, triple-masked, parallel-group, phase 4 study sponsored by Milton S. Hershey Medical Center. It lists enrollment of 3 and reports that the study was terminated. The recorded start date is 2017-01-05, and the primary completion date is 2018-06-08. These dates and the termination status give context for why the planned outcome should not be read as a completed comparison.
The two study groups differed in the route used to administer acetaminophen, with matching placebo treatments described for the other route. One group received IV acetaminophen and an oral placebo; the other received oral acetaminophen and an IV placebo. This arrangement is intended to maintain masking across the administration routes. The registry identifies masking as triple, but does not report which specific roles were masked or how masking was maintained.
The primary outcome concerned drug concentrations in CSF and blood. The planned schedule included samples at Time = 0, 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after first administration, followed by samples every 24 hours for 14 days. The description also planned a sample every 35 hours, timed 1 hour before the 6th loading dose, to assess steady-state acetaminophen levels. These are planned measurements, not evidence that the sampling schedule was completed.
Secondary outcomes included Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Thromboxane A-2 (TXA-2) concentrations in CSF and blood, number of febrile periods, and incidence of vasospasm. The registry record does not provide analyzed results for these outcomes. It also does not report a detailed protocol, eligibility criteria, the allocation procedure, or the operational definitions used for secondary outcomes.
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
| Stage | IV Acetaminophen + Oral Placebo | Oral Acetaminophen + IV Placebo |
|---|---|---|
| STARTED | 1 | 2 |
| COMPLETED | 1 | 2 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Outcome measure was not analyzed because study was terminated early.
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.
| Characteristic | Unit | IV Acetaminophen + Oral Placebo | Oral Acetaminophen + IV Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 1 | 2 | 3 | |
| Age, Continuous | years | 37 (37 to 37) | 45 (45 to 46) | 42.6 (37 to 46) |
| Sex: Female, Male: Female | Participants | 1 | 2 | 3 |
| Sex: Female, Male: Male | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 1 | 2 | 3 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Region of Enrollment: United States | participants | 1 | 2 | 3 |
6. Primary Endpoint
The registry lists the primary outcome as Bioavailability of Acetaminophen in Cerebral Spinal Fluid (CSF) and Blood, measured over Time = 0, 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after first drug administration.
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was bioavailability of acetaminophen in CSF and blood. Bioavailability concerns the concentration of a drug that reaches a measured biological compartment after administration. Comparing CSF and blood concentrations across administration routes can describe how drug exposure differs between those compartments. This is relevant to the study’s stated aim of comparing IV and oral administration in people with aSAH, but a concentration comparison alone does not establish a difference in temperature, inflammatory markers, or clinical outcomes.
The planned measurements were repeated over time after first administration, with additional sampling during the subsequent treatment period and at a specified interval before a later loading dose. A time course can distinguish early concentrations from later concentrations and can help characterize whether measured levels approach a steady state. The registry gives the intended collection times, but it does not provide the concentration data or an analysis of changes over time.
The outcome was not analyzed because the study was terminated early. Accordingly, the registry record contains no reported treatment estimate, uncertainty interval, or inferential test for the primary endpoint. The planned endpoint explains what the trial sought to measure; it does not supply evidence about the relative bioavailability of the two routes.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central interpretive fact is that the primary bioavailability outcome was not analyzed because the study was terminated early. The registry therefore does not report an estimated difference between IV and oral acetaminophen in CSF or blood concentrations. It also does not report a confidence interval, p-value, or other inferential result for that comparison. No conclusion about the direction, magnitude, or precision of a route difference can be drawn from this record.
The registry lists enrollment of 3. That is the recorded enrollment, not a substitute for outcome data. With the primary outcome unanalysed, there is no observed effect estimate to interpret and no reported measure of its uncertainty. The absence of an analysis is not evidence that the routes produce the same concentrations; it means the registered comparison is unresolved by the posted results.
The record’s secondary outcome descriptions do not change this interpretation. Cytokine and thromboxane concentrations, febrile periods, and vasospasm were listed as outcomes, but analyzed results are not reported in the registry record. The study summary also describes planned comparisons of temperature and inflammatory cytokines. A planned comparison should not be mistaken for a finding, and no result on temperature or these biological measures is available for interpretation.
