Safety and Pharmacokinetics (PK) of Raltegravir in HIV (Human Immunodeficiency Virus)-Infected Children and Adolescents: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Pharmacokinetics (PK) of Raltegravir in HIV (Human Immunodeficiency Virus)-Infected Children and Adolescents (NCT00485264), a non-randomized phase 1, phase 2 study. The primary outcome is Percentage of Participants With Grade 3 or 4 Adverse Events (AEs).

2. Clinical Question

3. Trial Design

This was a Phase I/II, multicenter, open-label, noncomparative study sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). The registry lists a nonrandomized allocation and a parallel model. It records enrollment of 153 and study status as completed. The study dates in the record are 2007-09-17 for start and 2013-06-03 for primary completion.

Participants were divided among age-based cohorts and received raltegravir formulations appropriate to those cohorts. Cohort I included participants aged 12 to 18 years and used the film-coated tablet. Cohort IIA included ages 6 to 11 years and used the film-coated tablet; Cohort IIB covered ages 6 to 11 years and used the chewable tablet. Cohort III included ages 2 to 5 years and used the chewable tablet. Cohort IV included ages 6 to 23 months, and Cohort V included ages 4 weeks to 5 months; both used oral granules for suspension.

The arm descriptions include starting-dose and final-dose information, but some descriptions end before all dosing details are stated. The complete protocol, dose-selection procedures, and any statistical rationale for cohort sizes are not reported in the registry record. The study’s stated aims included dose selection and collection of short- and long-term safety data, pharmacokinetic data, and efficacy experience. The registered primary endpoint was specifically a grade 3 or 4 adverse-event measure through Week 24 in the Final Dose Population.

Because allocation was nonrandomized and there was no comparator group, differences between cohorts cannot be interpreted as causal contrasts. Age, formulation, and cohort membership are linked in the design. The record therefore describes experience within cohorts rather than a controlled estimate of a treatment effect.

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: Final Dose Population: Participants accrued into Stage I and treated only at the dose ultimately selected for their cohorts were combined with those accrued into Stage II, where all participants received only the final selected doses for their respective cohorts.

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: All Treated Population: All patients exposed to raltegravir (at any dose)

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Grade 3 or 4 Adverse Events (AEs), measured over From study entry through Week 24.

The primary endpoint was the percentage of participants with grade 3 or 4 adverse events from study entry through Week 24. The registry says adverse events were graded with the Division of AIDS (DAIDS) AE Grading Table, Version 1.0, and that all grade 3 and higher signs, symptoms, and laboratory toxicities were included. The endpoint population combined participants accrued into Stage I who were treated only at their cohort’s ultimately selected dose with participants accrued into Stage II, in which all participants received the final selected doses for their cohorts.

A graded adverse-event endpoint describes the frequency of events meeting specified severity criteria during a defined observation period. In general, a severity-based endpoint can summarize clinically important safety observations across symptoms, signs, and laboratory findings. It is not identical to a measure of serious adverse events: seriousness and severity are distinct classifications, and the registry’s primary endpoint is defined by grade.

The endpoint description and a planned 95% confidence interval are in the registry record, but the percentage and interval estimate are not reported in the registry record. Without those results, the frequency and precision of the primary endpoint cannot be assessed from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a proportion: it concerns the percentage of participants who had at least one event meeting the stated grade threshold during the specified period. In general, a proportion is estimated by dividing the number of participants with the event by the number in the defined analysis population. The registry defines the Final Dose Population and endpoint window, but does not report the event count, denominator used for the primary result, estimate, or confidence interval. No primary endpoint value can therefore be interpreted from the registry record.

What does a confidence interval communicate?

In general, a confidence interval expresses uncertainty around an estimated quantity. For a percentage, its width depends in part on the amount of information available and the observed frequency. A narrower interval indicates greater precision under the method used; a wider interval indicates less precision. The registry specifies a 95% confidence interval for the primary endpoint, but its bounds are not reported in the registry record. The interval’s width and the precision of the endpoint estimate are consequently unknown.

Confidence intervals do not by themselves establish that a finding is clinically important, nor do they correct for limitations in study design. In a noncomparative study, an interval around an event percentage describes uncertainty in that group’s observed frequency; it does not provide a randomized estimate of a difference between raltegravir and another treatment.

Why does the design matter?

Randomization, when used, helps make treatment groups comparable in expectation and supports causal comparisons. This study was nonrandomized and noncomparative, so there is no randomized comparator against which to estimate a treatment contrast. Its cohorts also differ by age and formulation. A difference in observed counts across cohorts could reflect cohort composition or other differences, and the registry does not provide a basis for attributing such a difference to formulation or dose.

Open-label means the study was not masked. The record does not report whether or how knowledge of treatment assignment was considered in assessment or analysis. In general, lack of masking can matter for outcomes involving clinical assessment or reporting, although laboratory findings may have different assessment characteristics. The record does not give enough detail to assess these issues for individual events.

How should event counts be distinguished?

