PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection (NCT03239899), a na phase 1 study. The primary outcome is Frequency of Grade 3 or Higher Adverse Events.

2. Clinical Question

The title also signals an interest in the central nervous system HIV reservoir. The listed secondary outcomes include measures of HIV RNA in plasma and cerebrospinal fluid, antibody responses, cytokines, CD4 counts, FDG-PET/CT metabolic uptake, and PD-1 expression. These measures describe biological questions the investigators planned to examine; their presence does not establish that a change occurred.

The primary question is a safety question rather than a comparison of treatment effects. With no control group, the design cannot directly contrast the frequency of events under pembrolizumab with the frequency under another treatment or no study drug. The registry record does not report a primary endpoint count, so it does not permit a numerical answer to the primary question from the information available.

3. Trial Design

This was a completed Phase 1, single-group study sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). The registry record lists 13 participants enrolled, an allocation of NA, and no masking. The recorded start date is 2018-04-09, and the primary completion date is 2023-02-13. The study status is COMPLETED.

Participants with HIV received one 200 mg pembrolizumab infusion over 30 minutes. The brief summary describes screening that could include medical history, physical and neurological examinations, blood tests, lumbar puncture, and FDG-PET/CT. Leukapheresis was optional at baseline. It also describes up to 7 more visits, with some screening tests repeated. The primary endpoint timeframe is the study duration, up to 52 weeks following infusion.

Because all participants were in one group, there was no randomized treatment assignment or like-for-like control comparison. The absence of masking means the registry record describes the study as open-label. These features matter when interpreting safety observations: events recorded during follow-up can be described, but the design does not isolate how many would have occurred without the study drug.

The trial also listed seven secondary outcomes concerning immune and virological measures and CNS imaging. The record does not report analysis results for those measures. A detailed protocol, the rationale for the planned enrollment, and a statistical analysis plan are not reported in the registry record. The study's single-group structure and the information posted should therefore guide interpretation, rather than assumptions about unreported design choices.

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: 68 individuals were pre-screened and 13 individuals met the eligibility criteria and expressed interest in participating in the study.

Overall Study

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 Frequency of Grade 3 or Higher Adverse Events, measured over study duration (up to 52 weeks post infusion).

The primary endpoint is the frequency of Grade 3 or higher adverse-event occurrences that were judged probably or definitely causal to pembrolizumab. Its unit is number of occurrences, and the stated observation period is the study duration, up to 52 weeks after infusion. The endpoint is intended to capture more serious adverse events and to focus on events considered related to the study drug.

In general, a safety endpoint of this kind is used to describe the occurrence of events during treatment and follow-up. The severity threshold identifies events at or above the specified grade, while the causality criterion narrows the count to events attributed with a stated level of certainty. Those definitions affect what is counted: events below the grade threshold or not judged probably or definitely related would not meet the primary endpoint as described.

The endpoint is expressed as a count, not as a comparative effect estimate. No primary endpoint count is reported in the registry record. Thus, the definition and timeframe are available, but the posted information does not give the observed number of qualifying occurrences or a precision estimate for that number. The adverse-event summary includes separate safety counts, but those figures should not be substituted for the primary endpoint unless their definitions and event-level relationship to it are established.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies the primary endpoint as a count of Grade 3 or higher adverse-event occurrences judged probably or definitely causal to pembrolizumab. It does not report an analysis method for that endpoint, a confidence interval, or a statistical test. The count is therefore best understood as a descriptive safety measure in the available record, not as a comparative estimate.

What does a count measure?

A count records the number of qualifying occurrences. In general, a count may refer to events rather than to distinct people: one participant could have more than one occurrence, depending on the endpoint definition. The registry record labels this endpoint's unit as number of occurrences, but does not provide the event-level details needed to determine whether occurrences were repeated within participants. The count also depends on the stated grade threshold, attribution criteria, and observation period. Here, those criteria are Grade 3 or higher, probably or definitely causal, and up to 52 weeks after infusion.

A count alone does not show how precisely an underlying event frequency has been estimated. In general, a confidence interval communicates uncertainty around an estimate under a specified statistical model. No confidence interval for the primary endpoint is reported in the registry record. With limited enrollment, even a fully reported count could be imprecise as an estimate of event frequency in a wider population; the exact uncertainty would depend on the event count, denominator, follow-up, and analysis method.

Why does the study design matter?

