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 A Study of the Neurological Effects of Adding Maraviroc to HAART Regimen in Patients With HIV (HANDmac) (NCT01449006), a randomized phase 4 study. The primary outcome is Change in Neurocognitive Functioning.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01449006 |
| Phase | Phase 4 |
| Condition | Human Immunodeficiency Virus (HIV), HIV Associated Neurocognitive Disorders (HAND) |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 19 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Bruce Brew |
| Results posted | Yes |
2. Clinical Question
Population
People with HIV-associated neurocognitive disorders whose HIV was virally suppressed in blood and cerebrospinal fluid while receiving HAART. The study description refers to recent progression of HAND validated by neuropsychological assessment. The registry record reports total enrollment of 19.
Intervention
Participants continued their usual prescribed HAART regimen and added maraviroc. The record says maraviroc was prescribed according to its Product Information Sheet, with consideration given to background therapy.
Comparator
Participants continued their usual prescribed HAART regimen without the addition of maraviroc. The trial was randomized and unblinded, with a parallel-group design.
Primary question
Did intensifying HAART with maraviroc change overall neurocognitive performance over baseline, 6-months and 12-months, as measured by the global neurocognitive z-score? Numerical estimates of the primary outcome and the between-group comparison are not reported in the registry record, so the direction and precision of any difference cannot be assessed from this record.
The clinical question concerns a specific setting: cognitive impairment despite viral suppression in both blood and cerebrospinal fluid. It is not a comparison of maraviroc with no antiretroviral treatment. Both groups remained on HAART; the randomized contrast was the addition of maraviroc to the existing regimen versus continuing that regimen alone.
3. Trial Design
HANDmac is recorded as a phase 4, randomized, unblinded, parallel-group clinical trial. The registry lists total enrollment as 19 and status as completed. The recorded start is 2011-10 and primary completion is 2014-09. The sponsor is Bruce Brew.
Participants assigned to the standard-of-care group remained on their usual prescribed HAART regimen. Participants assigned to the maraviroc group also continued their usual regimen and added maraviroc. Because masking was absent, participants and study personnel were not blinded to treatment assignment. The registry record does not report further details about allocation concealment, the randomization procedure, or steps used to reduce bias in outcome assessment.
The planned clinical comparison described in the study summary was intensification with maraviroc versus no intensification. The summary states a target of 70 patients in each group, while the registry records total enrollment of 19. These figures describe the stated target and recorded enrollment; they do not establish how many participants contributed data to each primary-outcome analysis. The record lists safety populations of 8 in the standard-of-care group and 9 in the maraviroc group, but the primary analysis population is described separately.
The primary outcome was change in neurocognitive functioning, assessed at baseline, 6-months and 12-months. The registry also names secondary outcomes concerning CSF neopterin concentration and MRS cerebral metabolite ratios in basal ganglia and frontal white matter. Numerical results for the primary outcome are not reported in the registry record. Details of the full protocol, recruitment flow, and reasons for the difference between the target and recorded enrollment 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: Two enrolled participants failed screening (1 HCV+, 1 not cognitively impaired)
Overall Study
| Stage | Standard of Care HAART Regimen | Maraviroc |
|---|---|---|
| STARTED | 8 | 9 |
| COMPLETED | 5 | 9 |
| NOT COMPLETED | 3 | 0 |
Reasons for not completing this period:
| Reason | Standard of Care HAART Regimen | Maraviroc |
|---|---|---|
| Lost to Follow-up | 1 | 0 |
| Withdrawal by Subject | 1 | 0 |
| Protocol Violation | 1 | 0 |
Analysis population for the primary outcome, as defined in the registry: Modified intent-to-treat analysis. All randomized participants were included except for n=2 controls with baseline data only (1 lost to follow-up, 1 withdrew before 6-months) and n=1 control where a protocol violation was noted (randomized without conclusive evidence of neurocognitive impairment - see participant flow section).
