Hydroxychloroquine to Increase Tumor Suppressor PAR-4 Levels in Oligometastatic Prostate Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Hydroxychloroquine to Increase Tumor Suppressor PAR-4 Levels in Oligometastatic Prostate Cancer (NCT04011410), a na phase 2 study. The primary outcome is Participants With Greater Than or Equal to 50% Induction in Serum PAR4 Levels.

2. Clinical Question

The clinical rationale described in the registry is that hydroxychloroquine might raise levels of the tumor suppressor PAR-4 in people with recurrent oligometastatic prostate cancer. The record also describes possible longer-term aims, including delayed disease progression and delayed initiation of androgen deprivation therapy. Those aims are not the primary endpoint: the primary measure is the number of participants meeting the specified PAR-4 threshold at 90 days.

The study was not designed as a randomized comparison of hydroxychloroquine against another treatment or against no hydroxychloroquine. Participants were to undergo surgery or radiation as standard care and also receive hydroxychloroquine. The record does not specify which standard treatment each participant received. Consequently, the primary question is about the observed PAR-4 response within the treated group, not whether adding hydroxychloroquine changes outcomes relative to a control group.

3. Trial Design

This is a phase 2, single-group study listed as completed, with an enrollment of 20. The registry lists no allocation between groups and no masking. There is therefore no randomized control arm in the registered design. The registry record gives a start date of 2019-12-03 and a primary completion date of 2024-03-08.

The intervention is hydroxychloroquine sulfate, described as a 200 mg oral tablet taken twice daily, morning and night with food. The stated total daily dose is 400 mg, and the stated duration is 90 days. The brief summary describes hydroxychloroquine as an addition to standard-of-care surgery or radiation for recurrent oligometastatic prostate cancer. Further details about the surgery or radiation plans, or how those treatments were selected, are not reported in the registry record.

The primary endpoint is a count of participants who achieve at least a 50% induction in serum or plasma PAR-4 levels over baseline, assessed at 90 days. Secondary outcomes listed are change in serum prostate-specific antigen levels, the number of participants with progression-free survival, and the number with androgen deprivation therapy-free survival. The registry lists four outcome measures in total, but does not provide further outcome results in the record summarized for this analysis.

The stated enrollment is a planned or registered study size, not evidence that every enrolled participant completed treatment or contributed to every analysis. The number included in the primary endpoint analysis and the reasons for any exclusions or missing measurements are not reported in the registry record. A sample-size justification for the trial, including a target effect and power calculation, is 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

Reasons for not completing this period:

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 Participants With Greater Than or Equal to 50% Induction in Serum PAR4 Levels, measured over 90 days.

The primary endpoint counts participants whose serum or plasma PAR-4 level increased by at least 50% over the participant’s baseline level. The registry specifies a 90-day timeframe and describes the measure as the number attaining that threshold. It is a binary participant-level outcome: a participant either meets the stated threshold or does not. The registry record does not provide the observed count or the number assessed for this endpoint.

A threshold-based endpoint can make a laboratory response easier to summarize than a continuous change, but it also compresses information. Participants just below the threshold and participants with no increase are both outside the responder count, while participants who meet the threshold are grouped together even if their increases differ. The endpoint therefore does not describe the full distribution of PAR-4 changes. The registry record does not report how measurements were processed, how assay variability was handled, or how missing baseline or 90-day samples were treated.

The endpoint is used to address the study’s stated biological question: whether participants receiving hydroxychloroquine show the prespecified degree of PAR-4 induction by 90 days. It is not itself a measure of disease progression, symptom burden, quality of life, or survival. Those clinical outcomes are not interchangeable with a laboratory response, and the endpoint alone cannot establish that a PAR-4 change leads to a clinical benefit.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a count of participants meeting a defined threshold. Each participant is classified according to whether the 90-day PAR-4 measurement reaches at least a 50% increase over baseline. This differs from an outcome that records the exact amount of change for every participant. A count is easy to interpret as the number meeting a criterion, but it does not retain all the detail in the underlying laboratory measurements.

What does a threshold-based outcome capture?

A threshold turns a continuous measurement into a responder classification. That can be useful when a study has a clinically or biologically motivated target, but the interpretation depends on the threshold having been set and measured consistently. Participants close to the cutoff can be classified differently because of small measurement fluctuations, while the classification does not distinguish modest threshold-crossing responses from much larger responses. The registry specifies the 50% threshold and 90-day timeframe, but further details about threshold selection and assay procedures are not reported in the registry record.

General statistical explanation: counts are often presented with a denominator, because the count alone does not say how many participants were assessed. For a participant-level response, an estimate of the response proportion would depend on both the number meeting the criterion and the number included in the analysis. The registry record does not report either the primary count or its analysis denominator, so a response proportion cannot be interpreted from the available record.

What does a confidence interval contribute?

General statistical explanation: a confidence interval expresses uncertainty around an estimate. It indicates the range of values that would be compatible with the data under a specified statistical procedure; it is not a guarantee that the true value lies in that range. For a binary outcome, intervals can convey uncertainty around the response proportion. Their width depends on the amount of information in the data and on the method used. No interval or method for calculating one is reported for the primary endpoint in the registry record.

