TMC114IFD3001 - Study Providing Continued Access to Treatment With Darunavir (DRV)/Ritonavir(Rtv) in HIV1 Infected Adults, Adolescents and Children Aged 3 Years or Above and Coming From Previous Company Sponsored Studies With DRV: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for TMC114IFD3001 - Study Providing Continued Access to Treatment With Darunavir (DRV)/Ritonavir(Rtv) in HIV1 Infected Adults, Adolescents and Children Aged 3 Years or Above and Coming From Previous Company Sponsored Studies With DRV (NCT01281813), a na phase 3 study. The primary outcome is Number of Participants With Serious Adverse Events.

2. Clinical Question

3. Trial Design

This was a Phase 3, completed, single-group study of continued access to darunavir with ritonavir. The registry lists enrollment of 145, a start date of 2011-08-08 and primary completion on 2021-07-29. Masking is recorded as none, and allocation is recorded as NA. These design features mean that the record does not describe a masked, randomized comparison between treatment groups.

The intended participants had HIV-1 infection and had previously received darunavir/ritonavir in specified parent studies. The study objective was to continue access for people who continued to benefit from the combination, in settings where darunavir could not otherwise be obtained through commercial availability, reimbursement or another access route. Continued provision was intended to last until participants could move to locally available darunavir-based treatment or local standard of care, as appropriate. This access objective is distinct from testing a new treatment against a control.

The intervention is described as continued treatment with darunavir in combination with ritonavir. For children aged less than 12 years, the registry describes oral suspension of darunavir, 200 to 600 milligrams twice daily, with ritonavir 32 to 100 mg as oral solution or suspension twice daily. The full adolescent dosing description is not reported in the registry record. The primary outcome description says adults who received either darunavir/ritonavir 800/100 mg once daily or 600/100 mg twice daily in their parent study were included in a single arm, with a combined analysis planned because both doses had been extensively evaluated in those parent studies. The stated purpose was access, not dose comparison.

The primary endpoint was the number of participants with serious adverse events, with a timeframe of up to 9 years 11 months. The record gives age-specific event counts. It does not report a concurrent control group or an effect estimate contrasting continued treatment with another strategy, so the design supports description of events in the enrolled study population rather than a controlled causal 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: Adult participants who received either DRV/rtv 800/100 mg once daily or DRV/rtv 600/100 mg twice daily per parent study were included in single arm and combined analysis was performed as planned in protocol because the 2 doses were extensively evaluated in their respective parent studies (TMC114-C211,TMC114-C214 or TMC114-TiDP31-C229). Main purpose of this study was to provide continued access and not to compare the 2 doses (DRV/rtv 800/100 mg once daily or DRV/rtv 600/100 mg twice daily).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) included all participants who had taken at least one dose of Darunavir (DRV), regardless of their compliance with the protocol and adherence to the dose regimen.

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 Number of Participants With Serious Adverse Events, measured over Up to 9 years 11 months.

The primary endpoint counts participants with serious adverse events during follow-up of up to 9 years 11 months. The registry defines an adverse event as an untoward medical occurrence after administration of a pharmaceutical product, whether or not it has a causal relationship with study treatment. A serious adverse event is an occurrence that results in death, is life threatening, requires inpatient hospitalization or prolongs an existing hospitalization, causes persistent or significant disability or incapacity, or involves a congenital anomaly or birth defect.

Counting participants with at least one serious event is a way to describe the frequency of clinically consequential events during extended treatment access. It does not measure every event in the same way as an event total: a participant can have more than one event, while the endpoint title counts participants. The age-stratified posted counts are children less than 12 years, 0 of 4; adolescents aged 12-17 years, 1 of 4; and adults aged 18 years and above, 26 of 137. These are descriptive counts from a single-group study. Without a control group, they do not show how event frequency would compare under a different treatment or access arrangement.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is a binary participant outcome: a participant is counted as having experienced a serious adverse event or not. The registry presents counts of affected participants and participants at risk within age groups. For children less than 12 years, 0 of 4 were reported with a serious event; for adolescents aged 12-17 years, 1 of 4; and for adults aged 18 years and above, 26 of 137. This format preserves the group denominators alongside the observed counts. The counts are more informative than the numerator alone because they show the size of each age group, but they remain descriptive observations rather than comparative effects.

