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HIV Phase 3 Binary Endpoint NCT01967940

Efficacy of Tenofovir Alafenamide Versus Placebo Added to a Failing Regimen Followed by Treatment With Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Atazanavir in HIV-1 Positive, Antiretroviral Treatment-Experienced Adults: Complete Statistical Analysis

This analysis examines the registry results for the randomized Part 1 comparison of tenofovir alafenamide (TAF) with placebo, each added to a failing antiretroviral regimen. The primary outcome was the proportion of participants whose HIV-1 RNA decreased by more than 0.5 log10 at Day 10.

Trial start: 2013-10-25  ·  Enrollment: 55  ·  Sponsor: Gilead Sciences
Scope of this record

This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.

1. Trial at a Glance

This page covers the registry results for Efficacy of Tenofovir Alafenamide Versus Placebo Added to a Failing Regimen Followed by Treatment With Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Atazanavir in HIV-1 Positive, Antiretroviral Treatment-Experienced Adults (NCT01967940), a randomized phase 3 study. The primary outcome is Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10.

55
Enrollment
Phase 3
3
Arms
In the primary outcome
+58.3 pts
Risk difference
Part 1 Sentinel Cohort TAF
30.4 to 86.2 pts
95% CI
Two-sided
FeatureRegistry value
ClinicalTrials.gov identifierNCT01967940
PhasePhase 3
ConditionHIV, HIV Infections, Acquired Immunodeficiency Syndrome
AllocationRandomized
Design modelParallel
MaskingDouble
Enrollment55
Arms in the primary outcome3
Lead sponsorGilead Sciences
Results postedYes

2. Clinical Question

Population

Adults with HIV-1 who were antiretroviral treatment-experienced and whose current antiretroviral regimen was failing. The primary analysis population included participants who enrolled in Part 1 and received at least one dose of study drug in that part.

Intervention

In the randomized Part 1 cohort, TAF was added to the participant’s existing failing antiretroviral regimen for 10 days.

Comparator

Placebo was added to the existing failing regimen for 10 days in the randomized Part 1 comparison. A separate sentinel cohort received open-label TAF and was not the randomized comparator.

Primary question

At Day 10, what proportion of participants in each randomized group had a decrease in plasma HIV-1 RNA from baseline exceeding 0.5 log10, and how different were those proportions?

The central statistical question concerns a short-term binary response: whether each participant crossed the specified RNA-decline threshold by Day 10. The primary endpoint therefore counts participants meeting that criterion rather than estimating the average amount of RNA change. The registry’s primary comparison is between the randomized TAF and placebo cohorts. Results from the open-label sentinel cohort provide additional descriptive context, but that cohort was not part of the blinded randomized comparison.

The study also proceeded to a second part, in which eligible participants could receive elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) plus atazanavir. That later treatment phase addresses a different question from the primary endpoint: the Part 1 primary result concerns the threshold response during the brief add-on comparison, not the effects of the subsequent regimen. The registry record describes the study’s planned sequence and lists later outcomes, but the primary statistical interpretation should remain tied to the randomized Day 10 comparison.

3. Trial Design

This was a Phase 3, randomized, double-blind, parallel-group study with 55 participants enrolled. The study had two parts and began with a sentinel cohort in Part 1. Participants in that cohort received open-label TAF with their current failing antiretroviral regimen for 10 days. After review of safety and efficacy information from the sentinel cohort, the randomized cohort compared TAF with placebo, each added to the failing regimen for 10 days.

The primary endpoint is reported for three Part 1 groups: 12 participants in the sentinel TAF cohort, 28 in the randomized TAF cohort, and 15 in the randomized placebo cohort. Only the randomized TAF and placebo groups form the main blinded comparison. The sentinel cohort was open-label and was enrolled before the randomized cohort; its result should therefore be interpreted descriptively rather than as an additional randomized treatment contrast.