Safety information is reported separately from the efficacy and bioavailability outcomes. The adverse-event record lists no serious events and no deaths in either group. It lists one other adverse event in the oral acetaminophen plus IV placebo group and none in the IV acetaminophen plus oral placebo group. These are event counts in a very small enrolled study, not a precise comparison of safety rates. The record does not supply event descriptions or establish whether an event was caused by a study treatment.
Planning illustrations based on an observed effect, if considered alongside the record, must not be interpreted as observed power or as evidence that an effect was detected. The underlying outcome was not analyzed, and the registry does not report an observed effect estimate for the primary comparison. The sample-size framework is described as an illustration under specified assumptions, not as the trial’s original design justification.
Overall, this record documents a study question, randomized design, intended measurement schedule, and limited safety counts. It does not answer the primary comparative question. Any inference about relative exposure, temperature, inflammatory markers, or clinical events would go beyond the reported analyses.
9. Statistical Methods Explained
Statistical interpretation begins by distinguishing an outcome that was planned from one that was analyzed. The registry describes a primary bioavailability outcome and a schedule for collecting CSF and blood samples. It also explicitly states that this outcome was not analyzed because the study was terminated early. Thus, the schedule documents intended measurement, not an observed concentration profile. Without analyzed measurements, there is no estimate of the difference between groups to interpret.
What would an estimate describe?
In a randomized comparison, a treatment-effect estimate summarizes the observed contrast between assigned groups for a defined outcome. For this study, an estimate could have described a difference in measured acetaminophen concentrations between the IV and oral groups at a specified time, or a contrast across the planned time course. The registry does not state a single summary measure, such as a mean difference or a model-based contrast. The statistical estimand and the exact method for summarizing repeated concentrations are not reported in the registry record.
A confidence interval is a general statistical tool for expressing uncertainty around an estimate. It indicates which effect sizes are reasonably compatible with the data and the method’s assumptions. A narrow interval would indicate greater precision, while a wide interval would indicate less precision. Here, no primary-outcome estimate or confidence interval is reported, so precision cannot be assessed. A non-significant test, if one had been reported, would not by itself establish equivalence; in this record, even such a test is absent.
Why do repeated measurements matter?
The primary outcome was planned at multiple times after first administration and at later intervals. Measurements from the same participant are generally related rather than independent: a person’s concentration at one time can be associated with that person’s concentration at another time. General methods for repeated measurements account for this within-person dependence. Treating every measurement as if it came from a different person can understate uncertainty and give misleading inference.
Different summaries can answer different questions. A comparison at an individual time point focuses on that time. A model using the whole time course can describe the pattern over time, but requires choices about the time structure, the relationship between measurements, and missing observations. An overall exposure summary would answer another kind of question and would require an appropriate definition and data. The registry does not report which, if any, of these approaches was planned or used. Since the outcome was not analyzed, none can be attributed to the study’s results.
What does randomization contribute?
Random allocation is intended to make assigned groups comparable on average with respect to factors measured and unmeasured before treatment. It supports a causal comparison when the assignment is implemented as planned and outcomes are analyzed appropriately. Randomization does not guarantee balance in a particular small study, does not correct missing outcome measurements automatically, and does not create information when outcomes are unavailable. The registry reports randomized allocation, but does not describe the sequence-generation or concealment procedures.
The triple-masked designation indicates that the registry classifies the study as masked at three levels, but it does not identify those roles or provide operational details. Masking can reduce the chance that expectations influence treatment administration, outcome assessment, or reporting. The registry’s designation alone does not show how masking was maintained or whether it was successful.
How should the planning illustration be read?
The record describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It states that the effect to detect is a specified fraction of the observed effect. No illustration values or effect fractions are reported in the registry record, and the primary outcome itself was not analyzed. These calculations are planning illustrations, not the trial’s own sample-size justification and not observed power.
In general, a sample-size calculation asks how many participants would be needed under assumptions about the effect to detect, variability, significance level, allocation, and analysis. Altering any assumption can alter the planning result. When an illustration is based on an observed effect, that effect can itself be uncertain, especially in a small study. Such a calculation should therefore be treated as conditional on its assumptions rather than as a retrospective measure of whether the trial had a chance to detect a true effect.
Why is over-dispersion sometimes relevant?
