Hydroxychloroquine and Cognitive Function After Surgery: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Hydroxychloroquine and Cognitive Function After Surgery (NCT03025087), a non-randomized phase 4 study. The primary outcome is Ktrans Volume Transfer Constant.

2. Clinical Question

The clinical question is therefore about a postoperative imaging measure, rather than a reported clinical outcome such as cognitive function. Although the study title refers to cognitive function after surgery, the posted primary endpoint is Ktrans, a measure described as reflecting permeability or leakage across the blood-brain barrier. The record does not report a cognitive-function endpoint among its outcome measures.

3. Trial Design

The registry record identifies this as a phase 4 study with non-randomized allocation, no masking, and a parallel model. Enrollment is listed as 24. The record lists individuals undergoing cardiac and general surgery as the study population. The sponsor is Duke University. The study began on 2017-06-19, had a primary completion date of 2023-05-22, and is listed as terminated. A reason for termination is not reported in the registry record.

The intervention descriptions identify five groups, labelled Phase 1 through Phase 5. Each description specifies six evaluable subjects. The first two groups include cardiac and noncardiac patients, while the later descriptions refer to cardiac subjects. The dosing schedules differ across the groups: they include a 1000 mg dose before surgery and, in several groups, additional daily dosing through MRI on postoperative day 1-5. The fifth description places the initial dose after separation from CPB. These descriptions are not evidence of random assignment or of a controlled comparison.

The registry’s overall study phase designation and its group labels are different kinds of record information: the study is designated PHASE4, while the intervention descriptions use Phase 1 through Phase 5 as group names. The record does not explain the relationship between those labels. It also does not report a prespecified statistical analysis plan, a sample-size justification for the study, or whether interim analyses were planned. Because allocation was non-randomized and the groups differ in their stated patient populations and dosing schedules, comparisons between groups should not be interpreted as if they arose from randomized assignment.

4. Participant Flow and Accounting

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

Before assignment: There was no enrollment in Phase 3, Phase 4, or Phase 5.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who completed the MRI.

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.

Population: Data not collected on eight participants. There was no enrollment in Phase 3, Phase 4, or Phase 5.

6. Primary Endpoint

The registry lists the primary outcome as Ktrans Volume Transfer Constant, measured over Postoperative day 1-5.

The primary endpoint is the Ktrans Volume Transfer Constant, a unitless continuous measure assessed on postoperative MRI during postoperative day 1-5. The record describes Ktrans as a permeability or leakage constant across the blood-brain barrier. It is calculated from the amount of gadolinium-based contrast agent in the extravascular-extracellular space. The endpoint population is participants who completed the MRI.

As a continuous measure, Ktrans can represent variation in the measured imaging quantity rather than assigning each participant to a binary category. In general, an imaging measure may be useful for examining a biological process that is difficult to observe directly. Its interpretation depends on how the measurement relates to the underlying process and on the measurement procedure. The registry record defines the intended interpretation as blood-brain barrier permeability, but does not report validation details or measurement reliability.

The record does not report group means, standard deviations, participant-level values, an estimated contrast, or uncertainty intervals for Ktrans. It therefore does not establish the direction or magnitude of any observed difference. The title mentions cognitive function, but the one listed outcome measure is Ktrans; a cognitive-function result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is continuous, and the registry describes its summary parameter as a mean with standard deviation. In general, a mean describes the average value in a group, while a standard deviation describes how spread out participant measurements are around that average. Both pieces of information help characterize a continuous outcome, but neither alone estimates a treatment effect. A comparison requires a clearly specified contrast between groups or conditions, along with an analysis suited to the design and available data. The Ktrans means, standard deviations, and any contrast are not reported in the registry record.

A confidence interval is a statistical range that expresses uncertainty around an estimate under the assumptions of the analysis. A narrower interval generally indicates greater precision, while a wider interval indicates less precision. It is not a guarantee that the true value lies within the interval. For this study, no confidence interval for Ktrans is reported, so the precision of an endpoint estimate cannot be evaluated. A p-value, if reported, would address compatibility of the data with a specified null model; it would not by itself convey the magnitude, precision, or clinical importance of a result. No p-value is reported for the primary endpoint.

In general, an unadjusted comparison describes the observed groups without accounting for differences in other participant characteristics. An adjusted analysis can incorporate measured characteristics, but its interpretation depends on which variables were included, how they were measured, and the model assumptions. The registry record does not report a primary endpoint analysis or an adjustment strategy. Given the non-randomized allocation and the note that the arms are not a like-for-like control comparison, the record does not permit assessment of whether any group difference would be attributable to treatment rather than group composition or other factors.

The registry’s planning assumptions describe an illustration based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. The record also specifies that time-to-event planning uses a total event count, while other planning displays use participants per arm. These are planning conventions, not evidence about the study’s actual design or observed outcomes. The numerical planning illustrations and the observed effect on which they would depend are not reported in the registry record.