Part 2 followed a 14-day washout period. Participants who had received TAF in Part 1 needed a decrease in HIV-1 RNA greater than 0.5 log10 to continue to Part 2; placebo recipients were eligible regardless of viral-load change. Eligible participants then received E/C/F/TAF plus atazanavir for 48 weeks. The registry also describes an extension phase after Part 2. These later phases differ from the short randomized comparison because treatment and eligibility are not the same across the groups that proceed.

The study is marked completed in the registry record. The record identifies Gilead Sciences as sponsor and gives the study start and primary-completion dates as 2013-10-25 and 2015-05-21. Details beyond the design features and dates recorded there, including further protocol rationale, 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.

Before assignment: 259 participants were screened.

Part 1

StagePart 1 Sentinel Cohort TAFPart 1 Randomized Cohort TAFPart 1 Randomized Cohort PlaceboPart 2 E/C/F/TAF + ATV
STARTED1228150
COMPLETED1228150
NOT COMPLETED0000

Part 2

StagePart 1 Sentinel Cohort TAFPart 1 Randomized Cohort TAFPart 1 Randomized Cohort PlaceboPart 2 E/C/F/TAF + ATV
STARTED00038
COMPLETED00035
NOT COMPLETED0003

Reasons for not completing this period:

ReasonPart 1 Sentinel Cohort TAFPart 1 Randomized Cohort TAFPart 1 Randomized Cohort PlaceboPart 2 E/C/F/TAF + ATV
Enrolled in Part 2 and Never Treated0001
Adverse Event0001
Unknown Reason0001

Analysis population for the primary outcome, as defined in the registry: Part 1 Full Analysis Set: participants who enrolled into Part 1 of the study and received at least one dose of study drug in Part 1.

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: Full Analysis Set: participants who enrolled into Part 1 of the study and received at least one dose of study drug in Part 1.

CharacteristicUnitPart 1 Sentinel Cohort TAFPart 1 Randomized Cohort TAFPart 1 Randomized Cohort PlaceboTotal
Participants analysed12281555
Age, Continuousyears38 (SD 7.3)40 (SD 9.1)43 (SD 8.2)40 (SD 8.6)
Sex: Female, Male: FemaleParticipants316423
Sex: Female, Male: MaleParticipants9121132
Ethnicity (NIH/OMB): Hispanic or LatinoParticipants5016
Ethnicity (NIH/OMB): Not Hispanic or LatinoParticipants7281449
Ethnicity (NIH/OMB): Unknown or Not ReportedParticipants0000
Race/Ethnicity, Customized: AsianParticipants05510
Race/Ethnicity, Customized: BlackParticipants322934
Race/Ethnicity, Customized: WhiteParticipants4105
Race/Ethnicity, Customized: OtherParticipants5016
Region of Enrollment: Russian Federationparticipants2103
Region of Enrollment: United Statesparticipants5308
Region of Enrollment: Dominican Republicparticipants5016
Region of Enrollment: Ugandaparticipants019928
Region of Enrollment: Thailandparticipants05510
HIV-1 RNAlog10 copies/mL4.18 (SD 0.648)4.16 (SD 0.544)4.03 (SD 0.953)4.13 (SD 0.688)
HIV-1 RNA Category: ≤ 100,000 copies/mLParticipants12271251
HIV-1 RNA Category: > 100,000 to ≤ 400,000 copies/mLParticipants0134
CD4 Cell Countcells/µL269 (SD 207.1)245 (SD 244.6)232 (SD 162.4)246 (SD 213.7)
CD4 Percentagepercentage17.4 (SD 10.14)16.5 (SD 11.09)14.3 (SD 8.61)16.1 (SD 10.15)

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Percentage of Participants With Plasma HIV-1 RNA Decreases From Baseline Exceeding 0.5 log10 at Day 10, measured over Day 10.

