Tenofovir-lamivudine-dolutegravir Combination as Second-line ART: a Randomised Controlled Trial: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Tenofovir-lamivudine-dolutegravir Combination as Second-line ART: a Randomised Controlled Trial (NCT03991013), a randomized phase 2 study. The primary outcome is Virological Suppression at 24 Weeks.

2. Clinical Question

The clinical question concerns a short supplementary dolutegravir dosing strategy during the start of a second-line regimen. The study description gives the rationale for this lead-in as the inducing effect of efavirenz on dolutegravir metabolism. It also describes recycling the tenofovir-emtricitabine/lamivudine backbone with dolutegravir after failure of the first-line regimen.

The primary comparison is between the Stage 2 supplementary-dose group and the Stage 2 placebo-dose group. A further listed comparison is between the Stage 1 supplementary-dose group and the Stage 2 placebo-dose group. The registry record does not describe the relationship between the stages in enough detail to characterize their conduct beyond the arm labels and posted comparisons.

3. Trial Design

ARTIST (AntiRetroviral Therapy In Second-line: Investigating Tenofovir-lamivudine-dolutegravir) is a phase 2 randomized, double-blind, placebo-controlled, parallel-group trial. The registry record lists quadruple masking and an enrollment of 192. The study status is completed. The recorded start date is 2019-08-08, and the primary completion date is 2022-04-26.

The study compares the tenofovir-lamivudine-dolutegravir fixed-dose combination with and without an additional dose of dolutegravir during the first 14 days. In the Stage 2 supplementary-dose arm, participants took dolutegravir 50 mg 12 hours after the fixed-dose tablet; in the Stage 2 placebo-dose arm, they took a matching placebo at that time. A Stage 1 arm is also listed as receiving the fixed-dose combination with supplementary dolutegravir.

The primary outcome is a binary participant count: whether HIV viral load was <50 copies/mL at 24 weeks. The primary analysis is described as modified intention-to-treat and uses the FDA snapshot algorithm. The endpoint population excludes specified types of study-drug switching, transfer, pregnancy-related circumstances, and deaths from non-HIV and nondrug causes. The analysis-population details are reported, but further operational detail about handling other missing endpoint values is not reported in the registry record.

Posted primary outcome counts are 55.0 of 64.0 in Stage 2 with supplementary dose, 53.0 of 65.0 in Stage 2 with placebo dose, and 53.0 of 62.0 in Stage 1 with supplementary dose. These are analyzed group counts, not the overall enrollment. The registry record does not report the trial’s original sample-size justification, detailed allocation procedure, or a full statistical analysis plan.

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: Stage 1 of the ARTIST study was a single-arm prospective cohort study of second-line TLD regimen with supplementary dolutegravir dose (50 mg twice daily) for two weeks in patients failing a NNRTI-based regimen. After completion of stage 1, the study progressed to enrol 130 participants in stage 2.

Overall Study

Analysis population for the primary outcome, as defined in the registry: mITT analysis excludes those switching study drug for reasons of stopping contraception or desire to become pregnant, becoming pregnant, transfer out for nonclinical reasons, and death from non-HIV and nondrug causes.

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 Virological Suppression at 24 Weeks, measured over 24 weeks.

The primary endpoint is virological suppression at 24 weeks, defined as HIV viral load <50 copies/mL. It is recorded as a count of participants meeting that threshold and is analyzed by modified intention-to-treat using the FDA snapshot algorithm. The reported group counts therefore indicate how many participants in each analysis group met the endpoint, alongside the group denominators.

Viral load provides a measurable marker of virological response to antiretroviral treatment. A threshold-based endpoint makes the outcome interpretable as the proportion of participants who meet a prespecified suppression criterion at a defined follow-up time. This is a general explanation of the endpoint type; it does not establish that any particular treatment is effective.

