ACE Inhibitors to Decrease Lymphoid Fibrosis in Antiretroviral-Treated, HIV-infected Patients: A Pilot Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for ACE Inhibitors to Decrease Lymphoid Fibrosis in Antiretroviral-Treated, HIV-infected Patients: A Pilot Study (NCT01535235), a randomized phase 4 study. The primary outcome is Change in HIV RNA (Copies/Million Rectal Cells).

2. Clinical Question

3. Trial Design

This was a completed, randomized, parallel-group, placebo-controlled Phase 4 pilot study sponsored by the University of California, San Francisco. The registry records enrollment of 31 and study dates from 2012-02 to primary completion in 2014-12. The two groups were ACE inhibitor and placebo; the active intervention is identified as lisinopril. Participants were antiretroviral-treated people with HIV.

The registry describes quadruple masking. It does not specify which participants, clinicians, assessors, or other roles were masked, nor does it explain the masking procedures. Allocation is recorded as randomized, but the sequence-generation method, concealment procedures, and any stratification factors are not reported in the registry record.

The primary outcome was change in HIV RNA, measured in copies per million rectal cells, from baseline in GALT over 22 weeks. The registry describes the outcome summary as a median with inter-quartile range, although numerical inter-quartile ranges are not included in the posted arm results. HIV DNA in rectal cells was listed as a secondary outcome. The registry lists two outcome measures and two analyses, but detailed results for the secondary outcome are not available in the information.

The posted primary endpoint includes 15 ACE inhibitor participants and 12 placebo participants. The registry notes that three placebo participants did not have sufficient cells for analysis for one time point. Safety summaries use at-risk counts of 16 and 15, respectively. These differing counts describe the outcome and safety records; the registry does not provide a full accounting of participant flow or the analysis population definitions.

The study is explicitly characterized as a pilot and proof-of-concept investigation. Its brief description gives a broader biological rationale, but the registry record does not report a formal sample-size justification, a detailed protocol for the primary analysis, or planned interim analyses.

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: The trial over enrolled by one individual as one participant discontinued the study after enrollment due to an adverse event.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Three participants in the placebo group did not have sufficient cells for analysis for one of the time points.

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 HIV RNA (Copies/Million Rectal Cells), measured over 22 weeks.

The primary endpoint is change from baseline in HIV RNA measured in GALT at 22 weeks. The measurement is expressed as copies per million rectal cells, using rectal tissue as the source of cells. The outcome therefore describes a tissue-based HIV RNA measure over time, rather than a count of participants with a clinical event or a direct measurement of lymphoid fibrosis.

Change from baseline is used to describe how the measured quantity differs from each participant's starting value. In general, a change endpoint can focus the comparison on movement over the study period rather than solely on the endpoint value. In this trial, the posted arm summaries are medians: 1.1 for the ACE inhibitor group and -0.2 for placebo. The registry identifies inter-quartile range as the intended dispersion measure, but does not give numerical inter-quartile ranges in the posted arm results. It also lists bounds of -74.5 to 62.5 and -55.8 to 96.4, respectively, without identifying the type of interval those bounds represent.

The endpoint is relevant to the study's interest in HIV-related processes in lymphoid tissue, but it should not be treated as a direct assay of fibrosis or as a complete measure of immune response or latent reservoir. Those broader aims appear in the study rationale; the primary posted endpoint is change in HIV RNA in rectal cells.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary comparison uses the Wilcoxon (Mann-Whitney) method. This is a rank-based method for comparing observations between two independent groups. Rather than requiring a normal distribution and directly comparing arithmetic means, it uses the ordering of the observations. In general, rank-based methods can be useful when outcome distributions are skewed or contain influential values, but the registry does not state why this method was selected for this trial.

What does the rank-based comparison test?

In general, the Mann-Whitney test assesses whether observations in one group tend to be higher or lower than observations in the other group. Its interpretation is not automatically a test of equal medians. A median comparison and a rank-based comparison are closely related only under additional assumptions about the shapes and spread of the group distributions. The registry reports group medians but does not provide the participant-level distributions needed to assess those features.

