Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy (ART): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy (ART) (NCT02440789), a na phase 1, phase 2 study. The primary outcome is Number of Participants Who Met the Study-defined Composite Safety Endpoint.

2. Clinical Question

The study also set out to assess whether sirolimus affected inflammation and immune activation, HIV levels in blood, and the interaction between sirolimus and antiretroviral therapy in blood. Those aims provide context for the clinical question, but the registry record does not report numerical results for them in the information available for this analysis.

The primary question is about the number of participants meeting a safety definition, not about a comparison of sirolimus with another treatment. Without a control group, observed events cannot be contrasted with concurrent outcomes under a different intervention. The registry record also does not report the primary endpoint count or a statistical estimate of its uncertainty. The central question can therefore be described from the endpoint definition, but its observed result cannot be characterized from this record.

3. Trial Design

This completed study is registered as Phase 1 and Phase 2, with a single-group model and no masking. Allocation is listed as not applicable. The intervention was sirolimus, and the condition was HIV-1 infection. The registry record lists an enrollment of 32. That enrollment figure should not be treated as the number analyzed for every outcome: the primary endpoint population is described as participants initiating sirolimus, and the record does not give a primary-endpoint analysis count.

The study began on 2015-12-21, reached primary completion on 2017-11-02, and is listed as completed. The primary safety timeframe runs from screening to study week 32, which the record identifies as week 20 of sirolimus. Screening occurred within 60 days of study entry. These timing details define when the endpoint was assessed; they do not provide the endpoint result.

A single-group design can describe what was observed among participants receiving the intervention, but it does not create a like-for-like concurrent comparison. The registry record itself flags that the arms are not a randomized comparison. There is no separate control arm described in the trial design, so a between-arm treatment effect cannot be estimated from this design.

The record lists 46 outcome measures and 22 analyses, including measures concerning CD4+ T-cell counts, HIV-1 RNA, cell-associated HIV-1 DNA in total CD4+ cells, and HIV-1 Gag-specific T-cell responses. The listed outcomes indicate the breadth of measurement, not the direction or size of any changes. Detailed information about allocation procedures, masking beyond none, the statistical analysis plan, and analysis populations is 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:

Analysis population for the primary outcome, as defined in the registry: Participants Initiating Sirolimus.

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: Participants who initiated Sirolimus

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Met the Study-defined Composite Safety Endpoint, measured over Screening to study week 32 (week 20 of Sirolimus).

The primary endpoint counts participants who met a composite safety definition from screening through study week 32, corresponding to week 20 of sirolimus. A participant met the definition if either of two conditions occurred: a new Grade 3 or higher adverse event, including signs or symptoms, laboratory toxicity, or a clinical event, judged definitely, probably, or possibly related to study treatment by the core team; or a change in CD4+ cell count defined as a confirmed decline greater than 50% or a decline to below 300 cells/mm3 while taking sirolimus.

A composite endpoint brings more than one event type into a single outcome. In general, this can capture different ways a treatment period may raise a safety concern, while producing a count of participants meeting at least one part of the definition. The registry record does not report how many participants met the composite, or how many met each component. It also does not report whether participants meeting both components were counted separately in component-level analyses.

The endpoint is framed as a participant count rather than an event rate or time-to-event estimate. Its definition sets out the qualifying events and observation window, but interpretation depends on the observed count and the analysis population. Those numerical results are not reported in the registry record. The endpoint should therefore be understood as the planned safety measure, not as evidence of a particular safety outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either met the composite safety definition or did not, over the specified timeframe. In general, binary outcomes are commonly summarized as counts and proportions. A count gives the observed number meeting the definition; a proportion relates that count to the relevant analysis population. The registry record identifies the endpoint population as participants initiating sirolimus, but does not report the primary endpoint count or its analysis denominator. No proportion or uncertainty estimate can therefore be stated.

What does the composite definition combine?

The endpoint combines a treatment-related adverse-event criterion with a CD4+ cell-count criterion. The adverse-event component requires a new Grade 3 or higher event judged definitely, probably, or possibly related to treatment by the core team. The CD4+ component requires a confirmed decline greater than 50% or a decline to below 300 cells/mm3 while on sirolimus. In general, a composite can capture more than one clinically relevant type of event in one outcome. Its interpretation depends on the components, the rules for determining whether they occurred, and the number of participants meeting the definition. The record gives the criteria but does not report component-specific counts or details about overlap.

What does a confidence interval convey?

In general, a confidence interval describes the uncertainty around an estimate under the assumptions of the statistical method used. A narrower interval indicates greater precision than a wider interval, while neither interval alone establishes the importance of an effect. The registry information analyzed does not report a confidence interval for the primary endpoint. Because the endpoint count and analysis denominator are not reported, a numerical interval should not be reconstructed.

Why does the single-group design matter?

