Dolutegravir Antiretroviral Strategy to Promote Improvement and Reduce Drug Exposure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dolutegravir Antiretroviral Strategy to Promote Improvement and Reduce Drug Exposure (NCT02263326), a randomized phase 3 study. The primary outcome is Proportion of Participants With Treatment Failure.

2. Clinical Question

3. Trial Design

ASPIRE was a Phase 3 randomized, parallel-group trial with no masking. The registry reports enrollment of 89 and lists HIV infection as the condition under study. The study started in 2014-12, reached primary completion in 2017-07, and is listed as completed.

Participants were assigned to a strategy of dolutegravir plus lamivudine or to continue their current antiretroviral regimen. The intervention description specifies dolutegravir 50 mg plus lamivudine 300 mg once daily. The continuation group remained on a current DHHS-recommended or alternative three-drug regimen; the particular regimens are not reported in the registry record.

The planned treatment period described in the study summary was 48 weeks. The primary endpoint was assessed over 24 weeks, and the primary outcome description defines treatment failure to include virologic failure, loss to follow-up, or treatment discontinuation during that period. Other listed outcomes include virologic success, changes in CD4 count, total cholesterol, LDL cholesterol, and creatinine clearance from baseline to Week 48, and drug-resistance-associated mutations.

The posted primary outcome data give an arm size of 44 for dolutegravir plus lamivudine and 45 for continuation of current therapy. These are the group sizes associated with the reported primary outcome. Further details about sequence generation, allocation concealment, the masking of outcome assessment, adherence monitoring, and the analysis population are 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:

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 Proportion of Participants With Treatment Failure, measured over 24 weeks.

The primary outcome is the proportion of participants with treatment failure by 24 weeks. The outcome definition combines confirmed virologic failure, loss to follow-up, and treatment discontinuation. Virologic failure is described as confirmed plasma HIV-1 RNA >50 copies/mL before or at Week 24. Thus, the endpoint is broader than a measure based only on a viral-load threshold: a participant could meet the composite definition through loss to follow-up or treatment discontinuation as well.

A composite endpoint can capture several events that matter to an evaluation of a treatment strategy, but it also means that the overall result depends on how often each component occurs. The registry record does not give a breakdown of primary treatment failures by component, so it is not possible to determine how much the overall proportions reflect virologic failure versus loss to follow-up or treatment discontinuation.

Using a proportion makes the result interpretable as the frequency of participants meeting the defined outcome during the specified period. The registry also frames the primary comparison as a non-inferiority analysis. Such an analysis asks whether the outcome under the intervention is not unacceptably worse than under the comparison strategy, according to a prespecified margin. That margin and its rationale are not reported in the registry record, so the posted estimate and interval alone do not establish whether the non-inferiority criterion was met.

7. Results Posted in the Registry

• Continue Current ART Regimen: 0.0% (0/45) versus 0.0% (0/44) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Statistical Interpretation

9. Statistical Methods Explained

For a binary outcome such as whether a participant met the treatment-failure definition, the basic quantity is the proportion with the event in each group. The registry posts proportions of 0.068 for the dolutegravir-plus-lamivudine group and 0.067 for the current-regimen group. These are descriptive summaries of the recorded outcome. By themselves, they do not indicate how uncertain the comparison is or whether a non-inferiority criterion was satisfied.

What does a risk difference express?

A risk difference compares event proportions by subtraction. It is expressed on the proportion scale, so zero represents equal event proportions, positive values represent a higher proportion in the group defined first in the contrast, and negative values represent a lower proportion in that group. The registry reports a risk difference of 0.002. It does not fully document the contrast coding or method used to estimate this value, so interpretation of its sign should follow the trial's analysis specification, which is not reported in the registry record.

A risk difference is an absolute comparison rather than a relative one. It keeps the comparison in the same units as the event proportions and does not describe how many times more or less frequent an outcome was. The trial record provides no relative measure for the primary endpoint.

What does the confidence interval add?

A confidence interval expresses uncertainty around an estimate under the statistical model and its assumptions. The registry reports a 90% confidence interval from -0.098 to 0.102 for the risk difference. The interval spans values below and above zero, so the data are compatible with a range of possible differences in either direction. It is not a guarantee that the true value lies in the interval, and it does not convey the probability that a particular treatment effect is true.