This was a single-group study with no comparator and no masking. In general, a comparative trial can estimate a contrast between groups, while a single-group study describes outcomes in the group observed. Without a concurrent comparison group, background events and events that might have occurred without the study drug cannot be separated from events associated with treatment by a direct between-group contrast. The endpoint's causality assessment is part of its definition, but it does not create a control group or establish a treatment effect.

Masking can reduce the influence of treatment knowledge on some aspects of assessment. Since the record lists masking as none, readers should recognize that the study was not masked. The registry record does not describe assessor procedures or report whether knowledge of treatment affected event assessment, so the potential relevance of this design feature cannot be quantified from the record.

How should planning illustrations be read?

Any sample-size figures associated with this trial are planning illustrations, not observed power and not the number of participants enrolled. The described illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it considers detecting a stated proportion of an observed effect. For time-to-event settings, the planning quantity is a total number of events using the Schoenfeld approach; for other settings, it is participants per arm. These are assumptions for hypothetical two-arm planning and do not describe the actual single-group design.

In general, sample-size planning depends on the outcome, the effect one wants to detect, variability or event frequency, the statistical test, and the design assumptions. Changing an assumed target effect changes the planned sample size. Such calculations do not show that a study had a given probability of finding an effect after it was completed. Nor do planning figures supply evidence about the observed safety outcome. A trial-specific sample-size justification and statistical analysis plan are not reported in the registry record.

What is not available for independent checking?

The record does not provide the primary endpoint count, an analysis population definition, participant-level data, or a reported inferential analysis. Without those details, readers cannot independently reconstruct the primary result or assess the endpoint's uncertainty. The seven secondary outcomes are listed, but their analysis results are not reported in the registry record. General statistical concepts can clarify what the endpoints and design mean, but they cannot fill in unreported results or methods.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists seven secondary outcomes in addition to the primary safety endpoint. They cover HIV-specific antibody responses in cerebrospinal fluid and serum, the cerebrospinal-fluid cytokine profile, peripheral CD4 counts, HIV RNA in plasma and cerebrospinal fluid, CNS FDG-PET/CT metabolic uptake, and PD-1 expression in cerebrospinal fluid and blood cells. The record does not report analyses for these outcomes.

In general, testing several outcomes can increase the chance of finding at least one apparently notable result by chance if each is assessed separately. A statistical plan may specify which outcome is primary, how secondary outcomes will be interpreted, and whether any adjustment or hierarchical procedure will be used. Such a multiplicity plan is not reported in the registry record. No adjustment should be assumed, and no conclusions about secondary outcomes can be drawn from their listing alone.

Missing-data methods are also not reported in the registry record. The record does not state how incomplete follow-up, missing measurements, withdrawals, or unavailable outcome assessments were handled. It does not provide a detailed analysis population definition or the number contributing data to each outcome. These omissions make it difficult to assess whether the enrolled group and the people included in any outcome analysis were the same.

The safety summary lists 6 at risk for serious adverse events and 6 at risk for other adverse events, while enrollment is 13. The registry record does not explain the denominator difference. This should not be resolved by assuming a particular follow-up subset, missingness pattern, or analysis population. A complete account would identify the population and observation period for each endpoint and explain the handling of missing observations; that information is not reported in the registry record.

11. 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 safety summary lists 6 at risk and 0 affected for serious adverse events. For other adverse events, it lists 6 at risk and 6 affected. It also lists 0 deaths. These are category-specific counts in the registry record; they are not percentages, and no rates are calculated.

The serious-event summary is not the same as the primary endpoint definition. The primary endpoint concerns occurrences that are Grade 3 or higher and judged probably or definitely causal to pembrolizumab, across the study duration up to 52 weeks after infusion. The summary does not provide the event-level information needed to verify that its serious adverse-event category maps directly to that endpoint. No serious adverse-event terms are listed.

The safety summary's 6 participants at risk should not be replaced with the enrollment count of 13 when interpreting those entries. The record does not explain why the listed at-risk counts differ from enrollment, or whether the same participants contributed to all categories. The counts describe what the registry lists, but do not by themselves establish completeness of follow-up or the frequency of qualifying primary endpoint events.

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

The record describes a Phase 1 study designed to examine safety after one pembrolizumab infusion in people with HIV. It also lists biological outcomes related to HIV, immune measures, and CNS imaging. The primary safety endpoint is defined, and the safety summary reports counts for serious adverse events, other adverse events, and deaths. These details are useful for understanding the study's scope and the information recorded.