What does a participant count capture?

A count of participants with an event is not the same as a count of all event episodes. If one participant experiences more than one serious event, the participant-based endpoint still counts that person as one participant with an event. The registry’s primary endpoint title specifies participants, while its definition sets out the seriousness criteria. The endpoint therefore answers how many people met the participant-level outcome, not how many total episodes occurred.

Seriousness is defined by the consequences or nature of the occurrence: death, a life-threatening event, inpatient hospitalization or its prolongation, persistent or significant disability or incapacity, or a congenital anomaly or birth defect. The broader adverse-event definition includes untoward medical occurrences that do not necessarily have a causal relationship with the study treatment. This distinction matters: an event can qualify for reporting without being attributed to darunavir or ritonavir.

Why does the study design matter?

In a randomized comparative trial, outcome differences between assigned groups can support an estimate of the contrast between treatment strategies, subject to the design and analysis assumptions. This study is classified as single-group and has allocation recorded as NA. It therefore provides no randomized control-group outcome against which to compare the reported serious-event counts. A count observed during treatment cannot, by itself, show how many events would have occurred under another treatment or without the study access arrangement.

The registry describes adult participants from two parent-study dose regimens as one arm and says the combined analysis was planned because dose comparison was not the purpose. Combining those participants is consistent with the stated access objective, but it means the reported adult count is not a dose-specific comparison. The outcome data do not support separating effects of the two adult regimens.

How should precision be understood?

General statistical explanation: a confidence interval expresses a range of values compatible with data and a specified statistical method, under that method’s assumptions. Wider intervals indicate less precision. The registry record does not report confidence intervals for the serious-event counts, so the precision of an estimated event frequency cannot be read directly from an interval in the record. The denominators also matter: with only 4 participants in each pediatric group, the observed counts give limited information about event frequency beyond those specific participants. A zero observed count is not proof of zero underlying risk.

The record reports counts, not a model-based estimate adjusted for participant characteristics or duration of observation. The follow-up timeframe is stated as up to 9 years 11 months, but participant-specific follow-up durations and a time-to-event analysis are not reported in the registry record. Without those details, the counts should not be treated as rates per unit of time or as evidence that each participant contributed equal observation time.

What can the event terminology add?

The registry lists serious-event terms with associated percentages, including Intentional Self-Injury at 25.0%, Renal Failure at 2.2%, Pneumonia at 1.5%, Urinary Tract Infection at 1.5%, Angina Pectoris at 0.7% and Deafness Unilateral at 0.7%. These are listed event terms, not comparative treatment effects. The record does not provide enough detail alongside these terms to interpret them as a complete account of each participant’s experience or to infer causality. They should be considered alongside the participant-level serious-event counts and the registry’s definition of adverse events.

No additional inferential method, adjusted analysis, confidence-interval method or missing-outcome method is reported in the registry record. General statistical concepts can clarify what counts and uncertainty mean, but they cannot replace analyses that are not reported. The safest reading is therefore direct: the record reports observed participant counts in the specified age groups during an access-focused, single-group study.

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("Continued Treatment With DRV in Combination With R", "Continued Treatment With DRV in Combination With R", "Continued Treatment With DRV in Combination With R")
n      <- c(4, 4, 137)
events <- c(0, 1, 26)
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  Continued Treatment With DRV in Combination With R  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Continued Treatment With DRV in Combination With R  4  1  25.0  0.6  80.6  4.6  69.9  5.3  71.6
ARM  Continued Treatment With DRV in Combination With R  137  26  19.0  12.8  26.6  13.3  26.4  13.3  26.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 0 analyses. The primary outcome is the number of participants with serious adverse events. The statistical analysis plan, including any hierarchy among outcomes or adjustment for multiple testing, is not reported in the registry record. No set of comparative hypothesis tests is described in the posted results, and the single-group design does not provide a randomized comparison. It is therefore not possible to assess a multiplicity strategy or to interpret a collection of tests as a prespecified family of confirmatory results.