The modified intention-to-treat definition matters for interpretation because it excludes specified participants for reasons including pregnancy-related circumstances, nonclinical transfer, and certain deaths. The registry record identifies those exclusions but does not provide further detail on how every possible missing viral-load measurement was handled. The endpoint is therefore interpreted as the result in the stated analysis population and under the stated snapshot approach, not as a count that necessarily includes every enrolled participant.

7. Results Posted in the Registry

• Stage 2: Supplementary Dose: 85.9% (55/64) versus 81.5% (53/65) on control; risk difference 4.4 percentage points (95% CI -8.3 to 17.1), risk ratio 1.05 (0.91–1.23); unadjusted two-proportion z-test p = 0.499.
• Stage 1: TLD Regimen With Supplementary Dolutegravir Dose: 85.5% (53/62) versus 81.5% (53/65) on control; risk difference 3.9 percentage points (95% CI -8.9 to 16.8), risk ratio 1.05 (0.90–1.22); unadjusted two-proportion z-test p = 0.550.

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.

Virological Suppression at 24 Weeks (Sensitivity Analysis)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Stage 2: Supplementary Dose: 85.9% (55/64) versus 86.9% (53/61) on control; risk difference -0.9 percentage points (95% CI -13.0 to 11.1), risk ratio 0.99 (0.86–1.14); unadjusted two-proportion z-test p = 0.877.
  • Stage 1: TLD Regimen With Supplementary Dolutegravir Dose: 88.3% (53/60) versus 86.9% (53/61) on control; risk difference 1.4 percentage points (95% CI -10.3 to 13.2), risk ratio 1.02 (0.89–1.16); unadjusted two-proportion z-test p = 0.809.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Stage 2: Supplementary Dose and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Stage 1: TLD Regimen With Supplementary Dolutegravir Dose and the control. The interval gives the range of effects that remain compatible with the data.

Virological Suppression at 12 Weeks (Modified ITT)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Stage 2: Supplementary Dose: 82.8% (53/64) versus 84.6% (55/65) on control; risk difference -1.8 percentage points (95% CI -14.5 to 10.9), risk ratio 0.98 (0.84–1.14); unadjusted two-proportion z-test p = 0.782.
  • Stage 1: TLD Regimen With Supplementary Dolutegravir Dose: 75.0% (45/60) versus 84.6% (55/65) on control; risk difference -9.6 percentage points (95% CI -23.7 to 4.4), risk ratio 0.89 (0.74–1.06); unadjusted two-proportion z-test p = 0.179.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Stage 2: Supplementary Dose and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Stage 1: TLD Regimen With Supplementary Dolutegravir Dose and the control. The interval gives the range of effects that remain compatible with the data.

All-cause Mortality

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Stage 2: Supplementary Dose: 1.5% (1/65) versus 0.0% (0/65) on control; risk difference 1.5 percentage points (95% CI -1.5 to 4.5); unadjusted two-proportion z-test p = 0.315.
  • Stage 1: TLD Regimen With Supplementary Dolutegravir Dose: 0.0% (0/62) versus 0.0% (0/65) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Stage 2: Supplementary Dose and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Stage 1: TLD Regimen With Supplementary Dolutegravir Dose and the control. The interval gives the range of effects that remain compatible with the data.

The registry record lists secondary outcomes spanning virological suppression at another time point and under a sensitivity analysis, resistance mutations, CD4 change, adverse events, mortality, adherence, and dolutegravir trough concentrations. The posted secondary results do not provide complete numerical analyses for all of those outcomes. Where detailed results are absent, they are not reported in the registry record.

The available virological results do not show a consistent, clearly separated pattern across the listed comparisons. At 24 weeks, the sensitivity analysis and the primary modified intention-to-treat analysis address related outcomes using different analysis populations. At 12 weeks, the endpoint is earlier than the primary time point. These are related measures, but they do not replace the primary endpoint or settle its uncertainty.

All-cause mortality is also listed at 24 weeks, with event counts shown by group. Event counts alone are not a complete assessment of safety or comparative risk, particularly when events are sparse. The adverse-event data require their own interpretation and should not be combined with virological outcomes as though they measured the same construct.