The primary endpoint uses grade 3 or 4 severity criteria, as defined by the DAIDS AE Grading Table, Version 1.0, and includes signs, symptoms, and laboratory toxicities. The safety summary separately lists serious adverse-event counts, other adverse-event counts, deaths, and selected serious-event terms. In general, “serious” describes a regulatory or clinical classification, while “severe” describes intensity or grade; the categories are not interchangeable. The registry does not report participant-level cross-classification that would show which serious events also met grade 3 or 4 criteria.

The listed adverse-event counts are descriptive. They do not establish that an event was caused by raltegravir. The record does not report a causal assessment for each event in these group entries. The selected serious-event terms and percentages also should not be taken as a complete distribution of all events: further information on term selection, denominators, and repeated events is not reported in the registry record.

What do planning calculations mean?

Any sample-size figures associated with planning illustrations are hypothetical calculations based on an observed effect, not the trial’s own design. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. For time-to-event calculations, the stated quantity is a total number of events; other calculations refer to participants per arm. Such calculations are planning illustrations, not observed power and not evidence that this noncomparative study was designed around a particular sample-size target. The trial’s own sample-size justification is not reported in the registry record.

In general, power is a property of a planned statistical test under specified assumptions, not a retrospective measure of whether a completed study “had enough power.” A planning calculation also depends on the assumed effect and design. Because the trial was noncomparative, two-arm planning assumptions do not describe its actual cohort structure. No new effect estimate or sample-size calculation can be inferred from the cohort counts alone.

Why can event variability affect analysis?

In general, over-dispersion occurs when observed variability exceeds what a statistical model assumes. It can make standard errors too small if the model does not account for that extra variability, leading to intervals that appear more precise than warranted. The registry record does not report a model for the primary endpoint, an over-dispersion assessment, or model-based adjustments. Since the primary result itself is not reported, there is no basis for evaluating whether such issues affected its estimate.

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("Cohort I", "Cohort IIA", "Cohort IIB", "Cohort III", "Cohort IV", "Cohort V")
n      <- c(59, 4, 13, 20, 14, 12)
events <- c(12, 1, 2, 6, 5, 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  Cohort I  59  12  20.3  11.0  32.8  12.0  32.3  12.1  32.3
ARM  Cohort IIA  4  1  25.0  0.6  80.6  4.6  69.9  5.3  71.6
ARM  Cohort IIB  13  2  15.4  1.9  45.4  4.3  42.2  4.7  42.8
ARM  Cohort III  20  6  30.0  11.9  54.3  14.5  51.9  14.6  52.2
ARM  Cohort IV  14  5  35.7  12.8  64.9  16.3  61.2  16.3  61.6
ARM  Cohort V  12  4  33.3  9.9  65.1  13.8  60.9  13.9  61.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 0 analysis records. It names secondary outcomes covering grade 3 or 4 adverse events, treatment termination due to suspected adverse drug reaction attributable to study medication, deaths, HIV RNA response, and changes in CD4 count and CD4 percent. The statistical plan, including whether and how multiplicity was addressed across outcomes or analyses, is not reported in the registry record.

Multiplicity matters in general when many outcomes, subgroups, or statistical tests are examined: the chance of at least one apparently notable result can increase as the number of tests grows. Whether this concern applies to any particular reported result depends on the prespecified analysis plan and the analyses actually conducted. Those details are not reported in the registry record, so no adjustment strategy or prespecification status can be established.

The registry defines the primary endpoint population as a combination of Stage I participants treated only at the selected cohort dose and Stage II participants receiving final selected doses. It does not report the number included in this population, the number with missing endpoint data, how missing observations were handled, or whether any imputation was used. These details are important because the denominator and missing-data approach affect interpretation of a percentage.

The record does not report a complete statistical analysis plan, interim analyses, or the handling of participants who discontinued or lacked Week 24 assessments. The absence of analysis records in the registry should not be interpreted as proof that no analyses were conducted; it means analysis details and results are not reported in the registry record. The posted cohort safety counts do not fill these gaps for the primary endpoint.

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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hyperbilirubinaemia (25.0%), acute sinusitis (25.0%), neutropenia (14.3%), dyspnoea (14.3%), pneumonia (10.2%).

The adverse-event summary separates serious-event counts, other-event counts, and deaths by cohort. For example, Cohort I lists 26 serious events among 59 at risk and 57 other events among 59. Cohort IV lists 7 serious events among 14 at risk, 14 other events among 14, and 1 death. These are descriptive entries for the named cohorts, not treatment comparisons.

The serious-event terms listed include hyperbilirubinaemia and acute sinusitis at 25.0% each, neutropenia and dyspnoea at 14.3% each, and pneumonia and neutrophil count decreased at 10.2% each. The record does not report the term-specific denominators or explain whether the percentages represent participants or events. These terms should therefore be read as the registry’s selected serious-event entries, not as a full account of all adverse events.

Seriousness and severity grade are different concepts. The primary endpoint counts grade 3 or 4 events; the safety entries count serious events separately. A serious event is not necessarily grade 3 or 4, and a grade 3 or 4 event is not necessarily serious. The registry does not report enough detail to link the entries at the participant or event level. Nor do these counts establish that raltegravir caused the events.