A hypothesis test and a confidence interval answer related but distinct questions. A test evaluates the data against a specified null hypothesis and significance threshold. An interval conveys a range of compatible estimates and their precision. Neither substitutes for the observed estimate, and a statistical test alone would not show the magnitude or practical meaning of an effect. No primary endpoint test, p-value, or interval is reported in the registry record.

Why does the single-group design matter?

In a randomized comparison, treatment groups can be compared under a design intended to make their outcomes interpretable relative to one another. This study is registered as a single group, with allocation listed as not applicable and masking listed as none. It therefore has no between-group treatment contrast. A change from baseline can describe what happened among participants receiving the regimen, but it cannot by itself estimate what would have happened to those same participants without hydroxychloroquine.

General statistical explanation: baseline-to-follow-up comparisons can be affected by time trends, co-interventions, selection, and measurement variability. A control group can help address some competing explanations, depending on how the trial is designed and conducted. In this study, participants also received standard-of-care surgery or radiation, so the record does not support attributing any change specifically to hydroxychloroquine. Details on treatment timing and the analytical handling of co-interventions are not reported in the registry record.

How should planning illustrations be understood?

Sample-size calculations are planning tools based on assumptions about the design, target effect, variability, error rates, and allocation. The stated planning assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is described as a fraction of the observed effect. For time-to-event outcomes, the stated illustration concerns total events, while other illustrations concern participants per arm. These assumptions do not describe the registered study’s single-group design and should not be treated as its original sample-size justification.

General statistical explanation: power is the probability that a specified statistical test will reject its null hypothesis under a particular assumed effect and set of conditions. A retrospective calculation based on an observed effect is not observed power and does not replace an estimate with a confidence interval. The registry record does not report the trial’s own sample-size rationale, target power, or a statistical analysis plan. The primary outcome result needed to understand an effect-based illustration is also not reported in the registry record.

Why can over-dispersion matter?

General statistical explanation: for count outcomes, a model may assume a particular relationship between the average count and its variability. Over-dispersion means the observed variability is greater than the model assumes. If ignored, standard errors can be too small and statistical evidence can appear more precise than warranted. The primary endpoint is a participant count with a binary response definition, not a repeated event count, and the registry record does not report a model or an over-dispersion assessment. This concept should not be read as a claim that over-dispersion occurred in this study.

The registry’s outcome descriptions do not report how repeated or missing measurements were handled, what analysis population was used, whether analyses were adjusted for other variables, or whether any sensitivity analyses were conducted. These details matter because different analysis choices can affect which participants contribute and how uncertainty is represented. Without those details and the outcome results, the statistical evidence for the primary question cannot be reconstructed from the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Hydroxychloroquine")
n      <- c(19)
events <- c(11)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Hydroxychloroquine  19  11  57.9  33.5  79.7  36.3  76.9  36.1  76.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary PAR-4 endpoint and secondary outcomes involving serum PSA change, progression-free survival, and androgen deprivation therapy-free survival. Considering several outcomes can raise a multiplicity issue: the more statistical comparisons made, the greater the chance of at least one apparently notable result arising by chance if each is tested separately. Statistical plans sometimes address this by specifying a hierarchy of outcomes or adjusting significance thresholds. Such a plan or adjustment is not reported in the registry record.

The record does not report whether the secondary outcomes were analyzed, whether there were additional exploratory outcomes, or how many statistical comparisons were made. It lists four outcome measures in total, but does not supply corresponding analysis details. No p-values or confidence intervals for these outcomes are reported in the registry record. Accordingly, the extent to which multiplicity was considered cannot be assessed.

Missing data are also important for the primary endpoint because it requires baseline and 90-day blood measurements. The registry does not report how many participants had both measurements, whether any participants discontinued or missed the 90-day assessment, how missing measurements were handled, or whether the primary analysis used all enrolled participants or another analysis population. The registered enrollment is 20, while safety summaries list 19 at risk; the reason for this difference is not reported in the registry record. That safety denominator should not be assumed to be the primary endpoint denominator.

Without an analysis population, a missing-data approach, and outcome-level denominators, readers cannot determine how representative the analyzed participants were of those enrolled. The registry record also does not report sensitivity analyses that would show whether conclusions depend on assumptions about missing outcomes. These omissions limit assessment of both bias and statistical precision.

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 non-serious adverse event terms

The registry reports 0 participants with serious adverse events among 19 at risk, 9 participants with other adverse events among 19 at risk, and 0 deaths. These are counts, not comparative estimates: the trial has a single group and no control arm. The figures therefore do not establish how these counts compare with another treatment or with the events that would have occurred without hydroxychloroquine.

The record does not list serious adverse-event terms, and no serious-event types are reported in the listed summary. It also does not describe the nature or severity of the 9 other adverse events, their timing, or whether investigators considered them related to treatment. The safety denominator of 19 is distinct from the registered enrollment of 20; why one fewer participant is listed at risk is not reported in the registry record.