As a general matter, over-dispersion occurs when count data vary more than a simple statistical model expects. If febrile periods or events were analyzed as counts, a model that ignores extra variability could produce uncertainty estimates that are too small. This is a general methodological consideration, not a method reported for this trial. The registry does not report an analysis model for febrile periods, vasospasm, cytokines, or the primary concentration outcome.
The same distinction applies to safety counts. Counts alone do not show the uncertainty around a rate or a treatment contrast. With no detailed event descriptions and no inferential safety analysis reported, the counts should be presented descriptively rather than treated as evidence of a difference in risk.
10. Multiplicity, Missing Data and Analysis Populations
The study planned multiple types of outcomes: repeated concentrations in CSF and blood, temperature and inflammatory measures described in the summary, and secondary outcomes involving cytokines, thromboxane, febrile periods, and vasospasm. Looking at several outcomes or time points can create a multiplicity problem: the more comparisons made, the greater the general chance of finding an apparently notable result by chance if each is tested separately. A prespecified analysis plan can address this through a hierarchy of outcomes, adjusted testing, or a clearly defined primary contrast.
The registry record does not report a multiplicity strategy, a hierarchy among time points, or which comparisons were intended to support formal inference. The primary outcome was not analyzed, and no secondary analyses are reported. It is therefore not possible to determine how multiplicity would have been handled or whether any adjustment was applied.
Missing-data methods and analysis populations are also not reported in the registry record. The record does not say how many planned samples were collected, whether any participants had incomplete measurements, or how incomplete data would have been handled. It does not describe an intention-to-treat, per-protocol, or other analysis population. These omissions matter particularly for a repeated-measure outcome, because the timing and pattern of missing measurements can affect the analysis and interpretation.
The study’s early termination is documented, but the reason for termination and any planned interim analyses are not reported in the registry record. No statistical analysis plan or sample-size justification is reported. These details should not be inferred from the termination status or from planning illustrations.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| IV Acetaminophen + Oral Placebo | 0 | 1 | 0.0% |
| Oral Acetaminophen + IV Placebo | 0 | 2 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| IV Acetaminophen + Oral Placebo | 0 of 1 |
| Oral Acetaminophen + IV Placebo | 0 of 2 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| IV Acetaminophen + Oral Placebo | 0 of 1 |
| Oral Acetaminophen + IV Placebo | 1 of 2 |
Most frequent non-serious adverse event terms
| Event term | Organ system | IV Acetaminophen + Oral Placebo | Oral Acetaminophen + IV Placebo |
|---|---|---|---|
| Elevated Liver Function Tests | Hepatobiliary disorders | 0 of 1 | 1 of 2 |
The adverse-event record separates serious adverse events, other adverse events, and deaths. For the IV acetaminophen plus oral placebo group, the registry reports 0 serious events among 1 at risk, 0 other events among 1 at risk, and 0 deaths. For the oral acetaminophen plus IV placebo group, it reports 0 serious events among 2 at risk, 1 other event among 2 at risk, and 0 deaths.
These are descriptive counts, not a reliable comparison of event rates. The record lists only a small number of participants at risk, and it does not describe the single other event or report whether it was judged related to treatment. It also does not provide a statistical comparison or confidence interval for safety outcomes. The absence of a reported serious event or death in these groups does not establish that either treatment has no safety risks.
The registry lists no top serious-event terms. That should be read as no serious-event terms being listed in the record, not as evidence about unreported event types or causes. Safety interpretation is limited to the counts and classifications recorded.
12. What the Result Does, and Does Not, Mean
The record establishes that investigators planned a randomized comparison of IV and oral acetaminophen in adults with aSAH, using matched placebo treatments and a primary outcome based on concentrations in CSF and blood. It also documents a planned time course for sampling and lists secondary measures related to inflammatory markers, febrile periods, and vasospasm. Those details explain the clinical and pharmacological question the study was designed to address.
The record does not establish which route produced higher concentrations, whether concentrations differed at any particular time, or how precise a route comparison might have been. The primary bioavailability outcome was not analyzed because the study was terminated early. There is no reported effect estimate or inferential result for that question. The planned measurements therefore cannot be interpreted as findings.
Nor does the record establish a treatment effect on temperature, cytokines, thromboxane, febrile periods, or vasospasm. These outcomes are listed as planned measures, but their analyses and results are not reported in the registry record. A study objective is not an observed result, and a comparison that was not analyzed cannot support a claim of benefit, lack of benefit, or equivalence.