However, the primary endpoint's numerical result is not reported in the registry record. The posted safety counts do not provide a clear substitute because the serious-event category is not shown to have the same grade and causality criteria as the primary endpoint. The denominator difference between enrollment and the safety summary is also unexplained. The available information therefore does not support a precise estimate of the primary endpoint's frequency.

The single-group design does not permit a direct comparison with an untreated or alternative-treatment group. The study cannot establish from its design alone whether an event was caused by pembrolizumab, even though the primary endpoint includes a causality assessment. Nor can the trial's listed secondary outcomes establish changes in HIV measures or CNS activity without reported results and analyses.

In general, safety observations from a small study can describe events among participants followed, but should not be treated as a definitive estimate of event frequency in a broader population. The record does not report confidence intervals, detailed follow-up completeness, or the analysis populations needed to characterize precision. The study's status as completed does not itself fill in these missing outcome results.

13. Why This Trial Matters Statistically

This study illustrates how a trial's stated objective, endpoint definition, and posted results can answer different questions. Its primary endpoint focuses on severe adverse-event occurrences considered probably or definitely related to the study drug, while the available safety summary uses broader category labels. Keeping those definitions distinct prevents a descriptive count from being mistaken for the primary outcome.

The design also matters to statistical interpretation. A single-group study can record what happened after an intervention, but offers no concurrent control group for estimating a treatment contrast. The no-masking design is another relevant feature of outcome assessment, although the record does not say whether it affected any particular judgment. These features are not simply technical details: they determine the kinds of conclusions the data can support.

The difference between 13 enrolled participants and 6 at risk in each safety-summary category highlights the importance of denominators and analysis populations. Without an explanation of that difference, readers cannot assume that enrollment is the appropriate denominator for every safety count. Similarly, a listed secondary outcome is not a reported finding, and a completed study status is not a substitute for endpoint results.

Finally, planning illustrations should remain separate from observed evidence. Assumptions about hypothetical two-arm designs do not describe the actual single-group study and do not represent observed power. This distinction is useful when interpreting statistical material around a trial: planning calculations address design choices, whereas outcome counts and their uncertainty address what was observed. The registry record leaves important pieces of that observed-outcome account unreported.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record does not report the numerical result for the primary endpoint, despite defining the endpoint and its timeframe. This prevents a direct quantitative assessment of the study's principal safety question. It also does not provide event-level details that would allow readers to check how the primary endpoint relates to the serious adverse-event summary.

Enrollment was 13, while the safety summary lists 6 at risk for serious adverse events and 6 at risk for other adverse events. The reason for this difference is not reported in the registry record. The record also does not state whether the listed counts represent participants, event occurrences, or a particular follow-up subset beyond the labels shown. No rate should be inferred from an unmatched denominator.

The study had no comparator and no masking. Thus, it does not provide a randomized between-group estimate, and knowledge of treatment could be relevant to assessment in general. The record does not explain event adjudication procedures or whether assessors were independent.

Detailed eligibility criteria, the sample-size justification, a statistical analysis plan, missing-data methods, and analysis-population definitions are not reported in the registry record. The seven secondary outcomes are listed, but their analysis results are not reported. The record also does not report confidence intervals or other precision measures for the safety counts. These limitations leave substantial uncertainty about the completeness and precision of the posted results, beyond the inherent limits of a single-group Phase 1 study.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection — NCT03239899.
• Registry record last updated 2025-10-02; status last verified 2023-02-13.
• Results first posted 2024-02-13.
• 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.

18. Record Summary

NCT03239899, titled “PD-1 Inhibition to Determine CNS Reservoir of HIV-Infection,” is a completed Phase 1, single-group study sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). The record lists 13 participants enrolled, no masking, and one 200 mg pembrolizumab infusion over 30 minutes. The study's primary outcome is the number of Grade 3 or higher adverse-event occurrences judged probably or definitely causal to pembrolizumab during the study, up to 52 weeks after infusion.

The safety summary lists 6 at risk and 0 affected for serious adverse events, 6 at risk and 6 affected for other adverse events, and 0 deaths. The primary endpoint's numerical result and analyses of the seven listed secondary outcomes are not reported in the registry record. The record does not explain the difference between enrollment and the safety-summary denominators.