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: Data presented reflect baseline demographic and clinical characteristics for participants included in the primary analysis.
| Characteristic | Unit | Standard of Care HAART Regimen | Maraviroc | Total |
|---|---|---|---|---|
| Participants analysed | 5 | 9 | 14 | |
| Age, Continuous | years | 60 (SD 9.4) | 52.2 (SD 3.7) | 55 (SD 7.1) |
| Sex: Female, Male: Female | Participants | 0 | 0 | 0 |
| Sex: Female, Male: Male | Participants | 5 | 9 | 14 |
| Race/Ethnicity, Customized: Caucasian | participants | 5 | 9 | 14 |
| Region of Enrollment: Australia | participants | 5 | 9 | 14 |
| Education | years | 11.6 (SD 2.3) | 12.3 (SD 2.8) | 12.1 (SD 2.6) |
| Premorbid intelligence quotient (IQ) | units on a scale | 104.4 (SD 18.9) | 102.2 (SD 16.3) | 103 (SD 16.6) |
| Nadir cluster of differentiation 4 (CD4) | cells/mm3 | 310 (51 to 390) | 150 (33.5 to 253.5) | 174.5 (36.8 to 312.5) |
| Current CD4 | cells/mm3 | 980 (548 to 1041) | 499 (338 to 827.5) | 625.5 (400.8 to 979.3) |
| HAND Status: Asymptomatic Neurocognitive Impairment (ANI) | participants | 1 | 1 | 2 |
| HAND Status: Mild Neurocognitive Disorder (MND) | participants | 2 | 8 | 10 |
| HAND Status: HIV-Associated Dementia (HAD) | participants | 2 | 0 | 2 |
6. Primary Endpoint
The registry lists the primary outcome as Change in Neurocognitive Functioning, measured over Baseline, 6-months and 12-months.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | Standard Error |
| Unit | Global Neurocognitive Z-Score |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is change in overall neurocognitive performance, represented by a global neurocognitive z-score at baseline, 6-months and 12-months. The score combines results from a 5-domain brief neurocognitive battery. Individual raw test scores were converted to age-corrected z-scores, and the subtest scores were averaged to form a composite for each participant. The record describes the z-score scale as having M=0 and SD=1.
Standardizing and combining test results provides a common summary across the battery rather than treating each test as a separate primary measure. A composite can capture broad performance across cognitive domains, while also concealing variation in particular domains. The registry record defines lower, negative scores as indicating greater cognitive impairment. That direction is important when interpreting any change: the meaning of a higher or lower value depends on the scale and on which time points or groups are being compared.
The registry reports the endpoint parameter as a least-squares mean with standard error as the dispersion measure. However, the numerical estimates, the estimated treatment contrast, and its uncertainty are not reported in the registry record. The endpoint definition alone therefore does not establish whether neurocognitive scores changed, how the groups compared, or how precisely those quantities were estimated.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The record establishes the question and outcome definition, but it does not report the numerical primary-outcome findings. In particular, it does not give the least-squares mean estimates at the measured time points, a between-group contrast, a confidence interval, or a p-value for the primary comparison. Without those results, the direction, magnitude, and statistical precision of the observed cognitive changes cannot be described.
The reported total enrollment is 19. The planned target in the study summary was 70 patients in each group. The record does not explain the shortfall from that target, and enrollment alone does not show how many participants contributed outcome data at each time point. The modified intent-to-treat description says that randomized participants were included except for n=2 controls with baseline data only and n=1 control with a noted protocol violation. This makes the analysis population important to understanding any outcome estimate, but numerical primary-outcome results for that population are not reported in the registry record.
General statistical interpretation: an estimated difference is more informative when accompanied by an interval that shows the range of values compatible with the data under the analysis assumptions. A p-value, when reported, addresses compatibility with a specified null model; it is not a measure of effect size or of clinical importance. Neither an interval nor a p-value can be assessed from the primary-outcome information in this record.