General explanation: secondary outcomes can help describe consistency, mechanisms, and other consequences of treatment, but multiple outcome testing raises the chance of obtaining apparently notable results by chance. The registry record does not report a multiplicity adjustment or a prespecified hierarchy for interpreting secondary outcomes. Their unadjusted results therefore carry less confirmatory weight than a clearly specified primary analysis. The available secondary findings should be treated as supportive or exploratory evidence, not as independent proof of a treatment effect.

Because some listed outcomes lack posted analysis details, the absence of a reported result should not be mistaken for a finding of no difference. The overall pattern is limited by what the record reports and by the uncertainty in the primary comparison.

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

• Virological Suppression at 24 Weeks (Sensitivity Analysis)
• Virological Suppression at 12 Weeks (Modified ITT)
• Antiretroviral Resistance Mutations by Genotypic Resistance Testing
• CD4 Change at 24 Weeks
• Adverse Events
• All-cause Mortality
• Adherence to Treatment
• Geometric Mean Ratio (GMR) of Dolutegravir Trough Concentrations on Day 7 Versus Day 28

9. Statistical Interpretation

10. Statistical Methods Explained

What does the risk difference represent?

The primary outcome is binary: each participant either met the viral-load threshold at 24 weeks or did not. A risk difference compares the proportions meeting that endpoint in two groups by subtracting one group’s proportion from the other’s. A positive estimate in the posted Stage 2 comparison indicates a higher observed proportion in the supplementary-dose group than in the placebo-dose group. It does not, on its own, establish that the dosing strategy caused the difference.

General explanation: the risk difference is an absolute measure, expressed on the proportion scale. It is distinct from a risk ratio, which expresses a relative comparison. The registry record also includes relative measures for the primary comparisons, but the risk-difference estimate is the direct absolute contrast used in the interpretation above.

Why do confidence intervals matter?

A confidence interval conveys uncertainty around an estimated effect. General explanation: it is a range generated by a statistical procedure that, over repeated use under its assumptions, would cover the underlying effect at the stated confidence level at the corresponding frequency. It is not a guarantee that the true value lies within one particular interval, nor does it assign a probability to each value inside the interval.

For a risk difference, zero represents no difference between groups. The posted primary intervals cross zero, so values on either side remain compatible with the estimates. This is why the point estimate alone should not be treated as a definitive account of the comparison. The interval’s width also matters: a wide interval indicates that the data are consistent with a broad range of effects.

What do the p values say?

The posted p values for the primary comparisons are unadjusted: 0.499 for Stage 2 supplementary dose versus Stage 2 placebo dose, and 0.55 for the Stage 1 supplementary-dose comparison versus Stage 2 placebo dose. General explanation: a p value describes how unusual data at least as incompatible with a specified null model would be if that model and the test assumptions were correct. It is not the probability that the null hypothesis is true, and it does not measure the clinical importance of an effect.

The registry record does not report a complete sponsor statistical analysis for these comparisons. The p values and effect estimates are unadjusted recalculations from posted summary statistics. They should therefore be distinguished from any prespecified, adjusted or otherwise model-based analysis that may have been conducted but is not reported in the registry record.

Why does the analysis population matter?

The primary endpoint uses a modified intention-to-treat population and an FDA snapshot algorithm. The record specifies exclusions for participants switching study drug because of contraception-related reasons or desire to become pregnant, becoming pregnant, transfer for nonclinical reasons, and death from non-HIV and nondrug causes. Consequently, the primary group denominators do not represent all enrolled participants. Results describe this defined analysis population and endpoint rule.

General explanation: changing the analysis population or the handling of missing outcome data can change both the estimated group proportions and their uncertainty. The record’s stated exclusions help define the population to which the primary results apply. Further details about the treatment of other missing data are not reported in the registry record, so no additional assumptions about that process are warranted.

What can be inferred from these calculations?