ElementRegistry entry
Result typeNumber
Measure of spreadnot applicable
Unitpercentage of participants
Endpoint classificationBinary Endpoint

The primary endpoint is the percentage of Part 1 participants whose plasma HIV-1 RNA decreased from baseline by more than 0.5 log10 at Day 10. It is a binary outcome: each participant either met the specified threshold or did not. The reported percentage is the fraction of participants meeting that threshold in each group, expressed as a percentage.

A threshold-based endpoint can make a result easier to interpret as the proportion of participants reaching a defined short-term response. It does not describe how far each participant’s RNA changed, nor does it capture the full distribution of individual changes. The registry lists change from baseline in log10 HIV-1 RNA as a secondary endpoint, which retains information about the magnitude of change at the group level rather than reducing it to whether a threshold was crossed.

For the randomized cohort, the registry reports that 60.7% of participants receiving TAF met the primary threshold, compared with 0.0% receiving placebo. The sponsor’s reported difference in proportions is 60.7, with a 95% confidence interval from 42.6 to 78.8. This is a Day 10 measure of response while the study drug was added to the existing failing regimen. It is not, by itself, a measure of longer-term viral suppression, clinical outcomes, or the effects of the later Part 2 regimen.

The endpoint was used to assess the short-term contrast specified for Part 1. The registry record identifies the analysis population as participants who enrolled in Part 1 and received at least one dose of study drug in that part. Further endpoint-handling details, such as rules for missing Day 10 measurements, are not reported in the registry record.

7. Results Posted in the Registry

Risk difference: Part 1 Sentinel Cohort TAF

+58.3

95% CI: 30.4 to 86.2 percentage points

Recalculated from the posted summary statistics

Primary outcome by arm, with 95% confidence intervals
Primary outcome by arm with 95% confidence intervals0.017.735.553.271.088.7Part 1 Sentinel Cohort TAF (n=12)Part 1 Randomized Cohort TAF (n=28)Part 1 Randomized Cohort Plac… (n=15)% of participants (95% CI)
Treatment effect versus the control arm
Forest plot of risk difference (percentage points) vs control (95% CI)Part 1 Sentinel Cohort TAFPart 1 Randomized Cohort TAF-6.901333537393risk difference (percentage points) vs control (95% CI)

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Secondary outcomeTypeEffect measureEstimate (95% CI)Planning size, 80% power
Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10Continuous EndpointMean difference-0.68 (-1.03 to -0.33)6 per arm

Part 1: Change From Baseline in Plasma log10 HIV-1 RNA (Copies/mL) at Day 10

Treatment effect versus the control arm
Forest plot of mean difference vs control (95% CI)Part 1 Sentinel Cohort TAFPart 1 Randomized Cohort TAF-1.11-0.87-0.63-0.39-0.160.08mean difference vs control (95% CI)

The secondary outcomes cover related but distinct topics: short-term change in plasma HIV-1 RNA, later virologic suppression, and safety during the subsequent E/C/F/TAF plus atazanavir phase. The numeric secondary result described in the registry record includes the Day 10 mean change in log10 HIV-1 RNA. Its direction is consistent with the primary threshold result: the randomized TAF group had a larger mean decrease than the placebo group. This provides a different summary of short-term virologic change, not an independent replication of the primary comparison.

The registry lists later outcomes involving viral suppression thresholds and adverse events at follow-up, but results for those endpoints are not reported in the registry record. Their titles alone do not establish what occurred. The record lists 16 outcome measures and 15 secondary outcomes, while the detailed numeric information available for secondary interpretation is limited. The absence of result details should not be treated as evidence of either favorable or unfavorable findings.

In general, secondary outcomes help describe a trial across additional measures and time points. They can support context for the primary finding, but their interpretation depends on how many outcomes were tested, whether analyses were prespecified, and how missing measurements were handled. The registry record does not report a multiplicity procedure or a complete statistical plan for the secondary outcomes. Accordingly, unadjusted secondary p-values, including the one reported for mean change, carry less confirmatory weight than the sponsor’s stated primary analysis. They can be informative, but the available record does not establish that they were controlled as a family of tests or intended to support independent confirmatory conclusions.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

9. Statistical Interpretation

Clinical Biostats interpretation

In the randomized Part 1 cohort, 60.7% of participants assigned to TAF met the Day 10 threshold, while 0.0% in the placebo group met it. The sponsor’s reported difference in proportions was 60.7, with a 95% confidence interval from 42.6 to 78.8 and a Fisher exact p-value of <0.001. The posted values therefore show a clear separation between the observed proportions in these randomized groups at the prespecified short-term endpoint.