In general, a concurrent comparator can help distinguish changes associated with an intervention from changes that might have occurred over time for other reasons. A single-group study instead describes outcomes within the group receiving the intervention. The registry record lists a single-group model, no masking, and allocation as not applicable; it also notes that the arms are not a like-for-like control comparison. Thus, this design does not provide a randomized between-group estimate of treatment effect. An observed within-group change, if reported, would not by itself establish that the intervention caused it.

How should the planning illustrations be read?

The registry material describes sample-size illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect. These are planning illustrations, not observed power and not the design of this single-group trial. The record does not report the resulting sample-size values in the information analyzed. Such illustrations describe hypothetical future planning under stated assumptions; they do not alter what the completed study observed or establish that its design had a particular power.

General sample-size planning asks how many participants per arm would be needed to detect a chosen effect under assumptions about variability, significance level, allocation, and analysis. The calculated requirement depends on those assumptions. If the effect used for planning comes from an observed estimate, uncertainty in that estimate also matters. Smaller assumed effects generally require larger planned sample sizes to detect, all else equal. This general relationship is not a result for this trial, and no unreported planning value should be inferred.

What do the adverse-event counts represent?

The serious adverse-event summary reports participants at risk and participants affected, as well as deaths. In general, a participant count is not necessarily the same as an event count: a participant may experience more than one event, and the summary may use rules that are not described in the brief record. The posted serious-event figures should therefore be read as the specific participant counts given, not converted into an event rate or used to infer unreported event totals. The record does not give the details needed to interpret overlap between serious and other adverse-event categories.

Over-dispersion is a general concern for some count outcomes when variability exceeds what a simple model assumes. It matters because standard errors and uncertainty intervals can be too small if the model understates variability. That concept is not directly a description of the primary endpoint: the primary outcome is specified as a participant count meeting a binary composite, and the record provides no model or dispersion estimate for it. No over-dispersion adjustment or other specific model can be attributed to the trial from the available registry information.

The registry record does not report a detailed statistical analysis plan, the method used to estimate uncertainty for the primary endpoint, or whether adjusted or unadjusted analyses were performed. It also does not give numerical estimates for the listed secondary outcomes. The statistical interpretation is therefore limited to the design, outcome definition, and adverse-event figures explicitly recorded.

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("Sirolimus")
n      <- c(30)
events <- c(3)
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  Sirolimus  30  3  10.0  2.1  26.5  3.5  25.6  3.6  25.8

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 46 outcome measures and 22 analyses. A broad outcome set can raise multiplicity concerns because, in general, examining many outcomes or analyses increases the chance that at least one result appears notable by chance. How that concern should be handled depends on which outcomes were prespecified as primary, how analyses were grouped, and whether any adjustment or hierarchy was planned. The registry information analyzed does not report a multiplicity strategy, so it is not possible to say whether or how the study addressed that issue.

The primary endpoint is identified by name and definition, but the record does not report its observed result or a detailed analysis plan. It does not describe a missing-data method, the handling of participants without an endpoint assessment, or whether imputation was used. The analysis population beyond the stated population of participants initiating sirolimus is not reported in the registry record. The enrollment entry alone does not establish how many participants contributed data to each outcome.

These omissions matter because the denominator, analysis population, and approach to missing observations can affect how a binary endpoint is summarized. For secondary outcomes, the record lists measures such as CD4+ counts, HIV-1 RNA, cell-associated HIV-1 DNA, and T-cell responses, but does not provide enough information to assess completeness or the statistical handling of missing measurements. No assumptions about missingness, exclusions, or multiplicity adjustments should be made from the outcome list alone.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: diarrhoea (3.3%).

The serious adverse-event summary lists 1 participant affected among 30 at risk in the sirolimus group, and 0 deaths. Diarrhoea is listed among the top serious terms at 3.3%. The record separately lists 28 participants affected by other adverse events among 30 at risk. These are the posted figures and should be read as separate entries in the adverse-event summary.

These summaries are not the primary composite safety endpoint. The primary endpoint also includes a specific CD4+ cell-count criterion and is restricted to adverse events meeting a severity threshold and judged related to study treatment. A serious event is not automatically equivalent to an event meeting that endpoint's Grade 3 or higher criterion, and the record does not report the composite count. The adverse-event entries do not show whether participants overlapped across categories, or provide a complete event-level account in the information analyzed.

The figures describe events recorded during the study; they do not establish comparative risk because the study had no concurrent control group. The registry information does not report further details about event timing, duration, management, or causal assessment beyond the primary endpoint definition and the listed serious-event summary. Interpret the counts as descriptive safety information, not as a comparative estimate or a substitute for the missing primary endpoint result.

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

This completed Phase 1 and Phase 2 study records a single-group assessment of sirolimus in people with HIV-1 infection receiving suppressive antiretroviral therapy. Its primary safety outcome is a composite that includes specified treatment-related adverse events and specified CD4+ cell-count changes. The registry record makes the endpoint definition and observation timeframe clear, which helps readers understand what the investigators intended to count.

