The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART (NCT01319383), a na phase 1, phase 2 study. The primary outcome is Number of Participants Exhibiting an in Vivo Resting CD4+ T Cell- Associated HIV RNA (RCVL) Increase After Receiving a Single Dose of VOR 400 mg PO.

2. Clinical Question

The study asks whether vorinostat exposure is followed by changes in HIV RNA expression and HIV infection in resting CD4+ T cells among people with HIV receiving stable antiretroviral therapy. Its stated hypotheses concern increased resting CD4+ T cell-associated HIV RNA after single or repeated exposure, and reduced HIV infection within resting CD4+ T cells after repeated exposure.

3. Trial Design

The registry classifies this as a phase I/II, single-group, open-label study of vorinostat. It lists no masking and no randomized allocation. The study was sponsored by the University of North Carolina, Chapel Hill. The record lists a start date of 2011-02, primary completion on 2016-03-31, completed status, and enrollment of 25.

The study population was people with HIV infection receiving stable antiretroviral therapy. The broad purpose was to compare HIV RNA expression and infection within resting CD4+ cells before and after a single exposure to vorinostat, after short intervals of exposure, and after repeated short-interval exposure over several weeks. The intervention description says vorinostat was to be administered to eligible participants in each step of each phase or period.

The stated primary outcome concerns participants exhibiting an in vivo increase in resting CD4+ T cell-associated HIV RNA after a single 400 mg oral dose. Its timeframe specifies baseline and Visit 5 for Arm 1, and baseline and Visit 3 for Arm 2. Although those arm labels appear in the endpoint description, the registry’s overall design classification is single-group. It does not describe a randomized or like-for-like control comparison, and arm-specific procedures and participant counts are not reported in the registry record.

The record lists eight outcome measures and identifies secondary outcomes concerning measurable changes in plasma HIV-1 RNA and specified hematologic and non-hematologic toxicities related to vorinostat. The detailed visit schedule, dosing schedule beyond the stated primary dose and general exposure descriptions, and eligibility criteria are not reported in the registry record. The record also lists no statistical analyses.

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: Participants were recruited into the single and multiple dose Vorinostat (VOR) Arm alone, the VOR Interval Dosing Arm alone, or both = 25. Each Arm had multiple steps. Participants without a significant in vitro or in vivo response to VOR did not advance in either Arm; 3 Arm 1 and 13 new participants, enrolled Arm 2.

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 Number of Participants Exhibiting an in Vivo Resting CD4+ T Cell- Associated HIV RNA (RCVL) Increase After Receiving a Single Dose of VOR 400 mg PO, measured over Arm1: Baseline, Visit 5 and Arm 2: Baseline and Visit 3.

The primary endpoint is the number of participants exhibiting an in vivo increase in resting CD4+ T cell-associated HIV RNA, abbreviated RCVL, after a single dose of vorinostat. The endpoint description specifies a 400 mg oral dose and identifies baseline and follow-up visits for Arm 1 and Arm 2. It is a participant-count outcome: it concerns how many participants meet the increase classification, rather than reporting the magnitude of RNA expression for each participant.

Resting CD4+ T cells are the cell population named in the study’s biological question. Measuring HIV RNA associated with these cells is used to assess whether exposure is followed by a detectable change in viral RNA expression in that population. The registry states that the study also considered HIV infection within resting CD4+ T cells, including a hypothesis about repeated exposure, but that is not the primary endpoint.

The record does not define the operational threshold for classifying an increase, give the observed number of participants meeting the endpoint, or report the size or variability of any RNA change. It also does not describe how measurements were combined across visits or how missing measurements affected the endpoint. Without those details and the posted outcome count, the endpoint definition can be described, but the observed primary result cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a participant count. Each participant would need to be classified according to whether an increase in resting CD4+ T cell-associated HIV RNA was observed after the specified exposure. The reported count would then describe participants meeting that classification, not the number of RNA measurements, episodes, or cells. This distinction matters because several measurements may contribute to a participant-level classification, while the endpoint remains a count of participants.

As a general statistical concept, turning a measured quantity into an increase/no-increase classification makes the result easier to express as a participant count, but it can discard information about the magnitude of change. A small change and a larger change may both count as an increase if they meet the same rule. The registry record does not specify the threshold, measurement procedure, or rule for combining measurements across visits. Those omissions limit interpretation of what a qualifying increase represents.

A confidence interval is a general way to express the uncertainty around an estimated quantity. For a participant-count outcome, an interval would ordinarily need to be interpreted with the observed count, its denominator, and the method used to calculate it. No primary endpoint count, denominator, or interval is reported in the registry record. It is therefore not possible to assess the precision of the primary result from the registry information.

