A Study of the Safety, Tolerability, and Antiretroviral Activity of Raltegravir (MK-0518) in Combination With Other Antiretroviral Therapies in Russian Children and Adolescents Infected With Human Immunodeficiency Virus (HIV-1) (MK-0518-248): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of the Safety, Tolerability, and Antiretroviral Activity of Raltegravir (MK-0518) in Combination With Other Antiretroviral Therapies in Russian Children and Adolescents Infected With Human Immunodeficiency Virus (HIV-1) (MK-0518-248) (NCT01717287), a non-randomized phase 2 study. The primary outcome is Percentage of Participants With at Least One Clinical Adverse Experience.

2. Clinical Question

3. Trial Design

This was a phase II, multicenter, open-label, noncomparative study of raltegravir in two oral formulations, used with other antiretroviral agents. The registry lists a parallel model and non-randomized allocation. Participants and study personnel were not masked. These features describe the structure of the study; they do not establish that the two formulation groups were intended to support a direct causal comparison.

The study enrolled 32 participants with HIV-1 infection in Russia, including treatment-naive and treatment-experienced children and adolescents. The record does not report age ranges, baseline characteristics, the number with prior treatment experience, or how participants were assigned to formulation. Those omissions limit assessment of how similar the groups were at entry.

One arm used raltegravir film-coated tablets at 400 mg orally twice daily with other antiretroviral therapy for 24 weeks. The other used chewable tablets at a weight-based dose up to 300 mg orally twice daily, also with other antiretroviral therapy for 24 weeks. The record presents both as active treatment regimens rather than describing a placebo or untreated group.

The primary safety endpoint covered a timeframe of up to Week 26. The registry gives a study start date of 2012-11-16, a primary completion date of 2013-12-11, and a completed status. These dates describe the study record, not the duration of follow-up for each participant.

The stated purpose included gaining local treatment experience in the pediatric HIV-infected population in Russia. No protocol-level explanation of allocation, sample-size justification, or planned interim analyses is reported in the registry record. The posted design should therefore be read as descriptive and exploratory rather than as a randomized efficacy comparison.

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: Film-coated tablets were administered to participants \>=12 years old and to those 6 to \<12 years old who weighed \>=25 kg and could swallow pills. A weight-based dose of chewable tablets was administered to participants 6 to \<12 years old who could not swallow pills or preferred the chewable formulation, and to participants 2 to \<6 years old

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All patients as treated population included all enrolled participants who received at least one dose of study drug

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 Percentage of Participants With at Least One Clinical Adverse Experience, measured over Up to Week 26.

The primary endpoint is the percentage of participants with at least one clinical adverse experience, assessed up to Week 26. The record defines an adverse experience as an unfavorable and unintended change in body structure, function, or chemistry that is temporally associated with study-drug use. The definition does not require investigators to judge that the drug caused the event. Worsening of a preexisting condition is also included when temporally associated with study-drug use.

General statistical context: a participant-level endpoint of “at least one” event summarizes whether a participant experienced any qualifying event during the assessment period. It does not, by itself, describe how many events each affected participant had, how severe they were, or whether they were considered related to treatment. Those are separate dimensions of safety reporting.

The endpoint is used to describe the frequency of reported clinical adverse experiences in the treated population over the stated timeframe. Because the study is open-label and noncomparative, these observations do not establish that raltegravir caused an event or that one formulation has a different safety profile from the other. The posted record does not include a full arm-specific result for the primary percentage in the registry record; the safety figures instead list serious and other adverse-event counts. The endpoint’s estimate and its precision should not be inferred from those counts without a reported analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a noncomparative design imply?

General statistical context: a noncomparative study describes outcomes within the enrolled treatment groups rather than estimating a treatment effect against a control group. This study includes two formulations, but the registry calls it noncomparative and records non-randomized allocation. The presence of two arms does not by itself make the study a randomized comparison. Without random assignment, differences between groups may reflect who entered each group as well as any treatment-related difference. The registry record does not report a prespecified causal contrast or an adjusted analysis.

What does the endpoint count?

The primary outcome is the percentage of participants with at least one clinical adverse experience up to Week 26. This is a participant-level binary outcome: a participant either meets the “at least one” definition or does not, for purposes of the endpoint. General statistical context: such an outcome is useful for summarizing how many people experienced an event, but it does not show the total number of events, the timing of events, or the distribution of severity. The endpoint’s definition also does not require that an event be judged related to study drug.

How should event counts be read?

The posted figures list serious adverse events separately from other adverse events. In the film-coated tablet group, the record lists 4 participants at risk and zero serious events and zero other events affecting participants. In the chewable tablet group, it lists 28 participants at risk, zero serious events, and 8 participants affected by other events. These are counts as presented, not newly calculated percentages. They describe the safety observations recorded for these groups; they do not demonstrate that the regimens have equivalent safety or that the difference between the groups is attributable to formulation.