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

The record describes a study intended to evaluate raltegravir’s safety, tolerability, pharmacokinetics, and antiviral activity in children and adolescents with HIV-1 infection, with dose selection across pediatric age groups among its aims. The registered primary safety question is clear: the percentage of participants in the Final Dose Population with grade 3 or 4 adverse events from study entry through Week 24. The actual result for that endpoint is not reported in the registry record.

The cohort entries provide descriptive counts of serious and other adverse events, along with deaths. They offer information about events recorded in the cohorts, but they do not supply the missing primary endpoint percentage or its confidence interval. They also do not support a comparative estimate because the study was nonrandomized and noncomparative. Differences across age-based cohorts cannot be attributed to age, formulation, or dose from these counts alone.

These registry entries do not establish that raltegravir is effective or ineffective, or that it caused or did not cause any particular event. The record’s stated aims include pharmacokinetic and antiviral activity experience, and it lists secondary HIV RNA and CD4 outcomes, but the corresponding numerical results are not reported in the registry record. The safety information should therefore be interpreted as incomplete descriptive reporting rather than as a comprehensive assessment of all study findings.

In general, evaluating a safety percentage requires the event definition, observation window, analysis population, numerator, denominator, and a measure of precision. The registry supplies the endpoint definition and intended population but not the endpoint estimate, interval, or missing-data details. Readers cannot assess the magnitude or precision of the primary endpoint from this record alone. The posted results also do not provide a randomized basis for determining how the observed events compare with another treatment or with no study treatment.

14. Why This Trial Matters Statistically

Statistically, this trial illustrates the difference between defining an endpoint and reporting an estimate for it. The registry specifies a grade-based safety outcome, a Week 24 observation period, and a Final Dose Population, but does not report the percentage or its 95% confidence interval. Without those quantities, the central registered safety endpoint cannot be evaluated for magnitude or precision.

The design also shapes what can be learned. The study was open-label, nonrandomized, and noncomparative, with age-based cohorts receiving different formulations. Its structure supports descriptive reporting of experience within cohorts, but does not provide a randomized comparison. Cohort counts should not be interpreted as evidence that one formulation or age group had a higher or lower risk caused by treatment.

The record’s multiple safety and clinical outcomes make transparent reporting of analysis choices important. The registry lists 13 outcome measures but has no analysis records. Multiplicity procedures, missing-data methods, and the analysis plan are not reported in the registry record. Those omissions limit assessment of how the posted counts relate to prespecified questions and how completely outcomes were observed.

These features matter beyond this study: readers need the endpoint estimate, uncertainty, analysis population, and missing-data handling to judge how informative a safety result is. A stated endpoint alone does not reveal what was observed, and cohort-level counts alone do not substitute for a reported estimate with its precision.

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.

A key limitation is that the primary endpoint result is not reported in the registry record. Although the endpoint definition, time window, and Final Dose Population are described, the percentage and 95% confidence interval are absent. The number of participants contributing to that endpoint and the handling of missing Week 24 data are also not reported.

The study was nonrandomized, open-label, and noncomparative. There is no randomized control group, so the posted counts cannot estimate a causal difference between raltegravir and another treatment. Cohorts were defined by age and formulation, which prevents treating their observed event counts as direct comparisons of formulations or dose strategies.

The adverse-event summary is not sufficient to reconstruct the primary grade 3 or 4 endpoint. It lists serious events separately from other adverse events, while the primary outcome is based on severity grade. Participant-level overlap between these categories, event-level detail, and causal assessments are not reported in the registry record. The denominators underlying the selected serious-event term percentages are also not reported.

Further limitations arise from missing statistical details. The complete analysis plan, sample-size justification, multiplicity approach, missing-data methods, and interim analyses are not reported in the registry record. The cohort descriptions also contain some incomplete dosing details. These gaps restrict assessment of prespecification, precision, and how fully the registry summaries reflect the study’s analyses.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Pharmacokinetics (PK) of Raltegravir in HIV (Human Immunodeficiency Virus)-Infected Children and Adolescents — NCT00485264.
• Registry record last updated 2021-11-02; status last verified 2021-10.
• Results first posted 2014-12-22.
• 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

This completed Phase I/II study evaluated raltegravir in children and adolescents with HIV-1 infection. It was multicenter, open-label, nonrandomized, and noncomparative, with enrollment of 153. Age-based cohorts received film-coated tablets, chewable tablets, or oral granules for suspension.

The primary endpoint was the percentage of participants with grade 3 or 4 adverse events from study entry through Week 24 in the Final Dose Population. The endpoint result and its 95% confidence interval are not reported in the registry record. Cohort-level serious-event counts, other-event counts, selected serious-event terms, and deaths are listed, but they do not constitute a randomized comparison or replace the missing primary estimate.

The record does not report the statistical analysis plan, missing-data methods, multiplicity procedures, or sample-size justification. Interpretation is therefore limited to the trial design, endpoint definition, and descriptive safety entries recorded in the registry.