Raltegravir Augmentation on Persistent Central Nervous System (CNS) Immunoactivation in Treated HIV-1 Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Raltegravir Augmentation on Persistent Central Nervous System (CNS) Immunoactivation in Treated HIV-1 Patients (NCT00672932), a randomized na study. The primary outcome is Change in CSF Concentrations of Neopterin After 12 Weeks.

2. Clinical Question

The study asked whether adding raltegravir to an existing antiretroviral regimen was associated with a change in cerebrospinal fluid (CSF) neopterin over 12 weeks in treated people with HIV-1. Neopterin was used as a marker of CNS immune activation and inflammation. The rationale recorded for the study was a hypothesis that ongoing HIV-1 replication in the brain, at a level not detectable in CSF, might contribute to persistent CNS immune activation despite combination antiretroviral therapy.

The question is about a biomarker measured over a short follow-up period. It is not a direct measure of brain function, brain injury, or long-term clinical outcomes. The registry’s stated rationale presents reduction in CNS immune activation as a way to test the hypothesized mechanism; it does not establish that a biomarker change would itself demonstrate a change in health or function.

3. Trial Design

The registry describes a randomized, parallel-group study with no masking and lists the phase as not applicable. The study is identified as a pilot. Its recorded enrollment is 18, and its status is completed. The registry lists a start of 2008-04 and primary completion of 2010-10.

Participants assigned to the raltegravir group were to take 400mg twice daily by mouth while continuing their regular medications. Participants assigned to no augmented treatment were to continue their regular antiretroviral regimen. The intended comparison therefore concerns adding raltegravir to ongoing treatment, rather than replacing the regular regimen.

The posted primary outcome summaries are reported for a raltegravir group of 14 and a no-augmented-treatment group of 9. These are analysis-group counts in the outcome summary, not a reason to treat the study as having followed only two unchanged randomized groups throughout. The registry says that six participants randomized to no drug later rolled over to receive raltegravir. It also says the primary analysis treated rollover subjects as independent and compared 14 intensified to 9 non. The latter description is truncated in the record, so further details of the comparison are not available.

The record also notes that one subject in the raltegravir group was censored when a pharmacological study showed no drug in either plasma (n=9) or CSF. The exact handling of this subject beyond that statement is not reported in the registry record. The crossover-like rollover and censoring matter when interpreting the posted groups: the outcome summaries do not simply describe a clean, fixed assignment comparison without qualification.

The parallel model describes the recorded design classification. The rollover information adds an important feature of how participants’ treatment exposure changed during the study. Further protocol details, including the timing and rules for rollover, are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: One subject in the raltegravir group was censored when a pharmacological study showed no drug in either plasma (n=9) or CSF. Six subjects randomized to no drug later rolled over to receive raltegravir. Primary analysis treated the rollover subjects as independent and compared 14 intensified to 9 nonintensified subject experiences.

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 Change in CSF Concentrations of Neopterin After 12 Weeks, measured over three months (Rollover subjects were assessed for a second baseline after the initial 12 week period).

The primary endpoint is change in CSF concentrations of neopterin after 12 weeks, compared with baseline. Neopterin is recorded in nmol/L, and the summary statistic is the mean with standard deviation. The registry describes the endpoint more generally as CSF markers of immunoactivation and inflammation after 12 weeks compared with baseline.

CSF is the fluid sampled to assess biological activity in the central nervous system. Neopterin serves as a marker of immune activation and inflammation; it is not a direct measure of HIV-1 replication, brain injury, cognitive function, or a person’s overall clinical status. Its use reflects the study’s stated hypothesis that continued CNS viral activity might stimulate local immune activation. A change in the marker could therefore inform that biological question, but the marker alone cannot establish the proposed mechanism.

For a continuous endpoint, a mean change describes the group’s average observed movement from baseline, while the standard deviation describes variation among observations around that average. The posted mean changes are 0.1 nmol/L for the raltegravir group and 0.3 nmol/L for the no-augmented-treatment group. Their corresponding standard deviations are 0.3 and 1.1. The registry does not post confidence intervals for these group summaries or an estimable two-arm comparison.