The outcome summary is described as a median with inter-quartile range. The median is the middle value in an ordered set of observations. The inter-quartile range describes the interval between the middle half of the observations and is a measure of spread. In the posted results, the median values are given, but the numerical inter-quartile ranges are not. Consequently, the medians alone do not show how variable the changes were within either arm.

How should the reported p-value be read?

In general, a p-value is calculated under a null hypothesis and a statistical model or test procedure. It expresses how unusual data at least as incompatible with that null model would be if the null model held. It is not the probability that the null hypothesis is correct, and it does not indicate the size of a treatment effect. The registry reports p = 0.63 for the Wilcoxon (Mann-Whitney) comparison. The analysis record does not include a between-group effect estimate or a confidence interval, so the magnitude and precision of the group contrast are not fully described by the reported test.

Confidence intervals, in general, describe uncertainty around an estimated quantity under a specified procedure. They help distinguish a precise estimate from one compatible with a broad range of values. The primary arm records list lower and upper bounds, but the registry does not identify what those bounds represent. They should therefore not be described as confidence intervals on the basis of this record alone. No confidence interval for the between-group comparison is posted.

What do the medians and missing measurements imply?

In general, a change-from-baseline endpoint compares follow-up measurements with baseline measurements. Its interpretation can depend on how change is defined, whether paired measurements are available, and how missing values are handled. The record identifies the endpoint as change from baseline and notes insufficient cells for three placebo participants at one time point. It does not detail the change calculation, the handling of missing values, or whether all randomized participants were included in the primary analysis.

Missingness can affect an analysis if the chance of a missing measurement is related to the outcome or to participant characteristics. General approaches include analyzing available observations, imputing missing values, or using models that incorporate repeated measurements; the registry does not report which approach was used. Without the analysis plan and participant-level data, the impact of missing tissue samples cannot be determined from the posted summary.

Why might dispersion matter?

In general, over-dispersion means that observations vary more than a statistical model assumes. When a model underestimates variability, standard errors can be too small and statistical evidence can appear stronger than warranted. The reported primary test is rank-based, and the registry does not identify a distributional model or report an over-dispersion assessment. The broader principle remains relevant: the spread and shape of observed data matter when judging how informative a group summary is. Numerical inter-quartile ranges and participant-level values are not posted, limiting direct assessment of those features.

The study's pilot designation and small posted analysis groups mean that estimates may be imprecise. In general, a non-significant result from a small study does not establish no effect. Precision is most directly assessed with an interval estimate, but the comparison's interval is not reported in the registry record. The registry also does not report the detailed statistical analysis plan, assumptions checks, or any interim-analysis procedures, so these should not be inferred from the test name alone.

10. Analyses Reported by the Sponsor

The sponsor's posted analysis for the primary outcome is the Wilcoxon (Mann-Whitney) comparison, with p = 0.63. No separate recalculated between-group effect estimate or interval is available in the registry record for this endpoint. The comparison fields report the test and p-value but do not report an effect estimate, its confidence interval, or additional distributional details.

The arm-level medians are 1.1 for ACE inhibitor and -0.2 for placebo, and the record lists bounds for each arm. Those arm summaries do not by themselves provide a between-group estimate, and the bounds are not identified as a particular type of interval. The recorded p-value is therefore the main posted inferential result for the group comparison.

The registry record does not flag a discrepancy between a sponsor analysis and a recalculation. The comparison is reported as a Wilcoxon (Mann-Whitney) test, and the available record does not supply enough detail to reproduce that test from summary statistics alone. Any recalculation based only on arm summaries would not replace the sponsor's analysis and could not reconstruct the rank-based test without participant-level data.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists HIV RNA change as the primary outcome and HIV DNA change in rectal cells as a secondary outcome. It reports two outcome measures and two analyses. A single primary comparison is posted, but the registry record does not describe a multiplicity adjustment or explain how inference across multiple outcomes was planned. When several outcomes or analyses are examined, the chance of at least one apparently unusual result can increase; in general, a prespecified hierarchy or adjustment can help address that issue. The record does not say whether such procedures were used.