The displayed comparison estimates are simple unadjusted recalculations from the posted summary statistics. They describe the observed counts and provide an estimate of the absolute difference with uncertainty. They do not adjust for baseline variables or other factors, and no such adjustment is reported in the registry record. General explanation: adjustment may be useful when prespecified, especially to account for design features or prognostic variables, but it also depends on the model and its assumptions.

The record lists a randomized, double-blind, placebo-controlled design, which is relevant context for interpreting comparisons. However, the detailed randomization procedure and the relationship between the Stage 1 and Stage 2 groups are not reported in the registry record. The posted comparisons should be read as listed; the available record does not support additional claims about how the stages relate analytically.

Finally, statistical evidence should not be reduced to a threshold decision. A point estimate, interval, analysis population, outcome definition, and study design all contribute to interpretation. General explanation: a non-small p value does not prove absence of an effect, just as a small p value alone does not show that an effect is large or important. In this trial, the primary comparisons have uncertainty spanning both directions, and the record does not report a formal sponsor analysis to supplement the recalculated summaries.

11. Confidence Intervals and Precision

The posted primary risk-difference estimate for Stage 2 supplementary dose versus Stage 2 placebo dose is 0.044. Its confidence limits extend below and above zero. That span means the data are compatible with a modest difference favoring either group as well as no difference, rather than pinning down a single effect size.

For the Stage 1 supplementary-dose comparison, the posted group counts are 53.0 of 62.0 and 53.0 of 65.0. The registry record’s recalculated risk-difference interval likewise includes values on both sides of zero. The estimate is therefore not precise enough to establish the direction of the difference. The posted unadjusted p value is 0.55.

General explanation: precision concerns the range of plausible effects supported by the data, not whether a result crosses a significance threshold. A confidence interval that spans both negative and positive risk differences leaves uncertainty about direction; an interval that is also broad leaves uncertainty about magnitude. In a binary outcome, the number of participants and the frequency of the outcome influence the precision of the estimated group contrast.

The separate relative-risk interval for the Stage 2 comparison runs from 0.905 to 1.227, with a point estimate of 1.054. It includes 1, the value corresponding to no relative difference. No single measure resolves the uncertainty: absolute and relative scales answer different questions, and both should be read with the observed counts and the defined analysis population.

Confidence intervals do not establish that every value within their limits is equally plausible, and they do not compensate for limitations in the analysis population or missing information. The registry record does not report a sponsor analysis that could provide an additional precision estimate under a prespecified model.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for 80% power and participants per arm for 90% power. They are not total sample sizes. The sample-size calculations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. For each comparison, the effect to detect is set at the stated fraction of the observed effect. The original trial design assumptions and sample-size justification are not reported in the registry record.

Read the 80% power column as the approximate number of participants per arm required for an 80% chance of detecting the specified effect under those planning assumptions, if that effect and the assumptions were true. The 90% column uses a higher target chance of detection and consequently generally calls for more participants per arm. These are planning illustrations, not observed power.

Rows planning for 100%, 75%, or 50% of the observed effect make different assumptions about the effect size a future study aims to detect. A smaller target effect requires more participants because it is harder to distinguish from random variation. This general relationship is reflected in the planning values across the effect fractions. The calculations use the observed effect as their reference, so they are sensitive to the instability of estimates from the current trial.

The binary-outcome planning displays report participants per arm, not total events. The corresponding curve should be read as a visual expression of the same planning relationship between the target effect and required sample size, rather than as an additional trial result. These figures do not describe the number enrolled in ARTIST and do not show the trial’s actual power.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.815; treatment proportion p₁ = 0.859; average p̄ = 0.837.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5219 = 1.0228.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5209 = 0.4384.
4. n = (1.0228 + 0.4384)² / (0.0440)² = 1,103.5, rounded up to 1,104 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.815384615384615                          # control proportion
p1 <- 0.859375                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(3991013)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 1,104 (80% power), 1,477 (90% power)
 75% of observed effect: n per arm = 2,016 (80% power), 2,698 (90% power)
 50% of observed effect: n per arm = 4,655 (80% power), 6,231 (90% power)
power.prop.test: 1103.5 
Simulated power at n = 1,104 per arm: 0.805 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry record identifies one primary endpoint, virological suppression at 24 weeks, and lists multiple secondary outcomes. It does not report whether the statistical plan used a multiplicity adjustment, a testing hierarchy, or another procedure to control the interpretation of multiple comparisons. Those details are not reported in the registry record.