The primary analysis population is defined as the Full Analysis Set, including all participants who took at least one dose of darunavir regardless of protocol compliance or adherence to the dose regimen. This definition identifies who was included in that population, but the record does not report details of participant-level missing endpoint data, exclusions after dosing, or how missing outcome information was handled. The approach to withdrawal and loss to follow-up is also not reported in the registry record.

The registry does not report a sample-size justification, interim analyses, or a detailed statistical analysis plan. The enrollment of 145 is a study characteristic, not evidence by itself that the study was sized to test a treatment effect. Since this was an access study without a control group, its primary event counts serve a descriptive purpose; they are not a confirmatory estimate of treatment effect. Absence of reported information should not be interpreted as proof that a procedure was or was not used.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: intentional self-injury (25.0%), renal failure (2.2%), pneumonia (1.5%), urinary tract infection (1.5%), angina pectoris (0.7%).

The serious-event counts are reported by age group: children less than 12 years, 0 of 4 participants; adolescents aged 12-17 years, 1 of 4; and adults aged 18 years and above, 26 of 137. The registry separately reports deaths as 0, 0 and 3 in those groups. These are observed counts in the study population, with the stated follow-up timeframe of up to 9 years 11 months. The record does not report a control group or a comparative safety estimate.

The registry’s listed serious-event terms include Intentional Self-Injury, 25.0%; Renal Failure, 2.2%; Pneumonia, 1.5%; Urinary Tract Infection, 1.5%; Angina Pectoris, 0.7%; and Deafness Unilateral, 0.7%. These percentages are reported as event-term listings; they should not be treated as causal effects or as a comparison with another regimen. An adverse event is defined as an untoward medical occurrence that need not have a causal relationship with treatment. Seriousness reflects the registry’s specified criteria, not necessarily attribution to the study drugs.

Because the pediatric groups each contain 4 participants, their counts provide limited precision about event frequency outside the study participants. The adult count comes from a much larger group and combines the two dose regimens described in the parent studies. The reported figures are useful for characterizing the observed experience, but they do not establish comparative risk.

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

The results show that serious adverse events were reported among participants continuing darunavir with ritonavir, with counts differing across the registry’s age groups. The record reports 0 of 4 children less than 12 years, 1 of 4 adolescents aged 12-17 years, and 26 of 137 adults aged 18 years and above with serious adverse events. It also reports 3 deaths in the adult group and none in the two pediatric groups. These figures describe what was recorded in this study population over a timeframe of up to 9 years 11 months.

They do not show that treatment caused any particular event. The adverse-event definition explicitly includes occurrences without a necessary causal relationship to study treatment. Nor do the counts establish how outcomes would have differed with another regimen, without continued access, or in a broader group of people with HIV-1 infection. The study has a single group, no separate comparator and no randomized treatment contrast.

The adult endpoint combines participants who entered from parent studies using either of two dose regimens. The record states that this was planned and that dose comparison was not the purpose. Accordingly, the combined adult count should not be interpreted as a comparison between doses. The pediatric counts are based on 4 participants in each age group, so they provide especially limited information about event frequency in other children or adolescents.

The access objective is central to interpreting the study: continued treatment was intended for previously treated participants in settings where darunavir was not otherwise available through the stated routes, until a locally accessible option could be used. The results therefore contribute descriptive information about an extended-access cohort. They are not a controlled test of efficacy, comparative safety or treatment choice, and the registry record does not report precision intervals or adjusted comparative estimates.