The design is classified as single-group and open label. In general, an open-label design means participants and study personnel are not masked to the intervention. A within-participant comparison of measurements before and after exposure can be informative about observed changes over time, but does not by itself distinguish an intervention effect from other time-related influences or measurement variation. A randomized concurrent control group can help address some alternative explanations; the registry record identifies no randomized comparison. It describes the study as single-group, while the endpoint text refers to Arm 1 and Arm 2. The relationship between those arm labels and the overall design is not reported in the registry record.

The primary endpoint refers to an in vivo increase after a single 400 mg oral dose, with baseline and follow-up visits named for each arm. The broader study description also refers to short-interval and repeated short-interval exposure. These are distinct exposure questions: the primary endpoint statement is specifically about a single dose, while the stated hypotheses include repeated exposure. The record does not report a statistical model or analysis plan that connects these questions, nor does it give the outcome results needed to evaluate them.

The registry lists eight outcome measures and three secondary outcome topics: participants with measurable changes in plasma HIV-1 RNA, participants with confirmed non-hematologic toxicity at or above Grade 3 related to vorinostat, and participants with confirmed hematologic toxicity at or above Grade 2 related to vorinostat. It does not report how the primary and secondary outcomes were analyzed together. As a general statistical consideration, assessing multiple outcomes can increase the chance of at least one apparently notable finding when each is tested separately. Methods such as prespecifying a primary outcome or adjusting for multiple comparisons can address that issue, but the registry record does not report whether such methods were used.

The registry lists no statistical analyses. In particular, it does not report a test or model for the primary endpoint, a significance threshold for that endpoint, how repeated measurements were handled, or whether analyses were adjusted for any covariates. The general purpose of a statistical model is to specify how observed data are related to the quantity being estimated and to represent relevant sources of variation. Without a reported model or analysis description, the statistical basis of any inferential result cannot be assessed from the registry record.

Over-dispersion is a general concern when count data vary more than an assumed statistical model allows. If a model assumes a particular level of variability but the data are more variable, standard errors and resulting uncertainty estimates may be too small. The primary outcome is described as a count of participants meeting a criterion, but no model or variance assumptions are reported; over-dispersion is therefore a general concept, not a documented issue or analysis choice for this trial.

The record also describes planning illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect. Such illustrations concern the size a future study might plan for under those assumptions. They are not observed power, do not show that the study was adequately powered, and should not be mistaken for the trial’s own design rationale. The record does not report the study’s sample-size justification or the planning results’ underlying values in the registry record for interpretation.

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("1/Single & Multiple Dose, Step 2, Visit 5", "2/Interval Dosing, Visit 3")
n      <- c(12, 11)
events <- c(8, 4)
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  1/Single & Multiple Dose, Step 2, Visit 5  12  8  66.7  34.9  90.1  39.1  86.2  38.6  86.1
ARM  2/Interval Dosing, Visit 3  11  4  36.4  10.9  69.2  15.2  64.6  15.2  65.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists eight outcome measures and names secondary outcomes involving measurable changes in plasma HIV-1 RNA and confirmed hematologic and non-hematologic toxicities related to vorinostat. It does not report which analyses, if any, were prespecified beyond the listed primary outcome, whether outcomes were tested as a family, or whether a multiplicity adjustment was used. These details are not reported in the registry record.

As a general statistical issue, considering multiple outcomes or repeated comparisons can make isolated findings harder to interpret because the opportunity for chance findings increases as more comparisons are assessed. Prespecified outcome hierarchies or adjustments can help control that concern, but no such approach is described in the registry record. The record lists no statistical analyses, so there is no reported test strategy with which to evaluate multiplicity.

Missing-data handling is also not reported in the registry record. The enrollment figure does not establish how many participants contributed measurements at each specified visit or to the primary endpoint. The record does not describe whether missing measurements were excluded, imputed, or handled through another approach, nor does it give the reasons for missingness.

The analysis populations are not described. The registry record does not say whether all enrolled participants, only those receiving a dose, or another defined group contributed to the primary or secondary outcomes. It also does not describe exclusions or deviations from the intended exposure schedule. These omissions prevent assessment of whether the reported outcome population, if results are available elsewhere, matches the enrolled population or the planned endpoint population.

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’s safety figures are participant counts for the Open Label - Translational Research Study group. It reports 25 participants at risk for serious adverse events and 0 participants affected. For other adverse events, it reports 25 participants at risk and 21 affected. The record reports 0 deaths.

These figures describe participants affected, not the total number of adverse-event episodes or the severity, duration, or timing of each event. The “other” category should not be read as a count of events; it is reported as a number of participants affected. The record does not list top serious adverse-event terms, and the specific types of other adverse events are not included in the registry record for this interpretation.

The listed secondary outcomes include confirmed non-hematologic toxicity at or above Grade 3 and confirmed hematologic toxicity at or above Grade 2 when related to vorinostat. The safety figures above do not provide the results for those specific outcomes, so they cannot be used to infer how many participants met those toxicity definitions. The registry record does not report further detail about safety ascertainment or the analysis population.