General explanation: when many outcomes or comparisons are examined, the opportunity for chance findings increases. A prespecified strategy can help distinguish confirmatory tests from exploratory analyses. Without a reported strategy, unadjusted secondary p values should be interpreted cautiously and should not be treated as if each were the sole planned test.

The primary population is modified intention-to-treat, with specified exclusions, and the endpoint uses the FDA snapshot algorithm. This defines who contributes to the primary analysis, but the record does not give a complete account of missing outcome handling beyond the listed exclusions. The extent and pattern of missingness, and any sensitivity analyses for missing data beyond the named 24-week sensitivity analysis, are not reported in the registry record.

Analysis populations can affect the meaning of a comparison. An intention-to-treat analysis generally aims to preserve randomized group assignment, while a modified version applies stated exclusions. General explanation: excluding participants or classifying unobserved outcomes can affect estimated proportions if those participants differ in outcome risk from those retained. The available description is not enough to determine the impact of the exclusions or any additional missingness.

The detailed statistical analysis plan, model specifications, and original sample-size justification are not reported in the registry record. No interim analyses are reported in the registry record. These absences limit the ability to assess whether every displayed comparison follows the planned analysis or whether decisions were made after examining accumulating data.

15. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fractured tibia (1.6%), thrombocytopenia (1.6%), urinary tract infection (1.6%), incident pulmonary tuberculosis (1.6%), stab chest (1.6%).

The registry record reports serious adverse events among 2 of 65 participants at risk in the Stage 2 supplementary-dose group, 0 of 65 in the Stage 2 placebo-dose group, and 9 of 62 in the Stage 1 supplementary-dose group. It also lists the serious-event terms fractured tibia, thrombocytopenia, urinary tract infection, incident pulmonary tuberculosis, stab chest, and acute kidney injury, each at 1.6%.

These counts are descriptive. The groups are not all the same size, and the record does not provide enough detail in this summary to assess event timing, duration, relatedness, or whether multiple events occurred in the same participant. A difference in counts alone does not establish that an intervention caused an event or that groups have comparable safety.

General explanation: rare events are difficult to compare precisely, especially when the number of affected participants is small. Safety interpretation should consider the event definitions, follow-up, exposure, and full clinical context, not only a count. The registry record does not report further detail on these aspects in the posted summary.

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

The registry results describe a randomized, double-blind, placebo-controlled phase 2 study of supplementary dolutegravir during the first 14 days of a tenofovir-lamivudine-dolutegravir second-line regimen. In the primary modified intention-to-treat comparison, the observed counts were 55.0 of 64.0 with supplementary dolutegravir and 53.0 of 65.0 with placebo. The recalculated risk difference is 0.044, and its interval includes values below and above zero.

These data do not establish a clear difference between the Stage 2 groups, but they also do not demonstrate that the strategies are equivalent. The uncertainty is compatible with effects in either direction. The Stage 1 comparison is similarly uncertain, and the registry record does not provide enough detail about the stages to support interpretations beyond the posted comparisons.

The result applies to the defined endpoint, follow-up time, and modified intention-to-treat population. It does not answer whether results would be the same at other time points, in different populations, or under different rules for defining or handling the endpoint. It also does not resolve questions about longer-term outcomes, resistance, adherence, or the full safety profile.

General explanation: absence of compelling statistical evidence for a difference is not proof of no effect. Equivalence or noninferiority requires a suitable design, prespecified margin, and analysis; such details are not reported in the registry record. The observed data should therefore be read as an estimate with uncertainty rather than as a definitive judgment about the dosing strategy.