The timeframe is recorded as three months, with a note that rollover subjects were assessed for a second baseline after the initial 12 week period. That feature makes the baseline definition relevant to interpretation, but the record does not explain the detailed calculation of change for rollover observations.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a continuous outcome, a group mean is the arithmetic average of the observations included in that group’s summary. Here, the outcome is change in CSF neopterin concentration, expressed in nmol/L. A mean change near zero would indicate little average movement from baseline, whereas a positive or negative mean indicates the direction of average change according to the endpoint’s coding. The registry reports group means of 0.1 and 0.3; it does not state a prespecified threshold for interpreting a change as biologically important.

The standard deviation (SD) describes the spread of individual values around a group mean. It is not the uncertainty interval for the mean, and it is not the range of observed values. The recorded SDs are 0.3 for the raltegravir group and 1.1 for the no-augmented-treatment group. A spread statistic can help readers understand heterogeneity, but it does not show whether the difference between group means is statistically distinguishable from random variation.

What would a two-arm comparison add?

A comparative analysis would estimate the contrast between the groups and quantify uncertainty in that estimate. A confidence interval is a range of values generated by a statistical procedure that, under its assumptions and repeated use, has a stated coverage property for the quantity being estimated. It helps show both the direction and precision of an estimated contrast. The registry does not report a confidence interval for this primary comparison. No confidence interval should be reconstructed from the summary means and SDs because the record also describes rollover, censoring, and an analysis that treated rollover subjects as independent; the necessary analytic details are not reported.

A p-value, when used, measures how unusual the observed data or more extreme data would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The record gives no p-value for the primary two-arm comparison and indicates that a two-arm comparison was not estimable from the posted values. Consequently, no significance claim can be made from the means alone.

Why does outcome variability matter?

When observations vary widely, a group mean can be estimated less precisely unless the available information is sufficient to offset that variation. This is why SDs matter when considering the stability of a continuous-outcome estimate. A small pilot can produce imprecise estimates, and a few observations may have substantial influence when groups are small. This is a general statistical consideration, not a claim about which observations drove these results; participant-level data are not reported in the registry record.

Over-dispersion is a general term for variability greater than a model expects. If an analysis assumes less variability than is present, its uncertainty estimates may be too narrow. The posted summaries do not provide a model-based dispersion assessment, and no such assessment is reported in the registry record. The difference between the two SDs should therefore be read descriptively rather than treated as proof of a particular distribution or variance structure.

How do rollover and censoring affect interpretation?

Random assignment is intended to create comparable groups at the point of allocation, on average. Interpreting a result according to original assignment generally preserves that design feature, even when participants do not follow the assigned treatment exactly. This is a general principle; the registry does not fully describe an intention-to-treat analysis for this study. Instead, it states that six participants randomized to no drug later rolled over to receive raltegravir and that the primary analysis treated rollover subjects as independent, comparing 14 intensified to 9 non.

Repeated observations from the same person can be statistically related. Treating related observations as independent may affect the estimated uncertainty if the analysis does not account for that dependence. The record’s wording does not explain precisely which observations were counted as independent or how any within-person relationship was handled. It is therefore appropriate to flag the issue, but not to assert a specific direction or size of bias.

Censoring means that an observation or follow-up is excluded from a particular analysis under a stated rule, often because the outcome is unavailable or a condition for inclusion is not met. The record says one raltegravir-group subject was censored after no drug was found in plasma or CSF, and gives the parenthetical plasma sample notation (n=9). The reason and action are recorded, but further rules for censoring, the timing of that decision, and its impact on the estimate are not reported in the registry record.

What do the planning assumptions mean?

The registry’s sample-size assumptions describe a planning illustration based on the observed effect, rather than the trial’s own design. The illustration uses a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation; the effect to detect is stated as a fraction of the observed effect. These are assumptions for hypothetical future planning, not a description of the observed trial’s power. Any planning count is prospective and depends on the chosen effect and assumptions. It is not observed evidence, and it should not be described as observed power. The registry does not report that these assumptions governed the original study design.