14. Why This Trial Matters Statistically

Long-term access studies address a different statistical question from randomized trials. Their central contribution can be documenting what occurred among participants who continued treatment when ordinary commercial or other access routes were unavailable. In this study, the primary endpoint records participants with serious adverse events, and the registry presents counts by age group over follow-up of up to 9 years 11 months. Such observations can add to the description of experience in a continued-access setting.

The design also places clear boundaries on inference. The study is single-group, with no randomized comparator, and combines adults who had received either of two regimens in their parent studies. The reported counts therefore do not estimate a contrast between treatments or between doses. The design’s access purpose is consistent with the stated objective of continued provision, but it is not a substitute for a controlled comparative safety or efficacy analysis.

Age-stratified reporting is useful because children, adolescents and adults are represented separately in the adverse-event results. At the same time, the group sizes are uneven: the pediatric groups each have 4 participants, compared with 137 adults in the reported adult outcome group. This makes it especially important to distinguish an observed count from a stable population estimate. A zero count in a small group is a description of observed experience, not evidence that an event cannot occur.

For biostatistical interpretation, the record illustrates why study purpose, endpoint definition, denominators and comparator structure all matter. It also shows the limits of a registry summary: missing analysis details and absent precision estimates constrain conclusions. The appropriate statistical contribution is descriptive and context-specific, not a claim of comparative effect.

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 causal interpretation is the single-group design. The registry records allocation as NA and masking as none, and it does not describe a separate control group. Serious-event counts therefore cannot be contrasted with outcomes under another treatment strategy within this study. The posted results cannot isolate treatment effects from the other circumstances affecting participants during long-term follow-up.

Participant selection also shapes what the results represent. Participants had previously received darunavir/ritonavir in specified parent studies and entered a continued-access study under circumstances involving limited local access. The record does not establish how closely this cohort represents all people with HIV-1 infection or people starting treatment for the first time. The adult endpoint combines two parent-study dose regimens, so the reported adult count is not dose-specific.

The age groups have markedly different sizes, with 4 children, 4 adolescents and 137 adults in the reported serious-event analysis. The small pediatric groups make their event counts imprecise descriptions of experience in those participants and provide limited information about broader age groups. The registry does not report confidence intervals or participant-specific follow-up durations, even though the timeframe is up to 9 years 11 months; counts should not be read as time-adjusted rates.

Further limitations include analysis details not reported in the registry record: the statistical analysis plan, missing-data handling, interim analyses, sample-size justification and any adjusted analyses. The registry reports serious-event terms and percentages but does not provide enough information in this record to establish causality or fully interpret the denominator for each listed term. These gaps limit precision and interpretation, rather than demonstrating that a particular procedure was absent.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: TMC114IFD3001 - Study Providing Continued Access to Treatment With Darunavir (DRV)/Ritonavir(Rtv) in HIV1 Infected Adults, Adolescents and Children Aged 3 Years or Above and Coming From Previous Company Sponsored Studies With DRV — NCT01281813.
• Registry record last updated 2022-10-31; status last verified 2022-10.
• Results first posted 2022-10-31.
• 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

NCT01281813 is a completed Phase 3, single-group continued-access study of darunavir with ritonavir in people with HIV-1 who had received the combination in earlier company-sponsored studies. Registry enrollment was 145; the study started on 2011-08-08, with primary completion on 2021-07-29. The stated objective was continued access where darunavir was not otherwise commercially available, reimbursed or accessible through another source.

The primary outcome was the number of participants with serious adverse events during follow-up of up to 9 years 11 months. Reported counts were 0 of 4 children less than 12 years, 1 of 4 adolescents aged 12-17 years and 26 of 137 adults aged 18 years and above; deaths were reported as 0, 0 and 3, respectively. Adult dose groups were combined, and the study was not intended to compare them. With no separate comparator, these are descriptive observations rather than comparative treatment effects. Analysis-plan, missing-data and precision details are not reported in the registry record.