The registry record does not report the original sample-size justification or a sponsor inferential analysis for the primary comparison. The simple recalculations help describe the posted counts, but they are not a substitute for any prespecified analysis that is not reported in the registry record.

17. Why This Trial Matters Statistically

This trial illustrates why a clinical comparison should be read through its endpoint definition, analysis population, effect estimate, and uncertainty together. A count of participants achieving suppression is easy to understand, but interpretation depends on the viral-load threshold, the 24-week time point, the FDA snapshot approach, and the modified intention-to-treat exclusions.

It also highlights the distinction between a point estimate and the information available to support it. The primary risk-difference estimate is 0.044, but the interval extends across zero. The estimate alone might suggest a direction; the interval shows why that direction is not established with precision. Reporting the effect and its uncertainty gives a more complete account than relying on a p value alone.

The registry record also separates the primary outcome from a broad set of secondary questions, including suppression at other times, resistance, CD4 change, adverse events, mortality, adherence, and drug concentrations. These outcomes can contribute different kinds of evidence, but the record does not report full results or multiplicity methods for all of them. Their presence in a trial does not make each a confirmatory test.

Finally, planning calculations based on an observed effect are not a retrospective assessment of trial success. They illustrate how future sample-size requirements vary with an assumed target effect under stated planning assumptions. The original design justification is not reported in the registry record, so the planning display cannot establish why the trial enrolled its recorded number of participants.

18. 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 registry record contains limited detail about the trial’s statistical plan. It does not report the original sample-size justification, the detailed randomization procedure, or the relationship between the Stage 1 and Stage 2 groups. The listed primary comparisons can be described, but these missing details constrain assessment of the design and analysis choices.

The primary estimates discussed are unadjusted recalculations from posted summary counts. The record does not report a sponsor analysis for the primary comparisons, so the recalculated estimates should not be mistaken for a prespecified model-based result. The record also does not report whether multiplicity was addressed across the secondary endpoints or what analysis hierarchy was intended.

The modified intention-to-treat definition specifies several exclusions, but further missing-data handling is not reported in the registry record. The analysis denominators differ from overall enrollment, and the available information does not establish how any additional missing measurements may have affected the results.

Some secondary outcomes are listed without detailed posted results. The available safety summary gives counts and selected serious-event terms but does not provide full event-level context in this record. Follow-up beyond the stated outcome times, longer-term outcome results, and details needed to assess generalizability are not reported in the registry record.

The uncertainty around the primary estimates is substantial enough that the data do not establish the direction of a difference. These limitations call for restrained interpretation: the results characterize the posted comparisons, rather than providing a definitive answer to all clinical, safety, or mechanistic questions.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Tenofovir-lamivudine-dolutegravir Combination as Second-line ART: a Randomised Controlled Trial — NCT03991013.
• Registry record last updated 2024-10-01; status last verified 2024-09.
• Results first posted 2024-08-09.
• 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.

22. Record Summary

ARTIST (NCT03991013) is a completed phase 2 randomized, double-blind, placebo-controlled, parallel-group trial sponsored by the University of Cape Town. The recorded enrollment is 192. The study evaluated tenofovir-lamivudine-dolutegravir as second-line ART, with a comparison of supplementary dolutegravir and matching placebo during the first 14 days.

The primary endpoint was virological suppression at 24 weeks, defined as HIV viral load <50 copies/mL in a modified intention-to-treat analysis using the FDA snapshot algorithm. The posted Stage 2 counts were 55.0 of 64.0 with supplementary dose and 53.0 of 65.0 with placebo. The unadjusted recalculated risk difference is 0.044, with uncertainty extending across zero.

The registry record lists secondary outcomes in virological response, resistance, CD4 change, safety, mortality, adherence, and dolutegravir concentrations. Some secondary analyses and details of the statistical plan are not reported in the registry record. The primary findings are therefore best read as estimates with considerable uncertainty, limited to the stated population and endpoint.