Detailed secondary outcome results are not included in the information reported for this trial. The registry record therefore does not support a joint interpretation of the primary and secondary outcomes, nor does it show whether all planned outcomes were reported. It also does not report whether any additional exploratory analyses were conducted.

For the primary endpoint, the record states that three placebo participants did not have sufficient cells for analysis for one time point. The primary outcome counts are 15 for ACE inhibitor and 12 for placebo, compared with enrollment of 31. The registry does not provide a complete flow of participants from enrollment through follow-up and analysis, or explain the disposition of every participant. It does not report the missing-data method or whether the analysis used an intention-to-treat population, a per-protocol population, or another definition.

In general, missing outcome data can reduce precision and can introduce bias if the probability of having an observed measurement is related to the outcome. A missing-data plan might specify assumptions and sensitivity analyses, but neither is reported in the registry record. The reason given for the three unavailable placebo measurements is insufficient cells at one time point; the record does not say whether the same issue affected other measurements or how incomplete participant data were handled in the group comparison.

The analysis plan, sample-size justification, and interim-analysis procedures are not reported in the registry record. The pilot designation alone does not establish what hypotheses, outcomes, or analysis choices were prespecified. These omissions limit assessment of selective reporting, multiplicity, and the robustness of the primary comparison.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety summaries list serious adverse events in 0 of 16 participants at risk in the ACE inhibitor group and 0 of 15 at risk in the placebo group. These are the posted serious-event counts. The record lists no serious adverse event terms. The deaths field is not populated; deaths are not reported in the registry record.

For other, non-serious adverse events, the registry reports 1 of 16 participants at risk in the ACE inhibitor group and 0 of 15 in placebo. These counts describe what was recorded in the safety summary. They do not establish whether an event was caused by the intervention, and the record does not provide event descriptions or further detail about severity or timing.

In general, absence of reported serious events in a small study does not establish absence of risk. Safety counts are interpreted in light of the number of participants observed, follow-up duration, event definitions, and completeness of reporting. This study's primary endpoint timeframe is 22 weeks, but the safety summary does not specify a separate duration or provide detailed monitoring information. The counts should therefore be read as the registry's recorded safety results, not as a comprehensive estimate of safety.

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

The posted results describe a small randomized comparison of lisinopril and placebo in antiretroviral-treated participants with HIV. For the primary outcome, the median change in HIV RNA in GALT was 1.1 copies per million rectal cells in the ACE inhibitor group and -0.2 copies per million rectal cells in the placebo group. The reported Wilcoxon (Mann-Whitney) comparison has p = 0.63. These data do not show a statistically significant group difference by the reported test, but they do not establish that the groups are equivalent or that no effect exists.

The study's biological rationale extends beyond the primary endpoint. The brief description discusses lymphoid fibrosis, HIV-specific host immune responses, and the latent reservoir. The reported primary outcome is change in HIV RNA in rectal cells; it is not a direct measure of fibrosis, and the posted primary result alone cannot establish what happened to immune responses or the latent reservoir. HIV DNA in rectal cells is listed as a secondary outcome, but detailed secondary results are not reported in the registry record.

The result is also limited by incomplete reporting of uncertainty and analysis details. Numerical inter-quartile ranges are not posted, the type of the arm-level bounds is not specified, and no between-group effect estimate or confidence interval is reported. The registry notes three placebo participants without sufficient cells at one time point and does not describe the complete analysis population or missing-data method. These gaps limit assessment of precision and sensitivity to missing observations.

In general, a pilot study can inform the feasibility and estimation of outcomes for future research, but its result should not be treated as a definitive test of a broad mechanism. The registry does not report a sample-size justification or a threshold defining a meaningful difference. The primary comparison should therefore be interpreted as a limited statistical result for the measured endpoint and period, rather than as a definitive conclusion about ACE inhibition, fibrosis, or HIV-related processes overall.