In general, a sample-size calculation estimates how many observations may be needed to detect a specified effect under stated assumptions. It depends on the chosen significance level, target power, variability, allocation, analysis, and effect size. A planning illustration based on an observed effect does not establish the sample size that was used to design a trial, and it cannot replace a protocol-based justification. The registry record does not report the study’s own sample-size justification. Such planning calculations should not be called observed power: observed power is not a substitute for interpreting the estimate and its uncertainty, and no primary endpoint estimate is posted for this study.

General statistical concepts also clarify what cannot be inferred from the design label. A parallel model means groups are organized in parallel rather than participants necessarily crossing between conditions, but the registry record does not report a randomized assignment mechanism. A non-randomized study may describe outcomes across groups, yet causal interpretation is more vulnerable to baseline differences. Masking is listed as none. In general, masking can reduce some forms of knowledge-related influence on measurement or assessment; the absence of masking should be considered alongside the outcome’s measurement process. The record does not describe any additional protections against assessment bias.

The endpoint is defined for MRI completers. In general, limiting analysis to participants with an observed outcome can create bias if completion is related to treatment, participant characteristics, or the outcome itself. Other approaches to missing data may be appropriate depending on why data are missing and on the analysis plan. The registry record does not report how many MRI measurements were missing, why they were missing, or what method, if any, was used to address missingness. Therefore, neither the completeness of the endpoint data nor the robustness of an analysis to missing data can be assessed.

Multiplicity refers to the problem of interpreting several statistical tests or outcomes, where repeated testing can increase the chance of a false-positive finding if no appropriate strategy is used. The record lists one outcome measure and zero analyses, but it does not report whether other analyses, outcomes, or interim looks were planned outside the posted record. No multiplicity strategy or interim-analysis plan is reported. Those omissions mean it is not possible to evaluate how the investigators intended to handle multiple statistical questions.

Finally, a statistical result is most informative when the analysis population, endpoint definition, estimate, uncertainty, and assumptions are all clear. The registry record identifies the endpoint and its intended population, but does not report the endpoint estimate or the analysis details needed to assess it. General explanations of statistical methods cannot fill in those missing study results or establish what the study found.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Phase 1", "Phase 2")
n   <- c(4, 4)
m   <- c(0.225, 0.418)
sp  <- c(0.108, 0.069)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Phase 1  4  0.225  0.108  0.053  0.397
CARM  Phase 2  4  0.418  0.069  0.308  0.528

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure, Ktrans Volume Transfer Constant, and identifies participants who completed MRI as the endpoint population. It lists zero analyses. It does not report a statistical analysis plan, a multiplicity procedure, or whether interim analyses were planned. Consequently, the record does not show how multiple tests would have been handled if additional outcomes, contrasts, or repeated looks at the data were considered.

Missing-data information is also limited. The number of participants who completed MRI, the number without an MRI measure, and the reasons for any missing measurements are not reported in the registry record. No method for handling missing endpoint data is described. In general, an analysis restricted to observed measurements can be difficult to interpret if the likelihood of having a measurement is related to treatment, participant characteristics, or the outcome. The extent of that concern cannot be assessed without information on completion and missingness.

The endpoint population definition does not establish which participants were included in a particular analysis, because no endpoint results or analysis population counts are posted. The record also does not report whether analyses were planned for all enrolled participants or only for participants with evaluable MRI data. Without these details, readers cannot assess the effect of exclusions or missing observations on the reported findings; no findings are reported to evaluate in the first place.

12. 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: respiratory failure (8.3%).

The safety figures list Phase 1 and Phase 2 groups with 12 participants at risk for serious adverse events in each group. Phase 1 lists 0 serious adverse events affecting participants; Phase 2 lists 1. Both groups list 12 participants at risk for other adverse events and 3 affected participants. The registry identifies respiratory failure, at 8.3%, as the top serious adverse event term. No deaths are listed in either group.

For Phase 3, Phase 4, and Phase 5, the record lists zero participants at risk and zero affected participants for the adverse-event categories, with zero deaths. These zero-at-risk entries do not show that those groups had zero adverse events among treated participants; they indicate that the posted safety figures list no participants at risk in those groups.

These counts are descriptive. The record does not provide event-level timing, severity beyond the serious-event category, relatedness assessments, or further detail about the respiratory failure term. The listed figures do not establish comparative safety between groups, particularly given the non-randomized design and the absence of a like-for-like control comparison.

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

The record identifies a study designed to examine hydroxychloroquine and postoperative blood-brain barrier permeability, measured using Ktrans on MRI. It also documents a non-randomized, unmasked, parallel design, an enrollment of 24, five intervention group descriptions, and selected adverse-event counts. These details describe the study structure and what it set out to measure; they do not provide an outcome result.