The registry also reports 58.3% meeting the threshold in the open-label sentinel TAF cohort. That result is useful as a description of the sentinel participants but should not be treated as another randomized estimate against placebo. The sentinel cohort’s open-label status and position before the randomized cohort distinguish it from the primary randomized contrast. The two TAF percentages are broadly similar as reported, but that similarity does not turn the sentinel group into a concurrent control.

The primary outcome is binary, so the treatment contrast concerns proportions meeting a criterion, not an average RNA change. The registry’s secondary continuous endpoint provides complementary information: mean change from baseline was -0.7 log10 copies/mL in the randomized TAF group and -0.04 log10 copies/mL in the placebo group. The corresponding posted unadjusted comparison is a mean difference of -0.66, with p <0.001. These measures address related but not identical features of the Day 10 response.

The p-value indicates that, under the null model used for the reported test, a result at least as incompatible with equal group proportions would be unusual. It is not the probability that the null hypothesis is true, and it does not express the size or clinical importance of the difference. The confidence interval communicates uncertainty about the estimated difference under the analysis. Its lower and upper limits are both on the positive side of no difference, which is consistent with the reported test result.

These findings are limited to the short Part 1 comparison and its recorded analysis population. They do not establish the durability of the response, the comparative performance of the later regimen, or outcomes beyond those reported. The registry’s primary result should be read as evidence about the observed Day 10 threshold response in these study groups, with uncertainty and population limitations kept in view, rather than as a standalone conclusion about all treatment-experienced adults.

10. Statistical Methods Explained

The primary outcome is a binary percentage. Each participant is classified according to whether the Day 10 plasma HIV-1 RNA decrease from baseline exceeded 0.5 log10. Group percentages describe how often that event was recorded in each cohort. The primary randomized contrast is the difference in proportions between the randomized TAF and placebo groups.

What does a difference in proportions represent?

In general, a difference in proportions subtracts the event proportion in one group from the event proportion in the comparison group. It expresses the absolute gap between the observed group rates, rather than a relative ratio. For this trial, the sponsor reports a difference in proportions of 60.7 for the randomized comparison. The estimate should be interpreted alongside its confidence interval and the group sizes, rather than as a complete description of every participant’s response.

What does the reported test assess?

The sponsor reports a Fisher exact test for the randomized comparison. In general, Fisher’s exact test evaluates whether the observed allocation of binary outcomes across two groups is compatible with equal event proportions, using the observed group sizes. The reported p-value is <0.001. A small p-value indicates incompatibility with that null model; it does not measure the probability that the treatment effect is real, nor does it quantify the endpoint’s clinical importance.

The registry’s sponsor analysis gives the difference in proportions as 60.7, a 95% confidence interval from 42.6 to 78.8, and p <0.001. The unadjusted re-calculation is consistent with the direction of that reported result, and the registry record does not flag a discrepancy. The sponsor’s analysis is therefore the central reported inferential result for the randomized comparison.

How should the continuous secondary outcome be read?

The secondary change-from-baseline outcome is measured in log10 copies/mL and reported as a group mean with a standard deviation. The randomized TAF group’s mean change was -0.7, with a standard deviation of 0.628; the placebo group’s mean change was -0.04, with a standard deviation of 0.233. The unadjusted mean difference is -0.66, with a 95% confidence interval from -0.921 to -0.399 and p <0.001. In general, a mean difference compares the average change between groups, while the standard deviation describes variation among participant measurements within a group. The registry record does not list a sponsor-reported analysis for this secondary outcome.