The available safety counts describe participants recorded as at risk in each group. The registry lists no serious adverse events among 8 participants in the standard-of-care group and none among 9 in the maraviroc group. Other adverse events are listed for 2 of 8 and 5 of 9, respectively. Those counts should not be treated as a complete benefit-risk assessment: event definitions, timing, severity details, and exposure duration are not reported in the registry record. Death counts are also not reported.
Accordingly, the registry record supports a description of the randomized comparison, planned cognitive outcome, and stated analysis population, but not a conclusion about the size or direction of the primary treatment contrast. The numerical results needed to evaluate the primary question are not reported in the registry record.
9. Statistical Methods Explained
What does the primary outcome summarize?
The global neurocognitive z-score combines performance across a 5-domain brief neurocognitive battery. The registry describes converting raw scores to age-corrected z-scores and averaging individual subtest scores. This creates a composite measure intended to represent overall performance rather than a single test result. The scale is defined so that lower, negative scores indicate greater cognitive impairment. The registry record does not report the numerical values needed to see how the composite changed in either group.
What is a least-squares mean?
General statistical explanation: a least-squares mean is a model-based estimate of an average. Unlike a simple arithmetic average, it can reflect the structure and adjustments of the statistical model. The registry identifies the primary outcome parameter as a least-squares mean, but the particular model, covariates, and estimation details are not reported in the registry record. It is therefore not possible to determine from the record which adjustments were applied or how the repeated measurements were handled.
What does the standard error convey?
The registry names standard error as the dispersion measure for the primary outcome. General statistical explanation: a standard error describes the estimated uncertainty of a statistic, such as a mean, across repeated samples under a statistical model. It is not the same as the spread of individual participants' scores. A standard error can help show how precisely a mean has been estimated, but the numerical standard errors are not reported in the registry record.
Why do repeated measurements matter?
The primary outcome is scheduled at baseline, 6-months and 12-months. General statistical explanation: measurements from the same participant are related, so analyses of change over time commonly account for that within-participant relationship. The choice of model can affect estimates and uncertainty, especially when participants have incomplete follow-up. The registry record does not report the specific longitudinal model, assumptions about missing measurements, or any sensitivity analyses. No particular approach should be inferred from the endpoint label alone.
How should a confidence interval be read?
General statistical explanation: a confidence interval expresses uncertainty around an estimate under the assumptions of the analysis. A narrower interval indicates greater precision than a wider interval, while the interval's location helps show which effects are compatible with the data. No confidence interval for the primary outcome is reported in the registry record. Consequently, the precision of any estimated change or treatment contrast cannot be assessed.
What do the planning calculations represent?
The sample-size assumptions describe a planning illustration based on the observed effect, not the trial's own design. They specify a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. These calculations are planning illustrations, not observed power and not evidence that the trial had a particular probability of detecting an effect. The registry record does not report the trial's own sample-size justification. The numerical planning estimates are not reported in the registry record.
General statistical explanation: planning estimates depend on assumptions about the target effect, variability, significance threshold, allocation, and analysis. If the observed effect used as a reference is uncertain, planning based on it is uncertain too. Such calculations should not be confused with the results of a completed trial or with an estimate of what the trial actually demonstrated.
What cannot be inferred from analysis labels?
The record reports 13 analyses and 4 outcome measures, but does not provide the numerical primary-outcome results or a full statistical analysis plan. The number of analyses alone does not identify which comparisons were prespecified, how each was tested, or how multiplicity was handled. The record does not report whether interim analyses occurred, the model's assumptions, or any diagnostics. These details are necessary for a full appraisal of the inferential procedure and are not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The primary outcome is measured at baseline, 6-months and 12-months, and the record lists 4 outcome measures and 13 analyses. Multiple outcomes, time points, or contrasts can create multiplicity: the more statistical questions examined, the greater the chance that at least one result may appear notable by chance when each is considered separately. General statistical explanation: methods such as prespecifying a primary contrast or adjusting significance thresholds can address some multiplicity concerns. The registry record does not report whether such methods were planned or used, which analyses were prespecified, or whether any interim analyses occurred.