In general, a two-sided test allows for departures in either direction from a null value. Equal allocation is a planning choice that assigns the same planned number of participants to each arm. A normal approximation uses a mathematical approximation to the distribution of an estimator or test statistic. The illustration’s reliance on an observed effect is particularly uncertain in a pilot: an observed estimate may be unstable and may not represent the effect expected in a larger study. The resulting sample-size planning counts are not reported in the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Raltegravir Group", "No Augmented Treatment")
n   <- c(14, 9)
m   <- c(0.1, 0.3)
sp  <- c(0.3, 1.1)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Raltegravir Group  14  0.100  0.300  -0.073  0.273
CARM  No Augmented Treatment  9  0.300  1.100  -0.546  1.146

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures and one posted secondary outcome: change from baseline in CD8+ T cell co-expression of CD38 and HLA-DR. It does not report the detailed analysis results for that secondary outcome in the record. The number of analyses is recorded as 0. The registry does not report a multiplicity adjustment or a prespecified hierarchy for interpreting multiple outcomes.

Multiplicity is the general statistical issue that arises when several outcomes, time points, subgroups, or analytic choices are examined. With more opportunities to test a hypothesis, the chance of at least one apparently unusual result can increase if each test is interpreted separately. Adjustments or prespecified priorities can address that issue, but whether either approach was used in this study is not reported in the registry record. The existence of more than one outcome does not establish that a false-positive finding occurred; it means interpretation should account for the full analysis plan, which is not available.

For the primary endpoint, the record states that values were missing or not estimable for a two-arm comparison. It does not provide a complete accounting of missing baseline or follow-up measurements, the reasons for any unavailable values beyond the noted censored subject, or the method used to handle missing observations. The registry also does not report a sensitivity analysis assessing alternative missing-data assumptions.

The analysis-population description is complicated by six participants randomized to no drug later rolling over to raltegravir. The primary analysis is described as treating rollover subjects as independent and comparing 14 intensified to 9 non. The precise relationship between those records and the original randomized groups is not fully explained. The registry does not report enough detail to determine how this approach affected the comparative estimate, or whether other analysis populations were considered. These omissions limit assessment of both missing-data handling and the consequences of treatment changes after randomization.

12. Safety Results

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

Other (non-serious) adverse events

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

The safety summaries record zero serious adverse events among 15 at risk in the raltegravir group and zero among 9 at risk in the no-augmented-treatment group. The registry also records zero other adverse events among 15 at risk in the raltegravir group and zero among 9 at risk in the no-augmented-treatment group. No top serious adverse-event terms are listed.

These figures describe the recorded event counts and the corresponding at-risk counts. They do not establish that no adverse events of any kind occurred beyond those represented in the registry summaries, and they do not establish that the treatments have equivalent safety. In a small study, an absence of recorded events provides limited information about the frequency of uncommon outcomes. The summaries also do not give event timing, severity grading beyond the serious/non-serious categories, or participant-level follow-up details.

Deaths are recorded as null for both groups. That means death counts are not reported in the registry record; null should not be read as a recorded count of zero. The adverse-event summaries are separate from the primary CSF neopterin endpoint and do not alter the fact that the primary two-arm comparison was not estimable from the posted values.

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

The record shows that a pilot randomized study examined change in CSF neopterin after adding raltegravir to ongoing antiretroviral treatment. It reports a mean change of 0.1 nmol/L in the raltegravir group and 0.3 nmol/L in the no-augmented-treatment group, with SDs of 0.3 and 1.1. It also reports that a two-arm comparison of this continuous outcome was not estimable from the posted values. Those descriptive summaries are not a substitute for an estimate of the between-group contrast with uncertainty.

The results do not establish that raltegravir reduced CNS immune activation, nor do they establish that it had no effect. The record does not provide the comparative estimate, confidence interval, or p-value needed to assess the primary contrast. A difference in group means on its own cannot distinguish a treatment-related pattern from random variation, and the analysis is additionally difficult to interpret because some participants rolled over and one subject was censored.

The endpoint has a specific biological scope. CSF neopterin is used as a marker of immune activation and inflammation. It is not a direct measurement of viral replication in the brain, structural injury, cognition, or long-term function. The study rationale connects the marker to a hypothesis about CNS HIV-1 activity, but a marker observation cannot by itself prove that mechanism or establish a downstream clinical consequence.

