Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents (NCT01302847), a non-randomized phase 1, phase 2 study. The primary outcome is Percentage of Participants With Grade 3 or Higher Adverse Events (AEs).

2. Clinical Question

3. Trial Design

This was a Phase I/II, multicenter, open-label study of dolutegravir in combination regimens for HIV-1 infection. The registry lists a non-randomized allocation, no masking, and a parallel model. Enrollment was 181, and the study status is completed. The listed dates are 2011-04-20 for study start and 2021-01-20 for primary completion.

The study enrolled participants in age-based cohorts and evaluated different dolutegravir formulations. Cohort I included adolescents 12 to younger than 18 years receiving film-coated tablets. Cohorts IIA and IIB included children 6 to younger than 12 years, receiving film-coated tablets or granules for suspension, respectively. Cohort III included children 2 to younger than 6 years receiving granules, and Cohort IV included children 6 months to younger than 2 years receiving granules. Cohorts III-DT and IV-DT covered those same age ranges with dispersible tablets. Cohort V-DT included infants 4 weeks to younger than 6 months receiving dispersible tablets.

These cohorts are not randomized treatment arms. Age range and formulation vary across them, so differences between cohort entries could reflect differences in participant characteristics, regimen, follow-up, or other factors. The record does not describe a randomized comparison or a concurrent untreated control group. It also does not report the allocation process beyond stating that it was non-randomized.

The registry lists 30 outcome measures, including safety, virologic, and pharmacokinetic outcomes. It lists no analysis entries. The sponsor was the National Institute of Allergy and Infectious Diseases (NIAID). The record does not report the rationale for the enrollment target or describe any amendments that explain the duration of study conduct.

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: There was no study randomization. A participant was enrolled to a cohort based on their age at study entry.

Only the first 6 of 8 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who received at least one dose of DTG and were deemed safety evaluable by the protocol team.

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 received at least one dose of DTG.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Grade 3 or Higher Adverse Events (AEs), measured over From treatment initiation through Weeks 24 and 48.

The primary endpoint is the percentage of participants with grade 3 or higher adverse events. It covers all grade 3 or higher signs, symptoms, diagnoses, and laboratory adverse events, with grading based on the DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009). The specified observation period runs from treatment initiation through Weeks 24 and 48.

This endpoint is used to describe the frequency of more severe adverse events in the safety-evaluable population. A percentage expresses the number of participants meeting the endpoint relative to the relevant population, while the confidence interval conveys uncertainty about that estimate. These summaries can characterize safety experience during the specified follow-up; by themselves, they do not establish that the study drug caused an event.

The safety population is defined as participants who received at least one dose of dolutegravir and were deemed safety evaluable by the protocol team. The registry specifies a 2-sided 95% confidence interval calculated by the binomial exact method. The endpoint definition and method are reported, but the primary endpoint percentages and their confidence limits are not reported in the registry record. The serious-event entries are a separate set of registry figures and should not be treated as the primary endpoint result: the endpoint includes all grade 3 or higher adverse events, not only serious adverse events.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry specifies a binary percentage endpoint and a binomial exact confidence interval. The concepts below explain these methods generally; they do not add an analysis to the registry results.

What does a percentage describe?

For a binary endpoint, each participant either meets the endpoint definition or does not. The percentage describes the proportion meeting that definition in the population being analyzed. Here, the endpoint is having at least one grade 3 or higher adverse event within the stated follow-up period, among participants who received at least one dose of dolutegravir and were deemed safety evaluable. A valid interpretation depends on the endpoint definition, the analysis population, and the denominator used. The endpoint description supplies the population definition, but cohort-specific denominators for primary endpoint results are not reported in the registry record.

What does a confidence interval add?

In general, a confidence interval expresses the statistical uncertainty around an estimate. For a percentage, it provides a range of values compatible with the observed data under the method's assumptions. A narrower interval indicates greater precision; a wider interval indicates less precision. The 2-sided 95% confidence interval specified in the registry is not a guarantee that the true value lies within a particular interval, and it does not replace consideration of study design or data quality. The interval limits for the primary endpoint are not reported in the registry record, so its precision cannot be assessed from the endpoint description alone.

Why use the binomial exact method?

In general, the binomial model treats each participant's endpoint status as a binary observation and models the number meeting the endpoint relative to the analyzed group. An exact method obtains interval limits from the binomial distribution rather than relying on a large-sample normal approximation. This can be useful when event counts are small or the estimated percentage is near the boundary of its possible range. The registry identifies this method for the primary endpoint. The record does not report the observed endpoint count or interval limits, so the method choice can be described but its numerical output cannot be evaluated.