The stated analysis population is modified intent-to-treat. The record says all randomized participants were included except for n=2 controls with baseline data only, one lost to follow-up and one who withdrew before 6-months, and n=1 control with a protocol violation because randomization occurred without conclusive evidence of neurocognitive impairment. The record does not give the number contributing data at each follow-up time or explain the handling of missing measurements in the statistical model. The specific missing-data assumptions and sensitivity analyses are not reported in the registry record.
These details matter because excluding participants or relying on incomplete follow-up can affect which population an estimate describes and how uncertain it is. The record's modified intent-to-treat label does not, by itself, identify the exact model or establish that missingness was addressed without bias. A full statistical analysis plan, including multiplicity procedures and missing-data methods, is not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Standard of Care HAART Regimen | 0 | 8 | 0.0% |
| Maraviroc | 0 | 9 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Standard of Care HAART Regimen | 2 of 8 |
| Maraviroc | 5 of 9 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Standard of Care HAART Regimen | Maraviroc |
|---|---|---|---|
| Cerebrospinal fluid leakage | Nervous system disorders | 1 of 8 | 1 of 9 |
| Upper respiratory infection | Infections and infestations | 0 of 8 | 2 of 9 |
| Skin infection | Skin and subcutaneous tissue disorders | 0 of 8 | 2 of 9 |
| Blurred vision | Eye disorders | 1 of 8 | 0 of 9 |
| Renal calculi | Renal and urinary disorders | 1 of 8 | 0 of 9 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 8 | 1 of 9 |
| Fall | Injury, poisoning and procedural complications | 0 of 8 | 1 of 9 |
The registry lists serious adverse events for 8 participants at risk in the standard-of-care group and 9 at risk in the maraviroc group. It records 0 serious adverse events in each group. Other adverse events are listed for 2 of 8 participants in the standard-of-care group and 5 of 9 in the maraviroc group. These are event counts as recorded, not estimates of comparative safety.
The record does not provide descriptions of the other adverse events, their severity, timing, duration, or relationship to treatment. It also does not report the period over which participants were monitored for these events or the rules used to classify them. Death counts are not reported in the registry record, and no serious adverse event terms are listed. Without event-level detail and follow-up information, the counts cannot show whether groups differed in types of events or in their timing.
General statistical explanation: zero observed events does not establish that the underlying risk is zero. In a trial with limited enrollment, event counts can be imprecise, and comparison requires appropriate uncertainty estimates as well as clear definitions and comparable observation periods. Those additional details are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
This trial addresses a focused question: whether adding maraviroc to an existing HAART regimen changes overall neurocognitive performance in virally suppressed people with HAND. Its randomized, parallel-group design establishes the intended comparison between continued usual HAART alone and usual HAART with maraviroc. The primary outcome is a composite z-score measured at baseline, 6-months and 12-months, with lower, negative scores indicating greater impairment.
The registry record does not report the numerical primary-outcome estimates or the treatment contrast. It therefore does not establish the direction or size of the observed difference, nor its precision. The record also does not report the confidence interval, p-value, detailed model, or clinical threshold for interpreting a change in the composite score. The outcome definition is not a substitute for the outcome results.
The listed safety counts show no recorded serious adverse events among the participants at risk in either group, alongside other adverse events in both groups. These counts alone do not establish comparative safety, particularly because event descriptions, observation periods, and death counts are not reported in the registry record.
General statistical explanation: a trial result is best understood by considering the estimated effect, its uncertainty, the analysis population, and the outcome's meaning together. A statistical estimate does not automatically establish clinical importance, and absence of a reported result cannot be interpreted as evidence of no effect. In this case, the registry record supplies a study framework and outcome definition but not the numerical primary findings needed to assess the central comparison.