The record also does not settle broader questions about outcomes beyond the recorded 12-week timeframe. It does not report a long-term clinical comparison, nor does it provide enough detail to evaluate the handling of all missing data or the exact construction of the analysis groups. The safety summaries record no serious or other adverse events in the listed at-risk groups, but they do not establish that rare events are absent or that safety is equivalent.

The appropriate interpretation is therefore narrow: these are descriptive biomarker and safety summaries from a completed pilot study, accompanied by substantial limits on comparative inference in the registry record. They can help frame questions for further study, but they do not support a definitive conclusion about treatment effect, CNS viral activity, or clinical benefit.

14. Why This Trial Matters Statistically

This study is statistically informative because the recorded design and analysis population do not align as simply as a standard fixed-assignment comparison might suggest. Although the study is classified as randomized and parallel, six participants assigned to no drug later rolled over to raltegravir. The primary analysis is described as treating rollover subjects as independent and comparing 14 intensified to 9 non. That feature makes it important to distinguish original assignment from treatment received and to understand whether observations from the same person were handled as related.

The outcome is a continuous biomarker, so the group means and SDs offer a concise description of average change and observed variability. Yet descriptive statistics do not answer the principal comparative question without an estimate of the contrast and its uncertainty. The registry’s statement that values were missing or not estimable for a two-arm comparison is central: it limits what can be inferred more than the apparent ordering of the means does.

The pilot setting also illustrates why estimates from small studies should be read cautiously. Variability can be difficult to characterize, and estimates may be sensitive to individual observations. The sample-size assumptions are explicitly described as a planning illustration based on the observed effect, not as the original design basis. This separates an exploratory planning calculation from evidence about the effect or a claim of observed power.

Finally, the endpoint demonstrates the difference between a mechanistic marker and a clinical outcome. CSF neopterin can inform a question about immune activation, but it does not directly measure brain function or establish the proposed viral mechanism. Statistical interpretation must remain tied to what was measured, the available comparison, and the limitations documented in the registry.

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 registry record leaves key details of the primary analysis unclear. It notes that six participants randomized to no drug later rolled over to raltegravir, and that rollover subjects were treated as independent in the primary analysis, but does not fully explain how observations were assigned to the reported groups or how within-person dependence was addressed. This limits interpretation of the analysis as a comparison based strictly on original randomization.

The record also notes censoring of one raltegravir-group subject after a pharmacological study found no drug in plasma or CSF. Further censoring rules, the impact on the endpoint estimate, and sensitivity analyses are not reported in the registry record. The primary two-arm comparison is described as not estimable from the posted values, and no comparative confidence interval or p-value is reported.

The posted outcome is a biomarker measured after 12 weeks, not a long-term clinical endpoint. Participant-level observations and additional information about baseline values, follow-up completeness, and the precise calculation of change for rollover subjects are not reported. The registry does not give enough information to judge the extent of missingness or whether it was related to outcome values.

The adverse-event summaries have limited scope: they provide recorded counts and at-risk counts but not detailed event timing or longer-term follow-up. Death counts are not reported in the registry record. The registry also does not report a detailed statistical plan, multiplicity procedure, sample-size justification for the original study, or interim-analysis information. These limitations prevent fuller evaluation of the intended inferential framework and the robustness of the findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Raltegravir Augmentation on Persistent Central Nervous System (CNS) Immunoactivation in Treated HIV-1 Patients — NCT00672932.
• Registry record last updated 2013-07-05; status last verified 2013-05.
• Results first posted 2013-07-05.
• 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

NCT00672932 is a completed pilot study of raltegravir augmentation in treated people with HIV-1. The registry records randomized allocation, a parallel model, and no masking. Participants in the raltegravir group continued regular medications and received raltegravir 400mg twice daily by mouth; the comparator continued regular antiretroviral treatment without augmentation.

The primary outcome was change in CSF neopterin after 12 weeks, expressed in nmol/L. The posted mean changes were 0.1 for the raltegravir group and 0.3 for the no-augmented-treatment group, with SDs of 0.3 and 1.1. A two-arm comparison was not estimable from the posted values. The record notes crossover-like rollover of six participants and censoring of one raltegravir-group subject.

The registry reports zero serious and zero other adverse events in each listed at-risk group; deaths are not reported. The available summaries support descriptive interpretation but do not provide a precise comparative effect estimate or establish clinical outcomes.