No Ktrans values or statistical analysis are reported. Therefore, the posted information does not show whether the measure was higher or lower in any group, how large a difference might have been, or how precisely such a difference was estimated. It cannot establish whether the study’s stated aim was achieved. The study title’s reference to cognitive function does not change that limitation: cognitive-function results are not reported among the listed outcome measures.

Even if group outcome values were available, the non-randomized allocation and the registry’s warning that the arms are not a like-for-like control comparison would matter. In general, an observed difference between non-randomized groups may reflect differences in who entered each group or other aspects of care, as well as a relationship with the intervention. The record does not report an analysis that would allow those possibilities to be evaluated.

The registry lists the study as terminated, but does not state why. The status does not by itself explain whether the study stopped early, whether all planned measurements were collected, or whether the endpoint could be analyzed. Those details are not reported in the registry record. Likewise, no sample-size justification, analysis plan, missing-data approach, or multiplicity strategy is reported.

The appropriate interpretation is limited: the record sets out a research question and an imaging endpoint, and it contains some safety counts, but it does not report the primary endpoint result. No conclusion about the direction, size, precision, or clinical significance of a Ktrans effect can be drawn from the posted results.

14. Why This Trial Matters Statistically

This study illustrates why a clear endpoint definition is not the same as a report of an endpoint result. Ktrans is described as a unitless imaging measure of blood-brain barrier permeability, and the registry specifies the postoperative MRI window and the population of MRI completers. Those details help identify what investigators intended to measure. Without the observed values and an analysis, however, the central statistical question remains unanswered in the registry record.

It also demonstrates why design features shape interpretation. The study is listed as non-randomized and unmasked, and its arms are explicitly not described as a like-for-like control comparison. The intervention descriptions span different dosing schedules and patient groups. These features make it especially important to distinguish a descriptive difference across groups from an estimate that can be interpreted as a treatment effect. The registry record does not report the analysis needed to make that distinction.

The endpoint population is defined by MRI completion, drawing attention to a practical statistical issue: the participants with observed measurements may not necessarily represent everyone enrolled. The record does not report completion counts or missing-data handling. This leaves an important part of the interpretation—who contributed to the endpoint analysis—unclear.

Finally, the entry shows that a study status, intervention description, and safety count do not substitute for outcome reporting. The record gives a terminated status and some adverse-event figures, while the primary Ktrans result is not reported. For clinical researchers and statisticians, that separation is important: it prevents the study objective or design from being mistaken for evidence of an observed endpoint effect.

15. 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 limitation for statistical interpretation is that Ktrans results are not reported. No group means, standard deviations, estimated comparison, confidence interval, or p-value appear in the registry record, which lists zero analyses. The direction, magnitude, and precision of the endpoint findings therefore cannot be assessed.

The study is non-randomized, unmasked, and described as having arms that are not a like-for-like control comparison. The group descriptions differ in dosing schedule and in whether they include cardiac or noncardiac patients. The record does not report baseline characteristics or an adjusted analysis, so the extent of group differences beyond the stated descriptions cannot be evaluated.

The endpoint is defined for participants who completed MRI, but the number of completers and the handling of missing MRI data are not reported. This prevents assessment of the analyzed population and whether missingness could affect interpretation. The record also does not report a protocol-based sample-size justification, a statistical analysis plan, multiplicity handling, or interim-analysis plans. The stated planning framework is an illustration based on an observed effect, but numerical planning results and the endpoint effect are not reported.

The safety data are limited to the posted group counts and the top serious adverse event term. Further details on timing, severity, relatedness, or event-level reporting are not reported in the registry record. The reason for termination is also not reported. These limitations leave the clinical context and completeness of the posted results unclear.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Hydroxychloroquine and Cognitive Function After Surgery — NCT03025087.
• Registry record last updated 2024-08-20; status last verified 2024-07.
• Results first posted 2024-06-12.
• 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.

19. Record Summary

NCT03025087, titled “Hydroxychloroquine and Cognitive Function After Surgery,” is listed as a phase 4, non-randomized, unmasked, parallel study sponsored by Duke University. The record lists enrollment of 24 and a population undergoing cardiac and general surgery. The study is terminated; the reason is not reported. The start date is 2017-06-19, and the primary completion date is 2023-05-22.

The primary outcome is the unitless Ktrans Volume Transfer Constant measured on postoperative MRI during postoperative day 1-5 among participants who completed MRI. The record describes it as a blood-brain barrier permeability or leakage measure. It does not report Ktrans results or a statistical analysis. Safety entries list serious and other adverse-event counts for Phase 1 and Phase 2, while Phase 3 through Phase 5 list zero participants at risk. Respiratory failure is identified as the top serious adverse event term, at 8.3%.