The posted information does not report the number of participants meeting that primary endpoint. It also does not report numerical results for the listed secondary outcomes. As a result, the record analyzed cannot establish the observed frequency of the composite, the direction or size of changes in immune or HIV-related measures, or the precision of those outcomes. A completed status and an outcome list do not fill that gap.

The serious adverse-event summary provides descriptive information: 1 participant affected among 30 at risk, 0 deaths, and diarrhoea listed at 3.3% among the top serious terms. The separate other-adverse-event entry lists 28 participants affected among 30 at risk. These figures should not be taken as the primary composite result, and they cannot support a randomized comparison or an estimate of comparative treatment effect.

In general, single-group observations can describe what happened among people receiving an intervention, but without a concurrent control group they cannot isolate the effect of that intervention from other possible explanations. This limitation applies even when an outcome changes from an earlier measurement. The registry record does not provide the numerical primary or secondary outcome results needed to describe such changes in this study.

The appropriate reading is therefore bounded: the record documents the study design, the safety definition, the outcome areas assessed, and selected adverse-event counts. It does not report enough outcome information to determine the primary endpoint result or characterize effects on HIV reservoirs, inflammation, immune activation, or antiretroviral drug levels. No claim about efficacy or lack of efficacy follows from the missing results.

14. Why This Trial Matters Statistically

This study is statistically notable for the difference between a carefully specified safety question and the limited result information recorded alongside it. The primary endpoint spells out the event types, attribution categories, threshold, and timeframe. Those details make the target of measurement interpretable. Yet without the observed count and analysis denominator, readers cannot quantify the outcome or assess its precision. A well-defined endpoint and a reported endpoint result are both needed for statistical interpretation.

The single-group design also makes the distinction between describing outcomes and estimating comparative effects especially important. The registry record lists no randomized comparator and explicitly warns that the arms are not a like-for-like comparison. This means the design is suited to describing what was recorded among participants receiving sirolimus, but it does not provide a concurrent randomized estimate of what would have happened under a different intervention.

The number of listed outcomes and analyses also makes multiplicity a relevant consideration. The record does not report how analyses were prioritized or whether multiplicity was addressed. This is not evidence that a problem occurred; it is a limitation on how confidently readers can interpret any isolated result, particularly when numerical estimates and an analysis plan are not reported.

Finally, the registry illustrates why different safety summaries should not be conflated. The serious-event counts, other-adverse-event counts, and composite endpoint refer to distinct definitions. Careful reading preserves those distinctions rather than treating a selected adverse-event count as a proxy for the primary outcome. That discipline is essential when a public record contains a detailed endpoint definition but incomplete numerical results.

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 available registry information does not report the primary endpoint count, its analysis denominator, or an uncertainty interval. Consequently, the primary safety result cannot be quantified from this record. The information also does not provide numerical results for the listed secondary measures, so changes in CD4+ counts, HIV-1 RNA, cell-associated HIV-1 DNA, or HIV-1 Gag-specific T-cell responses cannot be characterized.

The single-group design has no concurrent randomized control for interpreting changes over time. No masking was used, and allocation is listed as not applicable. The registry record does not give detailed procedures for endpoint adjudication beyond stating that the core team judged treatment relatedness, nor does it describe blinding of outcome assessment or other safeguards against measurement bias.

The record does not report the statistical analysis plan, multiplicity handling, missing-data methods, or full analysis populations. Although enrollment is listed as 32, the number analyzed for the primary endpoint is not reported. Adverse-event summaries list 30 at risk, but the record does not explain the relationship between that denominator and enrollment. No explanation for the difference should be inferred.

The primary safety outcome is a composite, and component-specific counts are not reported. Readers therefore cannot determine which part of the definition, if any, accounts for the observed composite result. In fact, the composite result itself is not reported in the information analyzed. The serious and other adverse-event summaries cannot resolve that gap, and the record does not provide enough event-level detail to assess overlap or timing.

Finally, the planning illustrations described in the registry are hypothetical and are not the study's design or observed power. Their resulting values are not reported in the information analyzed. These limitations restrict interpretation to the documented design, definitions, and posted adverse-event figures.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy (ART) — NCT02440789.
• Registry record last updated 2021-08-03; status last verified 2019-12.
• Results first posted 2019-12-30.
• 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 NCT02440789, a completed Phase 1 and Phase 2, single-group study of sirolimus in people with HIV-1 infection receiving suppressive antiretroviral therapy. Enrollment is listed as 32. The primary endpoint is the number of participants meeting a composite safety definition from screening to study week 32, identified as week 20 of sirolimus.

The primary endpoint result and numerical results for the listed secondary outcomes are not reported in the registry information analyzed. The serious adverse-event summary lists 1 participant affected among 30 at risk and 0 deaths; diarrhoea is listed at 3.3% among the top serious terms. A separate other-adverse-event entry lists 28 participants affected among 30 at risk.

The study has no randomized comparator. The registry record also lists 46 outcome measures and 22 analyses, but does not report a detailed statistical plan, multiplicity strategy, missing-data methods, or the primary endpoint analysis population.