The confidence level is relevant to the intended inferential framework. The registry labels the analysis as non-inferiority and reports a 90% interval. To use that interval for a non-inferiority conclusion, a reader needs the prespecified margin, the contrast direction, and the analysis method. The margin and detailed method are not reported in the registry record. Without them, it is not possible to independently apply the trial's decision rule.

How is non-inferiority different from superiority?

A superiority analysis typically asks whether the data support a difference from no effect. A non-inferiority analysis instead asks whether the data rule out an unacceptable disadvantage, defined by a margin chosen before the results are examined. A confidence interval may include zero and still be consistent with non-inferiority if its unfavorable bound remains within the margin; conversely, a point estimate close to zero does not establish non-inferiority if the interval extends beyond the margin. The registry record does not report the margin or its justification, so the non-inferiority conclusion cannot be reconstructed from the reported estimate alone.

Why do event counts and group sizes matter?

Precision depends in part on the amount of information in the data, including the number of observed events and the sizes of the comparison groups. The primary outcome record associates 44 participants with the intervention group and 45 with the continuation group. The event proportions are low, and the confidence interval is wide enough to include differences on both sides of zero. The record does not provide all event-count details or a detailed account of the estimator, so a more specific assessment of the interval's construction is not possible.

For binary outcomes, methods may differ in how they handle sparse events, continuity adjustments, or confidence-interval construction. Those choices can affect estimates and uncertainty when event counts are limited. The registry record does not identify the method used for the primary risk difference, so it would be inappropriate to attribute the reported interval to a particular formula.

Why are missing outcomes important?

Loss to follow-up is part of the primary composite definition, but the registry does not explain how participants with missing measurements were classified in the analysis or whether any additional missing-data method was used. In general, missing data can affect a comparison if the chance of being missing differs between groups or is related to the outcome. Treating loss to follow-up as an endpoint component is not the same as explaining how unavailable outcome measurements were handled. The analysis population, imputation procedures, and sensitivity analyses are not reported in the registry record.

These methodological details matter because a non-inferiority conclusion can be sensitive to analysis choices. The registry record's summary supports a description of the posted proportions and reported interval, but not a reconstruction of the full analysis plan or an independent assessment of every assumption.

10. Confidence Intervals and Precision

The main measure of precision is the 90% confidence interval accompanying the reported risk difference. Its bounds are -0.098 and 0.102, around a point estimate of 0.002. Because the interval extends in both directions from zero, it does not establish that the underlying difference is exactly zero. Instead, it indicates that the observed data are compatible with a range of differences under the assumptions of the analysis.

The interval is broad compared with the point estimate. That means the point estimate should not be read as a highly precise estimate of the difference. A small point estimate can coexist with substantial uncertainty, particularly when the amount of outcome information is limited. The posted group sizes are 44 and 45, and the arm proportions are 0.068 and 0.067.

For a non-inferiority analysis, precision must be considered against the non-inferiority margin. A confidence interval is informative for this purpose only when the margin and contrast direction are known. The margin is not reported in the registry record. Therefore, the interval cannot establish from the registry information alone whether the unfavorable bound is within an acceptable limit.

The interval also reflects the primary composite endpoint, not each component separately. Since component-specific treatment-failure results are not reported in the registry record, there is no corresponding precision assessment for virologic failure, loss to follow-up, or treatment discontinuation individually. The registry record does not report additional interval estimates or detailed methods that would allow a fuller evaluation of uncertainty.

11. Analyses Reported by the Sponsor

The registry reports arm proportions of 0.068 for dolutegravir plus lamivudine and 0.067 for continuation of the current regimen. Its reported non-inferiority analysis gives a risk difference of 0.002 and a 90% confidence interval from -0.098 to 0.102. The record does not provide a p-value.

A simple unadjusted recalculation from arm-level summaries can serve as a descriptive check, but it does not replace the trial's reported analysis. The registry record does not identify a discrepancy between its recalculation and the reported analysis. The inferential result to interpret is the analysis reported in the registry, with its stated estimate and interval.