General statistical context: a confidence interval, when reported, communicates uncertainty around an estimate under the assumptions of the analysis. It is not a guarantee that the true value lies within the interval. No confidence intervals for the safety counts are reported in the record. Consequently, the degree of statistical precision cannot be quantified from these registry entries alone. A zero count is an observation, not proof of zero underlying risk.

What can the sample-size illustrations say?

The page includes calculated sample-size material, but the registry entries do not include its calculated participant-per-arm values. The described illustration uses a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. It is a planning illustration based on the observed effect, not the study’s original design justification. Any sample-size figures shown in that section are planning illustrations, not observed power. No sample-size justification for the trial itself is reported in the registry record.

General statistical context: planning calculations depend on the assumed effect, variability or event rate, significance level, allocation, and analysis method. A calculation based on an observed effect should not be interpreted as evidence that the trial had a particular probability of detecting an effect after the fact. The registry entries do not report the trial’s own assumptions, target power, or protocol-based calculation, so these should not be inferred.

What analyses are documented?

The registry lists nine outcome measures, including CD4 cell count, CD4 cell percentage, and HIV RNA thresholds. It lists zero analysis entries in the record. This means that the analysis details and outcome estimates are not available in the registry record; it does not identify what analytic work may have been conducted outside the registry. No statistical model, covariate adjustment, handling of repeated measurements, or multiplicity procedure is reported in the registry record.

General statistical context: an analysis plan specifies how data are converted into estimates and how uncertainty is summarized. Without details of the planned or completed analyses, readers cannot determine whether reported comparisons were adjusted, how missing observations were treated, or whether multiple outcomes were handled using a prespecified strategy. These uncertainties are particularly relevant when a record lists multiple outcomes but does not give their analysis results.

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("Raltegravir Film-coated Tablet", "Raltegravir Chewable Tablet")
n      <- c(4, 28)
events <- c(0, 12)
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  Raltegravir Film-coated Tablet  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Raltegravir Chewable Tablet  28  12  42.9  24.5  62.8  26.5  60.9  26.4  61.1

11. Multiplicity, Missing Data and Analysis Populations

The record lists nine outcome measures. These include CD4 cell count and percentage changes from baseline, the percentage achieving at least a 1 log10 reduction in HIV RNA or having an HIV RNA assessment below 200 copies/mL, and the percentages achieving HIV RNA below 40 copies/mL or below 200 copies/mL. The registry entries do not describe a hierarchy of outcomes, a multiplicity adjustment, or a plan for interpreting several statistical tests together. Such procedures are not reported in the registry record.

The record also lists zero analysis entries. It does not describe how missing outcome measurements were handled, whether participants with incomplete follow-up were included in particular analyses, or whether any sensitivity analyses were performed. These details are not reported in the registry record and should not be guessed. A stated safety population includes all enrolled participants who received at least one dose of study drug, but the registry entries do not describe analysis populations for the secondary outcomes.

General statistical context: when several outcomes are tested, the chance of at least one apparently unusual result can increase if each is assessed independently at a conventional threshold. A prespecified hierarchy or other multiplicity approach can clarify how evidence is interpreted, but no such approach is documented. Missing-data methods matter because the analysis can depend on whether unobserved outcomes are excluded, imputed, or addressed in another way. The record does not provide enough information to assess these choices.

The primary endpoint timeframe is up to Week 26. The registry entries do not report visit-level completeness or the number of participants with endpoint data at each time point. Readers should therefore distinguish the stated analysis population definition from evidence about completeness of the observed data.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The safety figures are presented by formulation. For raltegravir film-coated tablets, 4 participants were listed at risk; the record reports zero serious adverse events and zero participants affected by other adverse events. For raltegravir chewable tablets, 28 participants were listed at risk; the record reports zero serious adverse events and 8 participants affected by other adverse events. These are the counts in the posted safety record, not percentages calculated.

The serious-event counts should be interpreted as observations during the reported study experience, not as proof that serious events are impossible. The study was small and noncomparative, and the group sizes were not randomized. The figures cannot establish that one formulation causes more or fewer events than the other. The record does not report deaths in the safety figures, and deaths should not be inferred from a missing value.

The endpoint’s definition includes events whether or not considered related to study drug. Thus, an event count alone does not establish causation. The posted figures also do not describe event duration, severity beyond the serious classification, recurrence, or whether multiple events occurred in one participant. The registry record does not list serious-event terms in the material.

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

The posted record documents a phase II study of two oral raltegravir formulations given with other antiretroviral therapy to Russian children and adolescents with HIV-1. It reports enrollment of 32 participants, a broad primary safety endpoint through Week 26, and group-level safety counts. The serious adverse-event count is zero in both groups; other adverse events are listed as affecting 0 participants in the film-coated tablet group and 8 in the chewable tablet group.