The registry also gives planning illustrations based on the observed continuous-outcome effect. These are not observed power calculations and are not the trial’s own design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation; each illustration uses a stated fraction of the observed effect. For planning for 100% of the observed effect, the illustrations give 11 participants per arm for 80% power and 14 participants per arm for 90% power. For planning for 75% of the observed effect, they give 18 and 24 participants per arm, respectively. For planning for 50% of the observed effect, they give 41 and 54 participants per arm, respectively. These are hypothetical planning quantities, not evidence that the study had a particular probability of detecting its observed result.

Why do analysis populations and timing matter?

The primary analysis population is defined as participants who enrolled in Part 1 and received at least one dose of study drug in that part. This definition ties the result to participants who began study treatment, but it is not a full description of how every possible post-enrollment event was handled. Rules for missing outcome measurements, protocol deviations, or other exclusions are not reported in the registry record.

Timing also shapes interpretation. The primary binary endpoint is assessed at Day 10, during the short add-on comparison. Part 2 follows a washout and has treatment eligibility rules tied to response for participants who previously received TAF. Results from the later phase consequently address a different treatment period and a selected set of participants, not the same randomized comparison as the Part 1 primary endpoint.

11. Confidence Intervals and Precision

The sponsor’s reported 95% confidence interval for the randomized difference in proportions extends from 42.6 to 78.8. In general, a confidence interval describes a range of values compatible with the observed data under the assumptions of the analysis. It communicates uncertainty around the estimated group difference; it does not mean that individual participant outcomes fall within that interval. The interval is entirely on the positive side of no difference, consistent with the sponsor’s Fisher exact p-value of <0.001.

The interval also indicates that the estimate is not exact. Its width reflects uncertainty in estimating the contrast from the participants observed, and the group sizes are important context for that uncertainty. The point estimate of 60.7 should not be read as a precisely known effect for every setting or population. The registry does not report a confidence interval for the sentinel cohort comparison in the sponsor’s analysis.

The randomized groups contain 28 participants receiving TAF and 15 receiving placebo. With group sizes of this scale, a percentage can change meaningfully when the classification of one or a small number of participants changes. That general feature of binary outcomes is relevant when interpreting observed percentages, especially when one group has no participants meeting the endpoint. The confidence interval offers a more informative account of inferential precision than the point estimates alone, but it does not resolve questions about generalizability or missing-data handling.

The continuous secondary result also has an interval: the unadjusted mean difference is -0.66, with limits of -0.921 and -0.399. Its interpretation is specific to the mean change in log10 copies/mL, not to the binary threshold outcome. The registry does not provide a sponsor-reported confidence interval for that secondary analysis. Both intervals should be understood as estimates within their respective statistical analyses, rather than guarantees about future study results.

12. Analyses Reported by the Sponsor

MethodEstimate95% CIP-value
Fisher ExactDifference in proportions 60.742.6 to 78.8< 0.001

For the randomized Part 1 comparison, the sponsor reports a difference in proportions of 60.7, with a 95% confidence interval from 42.6 to 78.8, using a Fisher exact test. The reported p-value is <0.001. These results correspond to the posted event proportions of 60.7% in the randomized TAF group and 0.0% in the randomized placebo group.

The unadjusted re-calculation from the posted summary statistics points in the same direction and gives p <0.001. The registry record does not flag a discrepancy between the sponsor’s analysis and the re-calculation. The sponsor’s reported analysis is the primary inferential result; the re-calculation is a simple check from the posted group summaries and does not replace the sponsor’s analysis.

The registry does not report a sponsor analysis for the posted continuous secondary endpoint. Its unadjusted mean comparison should therefore be treated as a separate descriptive and inferential calculation, not as a sponsor-reported confirmatory result. No claim about a prespecified hierarchy or formal confirmation of that secondary analysis is warranted from the information in the registry record.

13. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary endpoint and lists numerous secondary outcomes, including virologic measures and safety outcomes at later time points. It does not report whether the study used a formal multiplicity adjustment, a testing hierarchy, or another procedure to manage the chance of false-positive findings across multiple analyses. Without that information, unadjusted secondary p-values should be interpreted cautiously and should not be treated as if they were independently confirmatory.

The sponsor’s reported primary comparison uses a Fisher exact test and gives a 95% confidence interval. The registry record does not provide a fuller statistical analysis plan describing all modeling choices, interim analyses, or decision rules. Those details are not reported in the registry record, so they cannot be inferred from the primary result or from the outcome listings.

The primary analysis population includes participants who enrolled in Part 1 and received at least one dose of study drug. This is the population definition stated in the record. It does not, by itself, explain how missing Day 10 outcomes were treated, whether any participants were excluded after receiving treatment, or whether sensitivity analyses were performed. Those details are not reported in the registry record. The same limitation applies to the secondary outcomes: specific missing-data approaches and analysis populations for each later measure are not described in the available record.

Part 2 eligibility differs by prior randomized assignment and response. Participants who received TAF needed a decrease in HIV-1 RNA greater than 0.5 log10 to continue, while all participants who received placebo were eligible regardless of viral-load change. As a result, Part 2 participants do not constitute an unchanged randomized comparison of the original groups. Later-phase findings, if reported, would need to be interpreted in light of this selection and the shared Part 2 regimen.

These reporting gaps limit how completely the statistical evidence can be reconstructed. They do not change the posted primary result, but they matter when judging the role of secondary analyses, the handling of incomplete measurements, and the strength of conclusions beyond the primary endpoint.

14. Safety Results

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

ArmParticipants with serious adverse eventsParticipants at riskPercentage
Part 1 Sentinel Cohort TAF0120.0%
Part 1 Randomized Cohort TAF32810.7%
Part 1 Randomized Cohort Placebo0150.0%
Part 2 E/C/F/TAF + ATV43710.8%
Participants with at least one serious adverse event
Serious adverse events by armPart 1 Sentinel Cohort TAF0.0%Part 1 Randomized Cohort TAF10.7%Part 1 Randomized Cohort Plac…0.0%Part 2 E/C/F/TAF + ATV10.8%% of participants with at least one serious adverse event

Deaths

ArmDeaths (participants affected of at risk)
Part 1 Sentinel Cohort TAF0 of 12
Part 1 Randomized Cohort TAF0 of 28
Part 1 Randomized Cohort Placebo0 of 15
Part 2 E/C/F/TAF + ATV0 of 37

Other (non-serious) adverse events

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

ArmParticipants affected of at risk
Part 1 Sentinel Cohort TAF7 of 12
Part 1 Randomized Cohort TAF6 of 28
Part 1 Randomized Cohort Placebo5 of 15
Part 2 E/C/F/TAF + ATV26 of 37

Most frequent serious adverse event terms

Event termOrgan systemPart 1 Sentinel Cohort TAFPart 1 Randomized Cohort TAFPart 1 Randomized Cohort PlaceboPart 2 E/C/F/TAF + ATV
Enlarged uvulaGastrointestinal disorders0 of 120 of 280 of 151 of 37
HyperbilirubinaemiaHepatobiliary disorders0 of 120 of 280 of 151 of 37
HypoglycaemiaMetabolism and nutrition disorders0 of 121 of 280 of 150 of 37
MyopathyMusculoskeletal and connective tissue disorders0 of 121 of 280 of 150 of 37
Abortion spontaneousPregnancy, puerperium and perinatal conditions0 of 121 of 280 of 150 of 37
AngioedemaSkin and subcutaneous tissue disorders0 of 120 of 280 of 151 of 37
HypotensionVascular disorders0 of 120 of 280 of 151 of 37