A count of 0 serious events should be read as no serious events recorded in the reported safety summary, not as proof that serious events cannot occur. The registry does not provide enough detail to assess event ascertainment, duration of safety follow-up, or the precision of the safety estimates. The brief summary’s expectation of few, if any, negative side effects is an expectation, not a substitute for the observed safety data.

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

This study is designed to describe whether participants receiving hydroxychloroquine alongside standard treatment attain a specified PAR-4 increase by 90 days. Its single-group design means it can describe outcomes among participants who received the regimen, but it cannot provide a randomized estimate of the difference attributable to hydroxychloroquine. There is no separate comparator group in the registry record.

Most importantly, the registry record does not report the primary endpoint result. It is therefore not possible to say how many participants met the threshold, how uncertain that count is, or whether the observed data were consistent with the expectation described in the brief summary. An expectation of a 50% increase is not an observed finding. The listed secondary outcomes also lack reported results in the registry record.

The endpoint is a laboratory measure, not a direct measure of progression, survival, symptoms, functioning, or quality of life. Even a documented PAR-4 change would not, by itself, establish that participants experienced a clinical benefit or that the change was caused by hydroxychloroquine. The trial’s secondary outcomes could address some clinical questions, but their results are not reported in the registry record.

The safety summary records 0 serious adverse events among 19 at risk, 9 participants with other adverse events among 19 at risk, and 0 deaths. Those counts are limited by the absence of event descriptions, comparative data, and detail on follow-up and attribution. They should not be interpreted as a comprehensive estimate of risk.

Thus, the registry record describes the question, regimen, and outcome definitions, but does not report the outcome results needed to judge the observed PAR-4 response or its precision. The absence of results in the record is not evidence that an outcome did or did not occur; it means that the result cannot be evaluated from this record.

14. Why This Trial Matters Statistically

Statistically, this trial illustrates the distinction between a biological response question and a comparative treatment question. The primary outcome asks whether participants cross a defined PAR-4 threshold after receiving hydroxychloroquine with standard treatment. The single-group design can describe that response if results are available, but it does not estimate the contrast between hydroxychloroquine and a control condition.

The threshold also highlights a common trade-off in endpoint design. A binary responder definition can be straightforward to communicate, while discarding information about the amount of change and making classification sensitive to measurements near the cutoff. Interpreting such an endpoint requires the response count, the number assessed, and an account of measurement and missing-data handling. Those details and the result are not reported in the registry record.

The study also underscores that a completed status and registered enrollment do not, on their own, convey evidence about an endpoint. To assess the result, readers need the observed estimate and its precision, as well as the analysis population and methods. For this record, the primary endpoint and secondary outcomes are defined, but their results and the statistical analysis details are not reported.

Finally, hypothetical sample-size illustrations should not be mistaken for the design rationale or power of a single-group study. The stated illustration assumptions involve equal allocation between two arms, whereas this study is registered as single-group. Keeping those design distinctions clear prevents planning calculations from being read as trial findings.

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 main limitation for statistical interpretation is that the registry record does not report the primary endpoint result, its denominator, or a measure of precision. Although the study is listed as completed and enrollment is 20, those details do not show how many participants contributed to the 90-day PAR-4 assessment. The number of participants analyzed and the handling of missing samples are not reported in the registry record.

The single-group design has no concurrent control arm and no random allocation between treatments. Participants received hydroxychloroquine in addition to standard-of-care surgery or radiation, but the record does not specify the treatment received by each participant or provide a basis for isolating hydroxychloroquine’s contribution to any observed change. Masking is listed as none, and further measurement or assessment procedures are not reported.

The primary endpoint depends on a thresholded laboratory measure. The registry does not report assay details, measurement variability, how the threshold was established, or how measurements near the cutoff were handled. The result also would not, on its own, establish a change in a clinical outcome. Secondary outcome results for PSA, progression-free survival, and ADT-free survival are not reported in the registry record.

Safety information is also limited. The record provides summary counts, but does not describe the 9 other adverse events, list serious-event terms, explain the safety denominator of 19 relative to enrollment of 20, or detail the safety follow-up period. Statistical analysis methods, the analysis population, multiplicity procedures, and missing-data analyses are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Hydroxychloroquine to Increase Tumor Suppressor PAR-4 Levels in Oligometastatic Prostate Cancer — NCT04011410.
• Registry record last updated 2025-04-11; status last verified 2025-04.
• Results first posted 2025-04-11.
• 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

NCT04011410 is a completed phase 2, single-group study of hydroxychloroquine in recurrent oligometastatic prostate cancer, with registered enrollment of 20. The regimen is 200 mg by mouth twice daily, for a total daily dose of 400 mg, over 90 days, alongside standard-of-care surgery or radiation.

The primary endpoint counts participants with at least a 50% increase in serum or plasma PAR-4 over baseline at 90 days. Secondary outcomes concern PSA change, progression-free survival, and ADT-free survival. The primary and secondary outcome results, analysis populations, and statistical methods are not reported in the registry record.

The safety summary reports 0 participants with serious adverse events among 19 at risk, 9 with other adverse events among 19 at risk, and 0 deaths. No randomized comparator is registered, so the design does not provide a between-group treatment comparison.