The trial's recorded enrollment was 19, whereas its study summary stated a target of 70 patients in each group. The record does not explain this difference. It also does not report enough detail to determine how missing data, multiple analyses, or other protocol features affected the primary estimate. Any conclusions beyond the design and recorded counts would go beyond what is reported in the registry record.
13. Why This Trial Matters Statistically
Statistically, HANDmac illustrates why a clear endpoint definition and numerical outcome results are both essential. The registry explains how the global neurocognitive z-score was constructed and indicates the assessment times, but it does not report the estimates or uncertainty for the primary comparison. Without these, readers cannot assess the size, direction, or precision of the result.
The distinction between a planned enrollment target and recorded enrollment is also important. The study summary stated a target of 70 patients in each group, while total enrollment is recorded as 19. This makes the analysis population and uncertainty especially relevant, yet the record does not report the primary estimates, follow-up counts at each time, or detailed missing-data methods. No conclusion about the adequacy of the original design or the reason for the enrollment difference can be drawn from the registry record.
The endpoint is a composite, which offers a broad summary of neurocognitive performance but may not reveal how individual domains behaved. The registry lists secondary measures, but their numerical results are not reported in the registry record. Further, the record lists 13 analyses without describing prespecification or multiplicity procedures. Those omissions limit assessment of how the multiple statistical questions were interpreted.
General statistical explanation: strong interpretation requires alignment among the research question, analysis population, model, estimate, and uncertainty. When key elements are not reported, transparent description of what is known—and what remains unavailable—is part of statistical reporting. Here, the design and endpoint are specified, while the numerical findings and several analysis details are not reported in the registry record.
14. 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.
Several limitations specific to this record constrain interpretation. Total enrollment is recorded as 19, while the study summary describes a target of 70 patients in each group. The registry does not explain the difference, report recruitment flow, or provide primary-outcome estimates. It is therefore not possible to assess whether the observed data were sufficiently precise for the intended comparison.
The trial was unblinded. The registry does not report how neuropsychological assessment was protected from knowledge of treatment assignment, whether outcome assessors were blinded, or what allocation concealment procedures were used. Those details are not reported in the registry record.
The modified intent-to-treat description excludes n=2 controls with baseline data only and n=1 control with a protocol violation. The record does not report the number of participants with outcome measurements at each follow-up, the specific missing-data approach, or sensitivity analyses. The reported endpoint uses repeated measurements, but the longitudinal model and its assumptions are not described.
The primary results are absent, including estimates, uncertainty intervals, and p-values. Although the record lists 13 analyses and 4 outcome measures, it does not describe prespecification or multiplicity handling. The sample-size illustration is based on the observed effect, but its numerical planning estimates are not reported in the registry record and it is not the trial's own design justification. Safety-event definitions and observation periods are also not reported. These limitations prevent a full assessment of efficacy, precision, and safety from the registry record alone.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of the Neurological Effects of Adding Maraviroc to HAART Regimen in Patients With HIV (HANDmac) — NCT01449006.
- Registry record last updated 2019-02-27; status last verified 2019-02.
- Results first posted 2016-05-20.
- 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.
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18. Record Summary
HANDmac is a completed, randomized, unblinded, parallel-group phase 4 trial of adding maraviroc to usual HAART for people with HIV-associated neurocognitive disorders who were virally suppressed in blood and CSF. Recorded enrollment was 19; the study summary stated a target of 70 patients in each group.
The primary outcome was change in global neurocognitive z-score at baseline, 6-months and 12-months. Lower, negative scores indicate greater cognitive impairment. The modified intent-to-treat description excludes n=2 controls with baseline data only and n=1 control with a protocol violation.
Numerical primary-outcome results and detailed statistical methods are not reported in the registry record. Serious adverse events are recorded as 0 among 8 at risk in the standard-of-care group and 0 among 9 at risk in the maraviroc group; other adverse events are recorded for 2 of 8 and 5 of 9, respectively. Death counts are not reported in the registry record.