Most frequent non-serious adverse event terms

Event termOrgan systemPart 1 Sentinel Cohort TAFPart 1 Randomized Cohort TAFPart 1 Randomized Cohort PlaceboPart 2 E/C/F/TAF + ATV
Upper respiratory tract infectionInfections and infestations0 of 121 of 280 of 1511 of 37
MalariaInfections and infestations0 of 120 of 280 of 155 of 37
Neuropathy peripheralNervous system disorders0 of 121 of 281 of 153 of 37
ToothacheGastrointestinal disorders0 of 120 of 281 of 153 of 37
HyperbilirubinaemiaHepatobiliary disorders0 of 121 of 280 of 153 of 37
JaundiceHepatobiliary disorders0 of 121 of 280 of 153 of 37
InfluenzaInfections and infestations0 of 121 of 280 of 153 of 37
HeadacheNervous system disorders0 of 120 of 280 of 154 of 37
DiarrhoeaGastrointestinal disorders1 of 120 of 280 of 152 of 37
NauseaGastrointestinal disorders2 of 121 of 280 of 150 of 37

Serious events with the highest arm-level rate: hypoglycaemia (3.6%), myopathy (3.6%), abortion spontaneous (3.6%), enlarged uvula (2.7%), hyperbilirubinaemia (2.7%).

Do not overextend the safety comparison. Serious-adverse-event counts are safety observations, not efficacy outcomes, and should not be combined with the primary result into a single benefit-risk number.

The registry lists serious adverse events for each study group. In Part 1, serious adverse events were recorded for 0 of 12 participants in the sentinel TAF cohort, 3 of 28 in the randomized TAF cohort, and 0 of 15 in the randomized placebo cohort. In Part 2, 4 of 37 participants receiving E/C/F/TAF plus atazanavir were listed as having a serious adverse event. The registry lists 0 deaths for each of these groups.

These are descriptive counts, not a randomized comparison of safety across all phases. The Part 2 group received a different regimen and was formed after Part 1 eligibility decisions, so its count should not be directly contrasted with the randomized Part 1 groups as though treatment assignment remained comparable. A serious adverse event count also does not, by itself, show whether an event was caused by study treatment. The registry record does not provide enough detail in these figures to establish causation or comparative risk.

The record lists serious-event terms and percentages as well, but such entries should be read within the study’s group sizes and reporting context. The counts alone do not establish the likelihood of an event outside this study or provide a basis for individual treatment decisions.

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

The primary result means that, among participants in the randomized Part 1 comparison, the proportion meeting the specified Day 10 HIV-1 RNA decline threshold was higher in the TAF group than in the placebo group. The sponsor’s estimated difference in proportions was 60.7, with a 95% confidence interval from 42.6 to 78.8 and p <0.001. The posted data therefore indicate a substantial observed separation for this short-term endpoint in the analyzed study groups.

The result does not mean that every participant receiving TAF met the threshold, nor that no participant could respond in other ways. It does not describe the full range of individual RNA changes, because the primary endpoint classifies participants according to a cutoff. The continuous secondary outcome provides a complementary group-level measure, but it does not turn the primary binary endpoint into a complete account of all individual responses.

The result is specific to adding TAF or placebo to a failing regimen over 10 days among the randomized cohort participants included in the primary analysis. It does not by itself establish longer-term viral suppression, effects on clinical outcomes, or results for the later E/C/F/TAF plus atazanavir regimen. Part 2 had a different treatment period and eligibility rules, including response-based eligibility for participants who previously received TAF.

The result also does not settle questions about missing-data procedures, multiplicity, or generalizability, because those details are not reported in the registry record. Nor does a small p-value mean that the null hypothesis has a particular probability of being true or that the result will necessarily recur in a different population. The confidence interval expresses statistical uncertainty under the reported analysis; it cannot account for every limitation in study design, reporting, or applicability.

These interpretations concern the posted statistical evidence and are not medical advice. The registry result is one study’s estimate for a defined endpoint, time point, and participant group. It should not be expanded into claims about treatment choice or individual outcomes beyond what the record reports.