14. Why This Trial Matters Statistically

This trial illustrates why the scientific motivation and the measured endpoint need to be kept distinct. The study rationale concerns lymphoid fibrosis and possible downstream effects on immune responses and the latent reservoir. The posted primary comparison instead measures change in HIV RNA in GALT, expressed per million rectal cells. A result for this endpoint can inform the stated tissue-based virologic question, but it is not an interchangeable measure of every biological process named in the rationale.

It also illustrates the difference between arm summaries and a group comparison. The medians describe each arm's center, while the Wilcoxon (Mann-Whitney) test evaluates the relative ordering of observations across groups. Without numerical dispersion summaries or participant-level distributions, the medians and p-value provide only a partial account of the observed data. A p-value alone does not communicate the size or precision of a group contrast.

The missing tissue measurements are another important statistical feature. The registry notes insufficient cells for three placebo participants at one time point, while the available primary outcome counts differ between arms. Transparent reporting of participant flow, missing-data handling, and analysis populations is important because each affects how a result can be interpreted and reproduced. Those details are not reported in the registry record.

Finally, the pilot context matters. A pilot result may be useful for understanding the observed endpoint and for informing further investigation, but a non-significant test in a small analysis cannot establish equivalence or rule out effects that the study could not estimate precisely. In this record, the comparison's interval estimate and sample-size justification are not reported. Careful interpretation therefore depends on acknowledging both the measured result and the limits of the posted statistical information.

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 primary outcome data are incomplete for some participants. The registry states that three placebo participants did not have sufficient cells for analysis for one time point, and the posted primary outcome includes 15 ACE inhibitor participants and 12 placebo participants. The record does not provide a full flow diagram or explain the analysis population, missing-data procedure, or sensitivity analyses. It is therefore not possible to determine from the registry record how missing observations affected the comparison.

The primary arm summaries do not include numerical inter-quartile ranges, although the outcome is described as a median with inter-quartile range. The record also lists lower and upper bounds for each arm without naming the interval type. No between-group effect estimate or confidence interval is posted. This limits evaluation of the magnitude and precision of the comparison beyond the reported p-value.

The primary outcome is HIV RNA change in rectal cells at 22 weeks. It is not a direct measure of lymphoid fibrosis, and the results reported for this endpoint cannot alone resolve the broader scientific questions about fibrosis, immune response, or the latent reservoir. The secondary outcome, HIV DNA change in rectal cells, is listed, but detailed results are not reported in the registry record.

The registry describes the trial as a pilot but does not report the sample-size justification, detailed statistical analysis plan, interim-analysis procedures, or multiplicity approach. It also does not give the rationale for choosing the Wilcoxon (Mann-Whitney) method, information about assumption checks, or enough detail to reproduce the analysis from the posted summaries. Quadruple masking is recorded, but the masked roles and procedures are not described. These limitations constrain assessment of design, analysis, and reporting choices.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: ACE Inhibitors to Decrease Lymphoid Fibrosis in Antiretroviral-Treated, HIV-infected Patients: A Pilot Study — NCT01535235.
• Registry record last updated 2016-06-16; status last verified 2016-05.
• Results first posted 2016-03-31.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

This completed Phase 4 randomized, quadruple-masked, parallel-group pilot study compared lisinopril with placebo in antiretroviral-treated participants with HIV. Enrollment was 31, and primary completion was recorded in 2014-12. The sponsor was the University of California, San Francisco.

The primary endpoint was change in HIV RNA in GALT, measured in copies per million rectal cells over 22 weeks. Posted medians were 1.1 for ACE inhibitor and -0.2 for placebo. The reported Wilcoxon (Mann-Whitney) comparison was p = 0.63. The registry notes insufficient cells at one time point for three placebo participants. HIV DNA in rectal cells was listed as a secondary outcome, but detailed secondary results are not reported in the registry record.

The posted result is a limited comparison for the stated tissue-based endpoint. The registry does not report a between-group effect estimate or interval, numerical inter-quartile ranges, the detailed missing-data method, or the sample-size justification. The result does not directly measure lymphoid fibrosis or establish conclusions about the broader biological aims.