Why does the design matter for comparisons?

As a general statistical principle, random assignment helps balance prognostic characteristics between treatment groups, on average, and supports causal comparisons when the trial is otherwise appropriately conducted. This study was non-randomized and open-label. Its cohorts are differentiated by age and, in some instances, formulation, rather than by randomized assignment to comparable alternatives. A difference in observed event counts between cohorts could reflect those differences or other factors, not necessarily a treatment effect. The registry explicitly cautions that the arms are not a like-for-like control comparison.

Open-label conduct means masking was absent. In general, awareness of treatment can influence reporting, clinical assessment, or decisions about evaluation, although the registry does not state that such bias occurred. The grading system and endpoint criteria help define what is counted, but do not remove every possible source of measurement variation.

How should planning illustrations be understood?

The planning assumptions described in the record specify a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect set as a stated fraction of the observed effect. For time-to-event planning, the method gives a total number of events; for other outcomes, it gives participants per arm. These are planning illustrations based on the observed effect, not the trial's own design justification and not observed power. No specific planning estimates are reported in the registry record. The record does not report the original sample-size justification or a protocol-based power calculation.

In general, an effect taken from observed data may be imprecise, especially when event counts are limited. A planning illustration therefore depends on the effect assumption and other design assumptions; it does not establish that a completed study was adequately powered. The number of analysis entries listed in the registry is 0, and no inferential analysis results are reported there. No p-value or adjusted treatment comparison is available for the primary endpoint.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 30 outcome measures spanning safety, virologic, and pharmacokinetic outcomes. When many outcomes are assessed, the chance of observing an apparently notable result by chance can increase. In general, multiplicity methods may control that risk, or investigators may designate a primary outcome and treat other outcomes as supportive or exploratory. The primary safety endpoint is identified, but the registry record does not report a multiplicity adjustment, a hierarchy for secondary outcomes, or how multiple time points and analyses were handled.

The record lists 0 analysis entries. It does not report a statistical analysis plan, planned interim analyses, or whether any analyses were conducted outside those entered in the registry. These details are not reported in the registry record and should not be inferred from the Phase I/II designation or the list of outcomes.

The primary endpoint population is defined as participants who received at least one dose of dolutegravir and were deemed safety evaluable by the protocol team. The record does not report how safety evaluability was determined in practice, whether all enrolled participants met that definition, or the analysis denominator for each cohort and time point. Missing-data methods, handling of participants with incomplete follow-up, and reasons for missing endpoint assessments are not reported in the registry record.

These omissions limit interpretation of both precision and possible bias. If follow-up or endpoint availability differed across cohorts, percentages based on available participants could describe different subsets. This is a general concern, not a claim that missingness occurred or affected the results. The record does not provide enough information to assess it.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pyrexia (14.3%), gastroenteritis (14.3%), pneumonia (14.3%), pneumonia viral (14.3%), alanine aminotransferase increased (14.3%).

The registry's serious-event entries list a count and an at-risk figure for each cohort. The counts are 8 in Cohort I, 5 in Cohort IIA, 1 in Cohort IIB, 8 in Cohort III, 2 in Cohort IV, 12 in Cohort III-DT, 8 in Cohort IV-DT, and 2 in Cohort V-DT. The at-risk figures are 23, 23, 15, 17, 7, 36, 35, and 25, respectively. These are cohort-specific entries, not a randomized comparison.

The registry also lists deaths as 0 in Cohort I, 1 in Cohort IIA, 0 in Cohort IIB, 0 in Cohort III, 0 in Cohort IV, 1 in Cohort III-DT, 1 in Cohort IV-DT, and 0 in Cohort V-DT. The entries do not establish that a death was caused by dolutegravir. The registry record does not report a causal assessment alongside these figures.

Serious adverse events and grade 3 or higher adverse events are distinct classifications. The primary endpoint includes all grade 3 or higher signs, symptoms, diagnoses, and laboratory adverse events, whereas the entries concern serious events. Do not substitute one for the other. The record does not report the primary endpoint percentages or confidence limits, nor the denominator and basis for the percentages attached to listed serious-event terms.

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

The registry record establishes that a completed, non-randomized, open-label Phase I/II study evaluated dolutegravir in combination regimens in infants, children, and adolescents with HIV-1. It describes age-based cohorts, several dolutegravir formulations, the primary safety endpoint, and selected serious-event and death entries. These details show what the study set out to assess and how the primary endpoint was defined.

They do not provide the primary endpoint result. The percentage of participants with grade 3 or higher adverse events, its 2-sided 95% confidence interval, and cohort-specific primary endpoint results are not reported in the registry record. The serious-event counts are not a substitute for those results, and the registry's term-level percentages have no reported denominator in the record. Therefore, the posted figures cannot be used to reconstruct the primary endpoint or its precision.