The safety counts provide only a limited descriptive account. They report no serious events or deaths and one other event in the oral acetaminophen plus IV placebo group. The event is not described, and the numbers are too limited to support a precise comparative safety interpretation. The counts should not be generalized beyond the participants represented in this record.
In short, the record is informative about study design and intended measurements, but it leaves the principal comparative question unanswered. This is a distinction between the rationale and structure of a trial and evidence from its analyzed outcomes.
13. Why This Trial Matters Statistically
This trial raises a useful statistical question about how to compare drug exposure across biological compartments and over time. A single concentration measurement may not represent the full time course, while repeated samples can provide a richer description only if the dependence among measurements is handled appropriately. The planned CSF and blood sampling illustrates why outcome definition and analysis strategy need to be aligned with the scientific question.
The record also shows why planned outcomes and analyzed outcomes must be kept distinct. A detailed measurement schedule does not yield an estimate unless the measurements are collected, processed, and analyzed. Early termination can leave a clinically motivated question unresolved, even when the intended comparison and outcomes are clearly described. The registry explicitly records that the primary outcome was not analyzed.
Randomization and masking are important design features, but they do not remove the need for adequate outcome information, transparent analysis methods, or uncertainty estimates. In a small study, random allocation may not ensure that groups are similar on every relevant characteristic, and sparse safety counts cannot support precise risk comparisons. These are general principles; the registry does not provide adjusted analyses or participant characteristics with which to assess their practical effects in this study.
Finally, planning illustrations should be separated from trial findings. Calculations using an observed effect and stated assumptions can help illustrate future planning, but they are not a substitute for a completed analysis and do not describe observed power. The value of this record is therefore chiefly in documenting the intended design and the limits of what can be inferred from the posted results.
14. 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 principal limitation is that the primary bioavailability outcome was not analyzed after early termination. No concentration estimates, treatment contrasts, confidence intervals, or p-values are reported. As a result, the planned comparison of IV and oral acetaminophen cannot be evaluated from the registry record.
The registry reports enrollment of 3, but does not report participant characteristics, the number with completed primary measurements, or whether the planned sampling schedule was followed. Without those details, the representativeness of the enrolled participants and the completeness of outcome collection cannot be assessed. The record also does not report eligibility criteria beyond the broad population description.
There is no reported statistical analysis plan, analysis population, missing-data approach, or method for handling repeated measurements. The record does not specify the primary time point or summary measure that would have represented bioavailability. It also does not describe how multiplicity across time points and secondary outcomes would have been managed. These gaps limit assessment of the planned inferential framework, independently of the fact that the primary outcome was not analyzed.
The reason for termination, any interim analyses, and the trial’s sample-size justification are not reported in the registry record. The planning framework described in the record is an illustration based on an observed effect, not the trial’s own design justification. It cannot fill the gap left by the absent outcome analysis.
Safety information is also limited: the record gives event counts but no description of the other event, causal attribution, or comparative safety analysis. Overall, the registry documents the study’s intended question and design, but the lack of analyzed efficacy and pharmacological outcomes prevents conclusions about the comparative effects of the two routes.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Clinical, Pharmacological and Molecular Effects of IV and Oral Acetaminophen in Adults With aSAH — NCT02549716.
- Registry record last updated 2019-04-10; status last verified 2019-03.
- Results first posted 2019-04-10.
- 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.
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18. Record Summary
NCT02549716 is a phase 4 randomized, triple-masked, parallel-group study sponsored by Milton S. Hershey Medical Center. It compared IV acetaminophen with oral acetaminophen in adults with aSAH, using placebo treatment by the alternate route. The registry lists enrollment of 3, a start date of 2017-01-05, a primary completion date of 2018-06-08, and terminated status.
The primary outcome was acetaminophen bioavailability in CSF and blood, measured on a planned schedule after first administration and during subsequent treatment. The registry states that this outcome was not analyzed because the study was terminated early. Secondary measures included inflammatory markers, febrile periods, and vasospasm, but analyzed results are not reported. Safety counts include no serious events or deaths in either group and one other event in the oral acetaminophen plus IV placebo group. The record does not support a comparative estimate of bioavailability, clinical effects, or safety.