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

The study was designed to examine whether exposure to vorinostat was followed by changes in HIV RNA expression and infection in resting CD4+ T cells among people receiving stable antiretroviral therapy. Its primary endpoint focused on the number of participants with an in vivo increase in resting CD4+ T cell-associated HIV RNA after a single 400 mg oral dose. The registry record does not report the observed primary endpoint count, so it does not establish how often that increase was observed.

The stated hypotheses should be distinguished from results. The record hypothesizes increased RCVL after single and repeated exposure and reduced resting-cell HIV infection after repeated exposure. It does not report outcome findings for those hypotheses in the information available for interpretation. The study’s completed status and enrollment figure do not substitute for endpoint results or show whether the hypothesized changes occurred.

The design also limits what can be concluded from before-and-after measurements. The registry classifies the trial as single-group and open label, without randomized allocation or masking. In general, changes observed within a group over time do not alone establish that the intervention caused those changes. The record does not describe a randomized control comparison, and arm details are not reported beyond the labels in the primary endpoint description.

Even if a participant count is available in another source, interpreting it requires the endpoint definition, analysis denominator, and information about missing measurements. The registry record does not provide these details or an uncertainty estimate. A count without those accompanying details cannot convey how precisely the endpoint frequency is estimated or how large any underlying change in RNA expression was.

Accordingly, the record supports a description of the study question, design, and reported safety counts, but not a conclusion about the primary biological outcome. It does not establish that vorinostat did or did not produce a change in HIV RNA expression or infection. Those conclusions would require outcome data and analyses that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial raises a statistical question about how to measure a biological response at the participant level. Its primary endpoint is not the amount of HIV RNA across all measurements; it is the number of participants classified as exhibiting an increase in resting CD4+ T cell-associated HIV RNA. That distinction illustrates how endpoint definitions shape the information a trial can report and what readers can infer from it.

The study also combines a specific single-dose primary endpoint with broader hypotheses concerning short-interval and repeated exposure. These questions involve different exposure patterns and cannot be treated as interchangeable. Clear separation of endpoint, exposure schedule, visit timing, and analysis population is important for interpreting any observed change. The registry record gives some of this structure, but does not report detailed arm procedures or the statistical analysis plan.

The single-group, open-label design is another important statistical feature. Before-and-after measurements can describe change over time, but a design without a randomized concurrent comparator has limited ability to distinguish an intervention-associated change from other explanations. This is particularly important when the outcome depends on defining whether a measured quantity has increased, because measurement variation and classification rules affect the participant count.

Finally, the record shows why outcome counts need context. Without the primary count, its denominator, endpoint threshold, missing-data approach, and uncertainty estimate, the central result cannot be evaluated for magnitude or precision. The registry does list safety counts, which must be read as affected participants rather than event totals. The distinction between a study hypothesis, a recorded design, and a posted result is essential to sound statistical interpretation.

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 interpreting the primary endpoint is that its observed result is not reported in the registry record. The record defines the outcome as a participant count but does not give the number meeting the endpoint or the denominator used for that calculation. It also does not specify the operational threshold for an RCVL increase, the measurement procedure, or how measurements across visits were combined.

The record classifies the study as single-group, open label, and without randomized allocation. Its general purpose refers to comparisons before and after exposure, but no randomized control comparison is described. Arm 1 and Arm 2 appear in the primary endpoint description; their procedures, relationship to the single-group classification, and participant counts are not reported in the registry record.

Information about the analysis population and missing data is absent. The record does not report how many participants contributed data at each visit, whether participants were excluded from the endpoint analysis, or how unavailable measurements were handled. It also lists no statistical analyses, so the test or model, uncertainty estimation, and any adjustments cannot be evaluated.

The record’s broader hypotheses concern repeated exposure and resting-cell HIV infection, but results for those questions are not reported in the information available for interpretation. The listed safety figures do not give adverse-event types or event totals, and they do not report the specific secondary toxicity outcome counts. These gaps mean that the study’s planned questions and design can be described, but the primary biological findings and their precision cannot be assessed from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART — NCT01319383.
• Registry record last updated 2017-06-29; status last verified 2017-04.
• Results first posted 2017-06-29.
• 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

The registry record describes a completed phase I/II, open-label, single-group study of vorinostat among people with HIV receiving stable antiretroviral therapy. It lists enrollment of 25, no masking, no randomized allocation, and the University of North Carolina, Chapel Hill as sponsor.

The primary outcome is the number of participants exhibiting an in vivo increase in resting CD4+ T cell-associated HIV RNA after a single 400 mg oral dose. The study description also refers to short-interval and repeated exposure. The record lists eight outcome measures, but the observed primary outcome count and statistical analyses are not reported in the registry record.

Safety reporting lists 0 participants affected by serious adverse events, 21 affected by other adverse events, and 0 deaths, among 25 at risk in the listed group. These are participant counts, not event totals.