The non-randomized cohort structure also limits comparative interpretation. Cohorts differ in age range and, in some cases, formulation; there is no randomized control group. Any apparent differences across cohort entries cannot be interpreted as causal effects of one formulation or regimen relative to another. The registry record does not report adjusted comparisons that might address measured differences between groups.

More generally, an event recorded during a study is not by itself evidence that treatment caused it. Assessing causality requires clinical context and an appropriate analysis, neither of which is posted by the listed cohort counts alone. Similarly, the study's completion status and enrollment do not establish that all participants had complete follow-up or contributed data to every outcome. Those details are not reported in the registry record.

The information supports a limited descriptive reading of the study design and selected safety entries. It does not support a treatment-effect conclusion, a precise estimate of the primary safety endpoint, or a comparison with an alternative treatment. Such conclusions would require outcome results and analysis details that are not reported in the registry record.

13. Why This Trial Matters Statistically

This study illustrates a common statistical challenge in pediatric clinical research: evaluating safety and pharmacokinetics across age ranges while using formulations suited to different cohorts. The cohort descriptions make clear that age and formulation are intertwined in parts of the design. Statistically, this means that differences between cohorts cannot be interpreted as formulation effects alone, especially without random assignment or an appropriate comparative analysis.

The primary endpoint also highlights why exact definitions matter. The registry specifies grade 3 or higher adverse events, a grading reference, the follow-up window, a safety-evaluable population, and an exact confidence-interval method. Those details give a framework for interpreting a result. Yet the endpoint estimate and interval are not reported in the registry record, so the framework cannot be connected to a numerical primary result or judged for precision.

The record also distinguishes between an endpoint covering all grade 3 or higher adverse events and separate serious-event entries. Keeping these classifications separate is essential: severity grading and seriousness are not interchangeable statistical outcomes. Reporting both requires clear labels, denominators, and analysis populations so that readers know what each number represents.

Finally, the registry demonstrates the difference between study completion and complete statistical reporting. Enrollment and cohort-level safety entries provide context, but without primary endpoint results, missing-data methods, and analysis details, readers cannot assess the endpoint's uncertainty or the possibility of selection effects. These limitations are important when interpreting any non-randomized safety study, particularly one spanning multiple age groups and formulations.

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 primary limitation for statistical interpretation is that the registry record does not report the primary endpoint percentages or confidence limits. Although the endpoint and its exact interval method are specified, readers cannot evaluate the observed frequency or precision from those details alone.

The non-randomized design and absence of masking constrain comparisons. The cohorts vary by age range and formulation, and the record identifies no like-for-like control group. Cohort differences may therefore reflect differences in participants or study context as well as differences in regimen. No adjusted comparative analysis is reported in the registry record.

The record lists serious-event entries and deaths by cohort, but does not provide causal assessments alongside them. It also lists percentages for serious-event terms without reporting their denominator or the basis for those percentages. These figures cannot be treated as fully specified risk estimates. Serious-event entries should not be used as proxies for the primary endpoint, which covers grade 3 or higher adverse events.

Although the safety population is defined, the registry does not report cohort-specific primary endpoint denominators, completeness of follow-up, or methods for handling missing assessments. A statistical analysis plan, multiplicity procedures, and interim-analysis details are also not reported in the registry record. The record lists 0 analysis entries, leaving no inferential results with which to assess the primary safety endpoint or account for cohort differences.

These limitations concern what can be concluded from the registry record. They do not establish that the study lacked further analyses or that any particular bias occurred; those matters are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents — NCT01302847.
• Registry record last updated 2024-12-12; status last verified 2024-10.
• Results first posted 2022-03-22.
• 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.

18. Record Summary

The registry describes a completed, Phase I/II, multicenter, open-label, non-randomized, parallel study of dolutegravir with optimized background therapy in HIV-1 infected infants, children, and adolescents. Enrollment was 181. The study began on 2011-04-20, with primary completion on 2021-01-20. Cohorts covered ages from 4 weeks to younger than 18 years and used film-coated tablets, granules for suspension, or dispersible tablets.

The primary endpoint was the percentage of safety-evaluable participants with grade 3 or higher adverse events from treatment initiation through Weeks 24 and 48, with a 2-sided 95% binomial exact confidence interval. The endpoint results and limits are not reported in the registry record. The record lists 30 outcome measures and 0 analysis entries. Serious-event counts and deaths are listed by cohort, but they do not constitute the primary endpoint result or establish treatment causality.