These observations describe what was recorded in this study. They do not establish that either formulation caused the events, that either formulation is safer, or that the groups had comparable risk. Non-randomized allocation and the noncomparative design make a causal comparison inappropriate on the basis of these counts alone. The record does not provide enough information to quantify uncertainty around the counts or to assess the completeness of follow-up.

The record lists secondary measures relating to CD4 and HIV RNA, but their results are not reported in the registry record. It therefore does not support a conclusion about changes in those measures. Nor does the safety information alone answer the broader clinical question of antiretroviral activity.

General statistical context: study results are most informative when the estimate, its uncertainty, the analysis population, and the method are all available. In this record, the design and outcome definitions are described, but detailed analyses are not. Readers should treat the displayed figures as descriptive evidence from the enrolled participants and avoid interpreting them as a randomized treatment comparison, a definitive safety profile, or evidence of efficacy.

14. Why This Trial Matters Statistically

This study is statistically useful as an example of why design labels matter. Two treatment arms are present, but the study is described as noncomparative and allocation was non-randomized. A reader who sees two sets of safety counts might be tempted to treat the arms as direct controls for one another. The design does not justify that interpretation. Formulation groups can differ for reasons other than the formulation itself, and the registry record does not describe a method that addresses those differences.

The endpoint also illustrates an important distinction between an adverse experience and an event judged to be caused by treatment. The primary definition includes unfavorable and unintended changes temporally associated with study-drug use whether or not considered related. That broad definition captures safety observations without making a causal claim. It is important to keep endpoint classification separate from attribution.

The study provides local treatment experience in a population identified as Russian children and adolescents with HIV-1, including treatment-naive and treatment-experienced participants. Its focus and setting are part of the context for interpreting the record. However, the registry entries do not report participant ages, baseline characteristics, or the distribution of treatment history, so the enrolled population cannot be characterized in more detail.

Finally, the record lists several secondary outcomes but no analysis entries in the registry record. That gap illustrates why outcome names alone do not communicate results. Statistical interpretation requires estimates and methods, not only a list of planned or registered measures. The posted safety counts can be described, but they cannot substitute for complete outcome reporting or a comparative analysis.

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 interpretation is the non-randomized, noncomparative design. Although the record presents two formulations in parallel arms, it does not support treating one as a like-for-like control for the other. The reason for formulation assignment and the comparability of the groups are not reported in the registry record. Potential differences between participants therefore cannot be separated from differences in the observed counts.

The total enrollment was 32, and the safety figures are distributed across groups of different sizes. The record does not provide confidence intervals for these counts in the registry record. This limits assessment of their precision. Zero serious adverse events in the posted data should not be interpreted as evidence of no underlying risk.

The study was open-label, so participants and investigators were not masked. The record does not describe procedures that might limit reporting or assessment effects. The primary endpoint is broad and includes events whether or not considered related to study drug. The safety counts do not supply event-level details such as timing, duration, or recurrence.

Important descriptive information is absent in the registry record: ages, baseline characteristics, group assignment rationale, and the distribution of treatment experience. The record does not report detailed analysis methods, missing-data handling, multiplicity procedures, confidence intervals, or results for the listed CD4 and HIV RNA measures. It also does not report deaths in the safety figures. These limitations mean that the available material supports only a narrow descriptive reading of the posted safety counts, not a comprehensive assessment of treatment effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of the Safety, Tolerability, and Antiretroviral Activity of Raltegravir (MK-0518) in Combination With Other Antiretroviral Therapies in Russian Children and Adolescents Infected With Human Immunodeficiency Virus (HIV-1) (MK-0518-248) — NCT01717287.
• Registry record last updated 2018-08-21; status last verified 2018-07.
• Results first posted 2014-07-29.
• 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 II, multicenter, open-label, noncomparative study with non-randomized allocation and a parallel model. It enrolled 32 Russian children and adolescents with HIV-1 infection who were treatment-naive or treatment-experienced. Participants received raltegravir film-coated tablets or chewable tablets with other antiretroviral therapy; both regimens were described as lasting 24 weeks.

The primary endpoint was the percentage of participants with at least one clinical adverse experience through Week 26. Posted safety figures list zero serious adverse events in each formulation group, and other adverse events affecting 0 participants in the film-coated tablet group and 8 in the chewable tablet group. The record also lists nine outcome measures, including CD4 and HIV RNA measures, but the registry entries contain no analysis entries or results for those secondary outcomes.

The study started on 2012-11-16, reached primary completion on 2013-12-11, and has completed status. Its design supports a descriptive account of the recorded safety experience, not a randomized comparison between formulations.