The comparison also depends on analysis specifications that are not reported in the registry record, including the non-inferiority margin, the detailed estimator, and the analysis population. Those missing details limit independent verification of the non-inferiority decision. The posted risk difference and confidence interval describe the reported comparison, but they cannot by themselves establish that the sponsor's prespecified criterion was met.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists six secondary outcomes, including virologic success, changes in CD4 count, total cholesterol, LDL cholesterol, and creatinine clearance from baseline to Week 48, and drug-resistance-associated mutations. It also reports eight outcome measures and seven analyses. These figures indicate that the record includes multiple outcomes and analyses, but do not show how the analyses were prioritized or interpreted together.

When multiple outcomes or comparisons are examined, the chance of observing an apparently notable result by chance can increase. Statistical approaches to multiplicity may adjust significance thresholds, control an error rate, or designate outcomes as exploratory. The registry record does not report whether multiplicity was addressed, what procedure may have been used, or which secondary outcomes had confirmatory status. No secondary-outcome results are included in the registry record described for this analysis, so none can be interpreted.

The primary outcome definition includes loss to follow-up and treatment discontinuation, but details on other missing data are not reported in the registry record. In particular, the record does not state how missing viral-load assessments were handled, whether participants with incomplete follow-up were included in the analysis, or whether any imputation or sensitivity analysis was performed. Loss to follow-up as a component of the endpoint does not resolve these questions about missing measurements.

The analysis population is also not reported in the registry record. It is therefore unclear from the registry entry whether the reported result was based on all randomized participants, participants who received assigned treatment, participants with outcome data, or another defined group. The detailed statistical plan, including any interim analyses and the handling of protocol deviations, is not reported in the registry record. These omissions limit assessment of the risk difference and its relevance to the non-inferiority framework.

13. 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: grade 4 myocardial infarctions (4.4%), grade 4 viral syndrome (2.3%).

The registry reports serious adverse events affecting 1 participant in the dolutegravir-plus-lamivudine group, with 44 at risk, and 2 participants in the current-regimen group, with 45 at risk. It reports deaths of 0 in both groups. For other adverse events, the record reports 0 affected among 44 at risk in the intervention group and 3 affected among 45 at risk in the continuation group.

These counts describe what is recorded for the trial groups; they do not establish that a treatment caused or prevented an event. The registry also lists Grade 4 myocardial infarctions at 4.4% and Grade 4 viral syndrome at 2.3% among the top serious-event terms. The record does not provide enough context to determine the event-level denominator or whether these terms refer to participants or event occurrences, so the percentages should be read as registry-reported figures rather than converted into participant counts.

Safety comparisons can be difficult to interpret when events are uncommon and the group sizes are limited. The registry summary does not report event timing, relatedness assessments, severity details beyond the listed terms, or an analysis comparing safety between groups. The figures are descriptive and should not be used alone to infer a causal safety difference.

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

The result describes the recorded frequency of a composite treatment-failure outcome over 24 weeks in the two randomized groups. The arm proportions were 0.068 for dolutegravir plus lamivudine and 0.067 for continuation of current therapy. The reported risk difference was 0.002, with a 90% confidence interval from -0.098 to 0.102.

The estimate is not a standalone proof that the strategies are equivalent. A failure to establish a difference is not the same as showing equivalence, and a non-inferiority claim requires comparison with a prespecified margin. That margin is not reported in the registry record. The interval's breadth also means that the point estimate should not be treated as a precise account of the underlying difference.

The endpoint combines virologic failure with loss to follow-up and treatment discontinuation. Since the registry does not report component-specific results, the primary result does not show whether the groups differed in viral-load outcomes alone. The study summary specifies follow-up of 48 weeks, but the primary endpoint concerns 24 weeks; the primary result should not be interpreted as an estimate of the listed Week 48 outcomes.

The registry record also does not provide full details on missing-data handling, analysis populations, or the statistical method. Those limitations prevent a complete independent appraisal of the reported non-inferiority analysis. The results apply to the study's described eligibility conditions and comparison strategies; the registry entry does not establish how they generalize to other populations or treatment settings.