16. Why This Trial Matters Statistically

This trial illustrates how endpoint definition shapes a treatment comparison. The primary outcome uses a threshold for change in HIV-1 RNA, so the result is a difference in the percentage meeting a defined response criterion. A continuous measure of mean change is also listed as a secondary outcome, showing how a trial can describe the same short-term biological domain using both a threshold-based endpoint and a measure of average magnitude.

The study’s sequence also matters statistically. The open-label sentinel cohort preceded the randomized double-blind cohort, and the randomized comparison was brief. The sentinel results can provide context, but they should not be pooled conceptually with the randomized contrast as though both groups were assigned under the same design. Keeping cohort structure visible helps prevent an apparently simple three-group summary from obscuring the different roles of those groups.

The transition into Part 2 is another instructive design feature. Eligibility for prior TAF recipients depended on an RNA-change threshold, while placebo recipients could enter regardless of viral-load change. This means later results would describe participants selected under different rules, all receiving the later regimen, rather than preserve the original randomized comparison. The registry’s sequence therefore demonstrates why treatment phase and selection criteria are essential to interpreting follow-up data.

Finally, the record emphasizes the distinction between an estimated effect and its precision. The sponsor reports a primary confidence interval and a Fisher exact test, while detailed analysis-plan information is limited. Reading the estimate together with uncertainty, population definition, and reporting gaps is more informative than relying on a p-value alone. These are broadly useful principles for interpreting clinical-trial statistics.

17. Limitations

The primary endpoint is assessed at Day 10, so it captures a short-term threshold response rather than durability. The randomized comparison lasted 10 days, and the primary outcome does not describe longer-term suppression or clinical outcomes. Although later outcomes are listed, their numeric results are not reported in the registry record.

The study includes a sentinel cohort as well as the randomized cohort. Sentinel participants received open-label TAF, so their 58.3% response proportion is not a randomized estimate against placebo. The randomized TAF and placebo groups also have different group sizes, and the event percentages are based on the participants recorded in each group. The registry’s primary analysis population is described, but detailed handling of missing Day 10 measurements is not reported in the registry record.

Part 2 is not a continuation of the original randomized contrast in a way that preserves its group comparability. TAF recipients had to meet a response criterion to continue, whereas placebo recipients could proceed regardless of viral-load change. All eligible participants then received E/C/F/TAF plus atazanavir. This selection and shared later treatment limit any direct comparison based on Part 2 outcomes.

The registry record does not report a complete statistical analysis plan, including multiplicity methods for the listed outcomes or details about interim analyses. The available numerical secondary information is limited, and the later listed virologic and safety outcomes cannot be assessed from titles alone. The sample-size figures associated with the continuous secondary result are planning illustrations based on observed effects, not the trial’s original design justification or observed power.

These limitations do not erase the randomized Day 10 finding, but they narrow what it can support. The estimate pertains to the recorded endpoint, groups, and analysis population; it should not be generalized beyond those boundaries without additional evidence.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

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Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.

21. Record Summary

NCT01967940 is a completed Phase 3, randomized, double-blind, parallel-group study sponsored by Gilead Sciences. The study enrolled 55 adults with HIV-1 who were antiretroviral treatment-experienced and had a failing regimen. Part 1 included an open-label sentinel cohort and a randomized comparison of TAF versus placebo added to the existing regimen for 10 days.

The primary endpoint was the percentage with a Day 10 HIV-1 RNA decrease from baseline exceeding 0.5 log10. In the randomized cohort, the reported proportions were 60.7% for TAF and 0.0% for placebo. The sponsor reported a difference in proportions of 60.7, a 95% confidence interval from 42.6 to 78.8, and p <0.001 using Fisher’s exact test. The registry also describes a washout followed by a 48-week Part 2 regimen for eligible participants.

Interpretation is limited to the short-term primary comparison and the analysis information recorded in the registry. Detailed missing-data and multiplicity methods are not reported in the registry record.

Clinical Biostats