In statistical terms, the posted evidence is a descriptive comparison accompanied by an uncertain risk-difference estimate. It should not be turned into medical advice or a claim that either strategy works or does not work. The data reported in the registry support discussion of the observed proportions and their uncertainty, while leaving important aspects of the non-inferiority decision and broader interpretation unresolved.

15. Why This Trial Matters Statistically

This trial raises a common statistical challenge: a non-inferiority question cannot be answered from a point estimate alone. The reported risk difference is 0.002, but a meaningful conclusion depends on the confidence interval, the direction of the comparison, and the prespecified margin. The registry record reports the estimate and a 90% confidence interval but does not report the margin. That gap illustrates why the decision rule is central to interpreting non-inferiority evidence.

The endpoint also demonstrates how composite outcomes require careful reading. Treatment failure includes confirmed virologic failure, loss to follow-up, and treatment discontinuation. Combining events can produce a useful overall measure of treatment strategy performance, but without component results a reader cannot see which event types shaped the comparison. The endpoint definition must therefore remain attached to any interpretation of the overall proportions.

Precision is another key issue. The group proportions are close, yet the confidence interval spans values on either side of zero and is broad relative to the point estimate. A near-zero estimate does not remove uncertainty. This distinction is important in clinical research, where descriptive similarity and statistical evidence for a prespecified claim are not interchangeable.

Finally, the registry entry illustrates the limits of a results summary. Missing details about the analysis population, missing data, multiplicity, and the non-inferiority margin constrain independent assessment. Statistical interpretation depends not only on the observed data but also on how the analysis was specified and carried out. Those details are not reported in the registry record.

16. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary outcome record does not report the non-inferiority margin or its rationale. Without that information, readers cannot independently judge whether the reported confidence interval met the trial's non-inferiority criterion. The record also does not fully explain the contrast direction or the statistical method used to calculate the risk difference.

The treatment-failure endpoint combines confirmed virologic failure, loss to follow-up, and treatment discontinuation. Component-specific counts are not reported in the registry record, so the overall proportions cannot be separated into their clinical and follow-up components. Details about how missing outcome measurements were treated are also not reported.

The analysis population, allocation-concealment procedures, sequence-generation method, adherence information, and masking of outcome assessment are not reported in the registry record. No information is given about any interim analyses or a detailed statistical plan. The record also does not report whether multiplicity was addressed across the secondary outcomes and analyses.

The comparator is described as continuation of a current DHHS-recommended or alternative three-drug regimen, but the individual regimens are not identified. As a result, the registry summary does not specify the exact treatment mix represented by that group. The posted safety figures are limited summaries and do not report event timing, relatedness, or a comparative safety analysis.

These limitations do not negate the reported proportions, estimate, or interval. They do restrict what can be concluded from the registry entry alone, particularly about the non-inferiority decision, the components of treatment failure, and the robustness of the analysis.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Dolutegravir Antiretroviral Strategy to Promote Improvement and Reduce Drug Exposure — NCT02263326.
• Registry record last updated 2019-10-14; status last verified 2019-10.
• Results first posted 2018-11-13.
• 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.

20. Record Summary

ASPIRE (NCT02263326) was a completed Phase 3 randomized, unmasked, parallel-group trial of dolutegravir plus lamivudine versus continuation of a current antiretroviral regimen in people with HIV infection. Enrollment was 89. The study began in 2014-12 and reached primary completion in 2017-07.

The primary outcome was treatment failure by 24 weeks, defined as virologic failure, loss to follow-up, or treatment discontinuation. The posted proportions were 0.068 in the dolutegravir-plus-lamivudine group and 0.067 in the continuation group. The registry-reported risk difference was 0.002, with a 90% confidence interval from -0.098 to 0.102. The non-inferiority margin and important details of the analysis are not reported in the registry record.

The listed secondary outcomes include virologic success, laboratory changes through Week 48, and drug-resistance-associated mutations. The registry also reports serious adverse events and deaths by group, but these summaries do not establish causal effects. Interpretation is limited by missing details on component outcomes, missing-data handling, and the analysis population.