Studying the Effects of Antihypertensives on Individuals at Risk for Alzheimer's: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Studying the Effects of Antihypertensives on Individuals at Risk for Alzheimer's (NCT00980785), a randomized phase 4 study. The primary outcome is Change in Cerebrospinal Fluid (CSF) Amyloid Beta-42 (Aβ42) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo.

2. Clinical Question

The study’s stated biological question is narrower than whether ramipril prevents Alzheimer’s disease. It asks about change in a biomarker over a four-month period, alongside measures of vascular function. The registry summary presents these measures as part of research intended to inform future studies; it does not state that this trial directly tests prevention of memory loss or Alzheimer’s disease.

3. Trial Design

This was a Phase 4, randomized, double-masked, parallel-group trial sponsored by the University of Wisconsin, Madison. The registry record lists an enrollment of 14 and identifies ramipril and placebo as the interventions. The placebo arm is described as receiving matching placebo, while the active arm is described as receiving ramipril 5mg/day. The record does not report the allocation ratio or describe the randomization and masking procedures in detail.

The listed primary endpoint is change in cerebrospinal fluid amyloid beta-42 (Aβ42) between baseline and month 4, measured in pg/ml. The primary endpoint description states that cerebrospinal fluid was taken at the baseline visit and month 4, and that measurements were made by Dr. Henrik Zetterberg’s laboratory. The record lists three secondary outcomes: change in cerebrospinal fluid ACE levels, change in flow-mediated vasodilation, and change in augmentation index, each between baseline and month 4.

The registry record gives a start date of 2009-04-09 and a primary completion date of 2011-07-26. Its status is completed. It lists four outcome measures and eight analyses, although details of every analysis are not present in the available posted results. The record does not report a statistical analysis plan, a sample-size justification, interim analyses, or detailed definitions of the analysis populations. Those omissions limit what can be concluded about how the trial was designed to handle analysis choices or incomplete observations.

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

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 Cerebrospinal Fluid (CSF) Amyloid Beta-42 (Aβ42) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo, measured over Baseline to 4 months.

The primary endpoint is change in cerebrospinal fluid amyloid beta-42 (Aβ42) from baseline to month 4, expressed in pg/ml. Cerebrospinal fluid is the liquid around the brain and spinal cord. The registry summary describes beta-amyloid as a substance found in the brain and this fluid, and explains that high amounts may be associated with greater risk of Alzheimer’s disease. The endpoint therefore assesses a biomarker over the study period rather than the occurrence of Alzheimer’s disease itself.

Change from baseline is used to describe how a measurement differs between the start and follow-up assessment. Comparing change between randomized groups is intended to assess whether the observed pattern differs between participants assigned ramipril and those assigned placebo. The record’s endpoint description specifies measurements at baseline and month 4, with analysis by a laboratory named in the record.

A biomarker can be relevant to a biological hypothesis without being equivalent to a clinical outcome. The posted endpoint does not directly measure whether participants developed Alzheimer’s disease, experienced memory loss, or had a change in daily functioning. The registry record does not report evidence that a change in this marker predicts a later clinical outcome in this study. As a result, the endpoint should be read as a short-term biomarker measure, not as a direct measure of disease prevention or patient benefit.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is continuous: it is a measured quantity expressed in pg/ml, and the record describes the arm summaries as means with standard deviations. A mean is the arithmetic average of observations. A standard deviation describes how spread out observations are around that mean. General statistical interpretation: the mean gives a compact description of the center of the observed values, while the standard deviation gives information about their variability. Neither one alone gives the uncertainty of a between-arm effect.

What does a change score represent?

The primary endpoint is defined as change from baseline to month 4. In general, a change score describes the difference between a participant’s follow-up measurement and baseline measurement. A group mean change summarizes those participant-level changes. To answer a randomized comparison question, the key quantity is typically the contrast between the groups’ changes, together with an estimate of its uncertainty. The posted arm summaries do not supply an estimable recalculated two-arm contrast for this endpoint.

What does the reported test tell readers?

The registry record labels the reported method Wilcoxon (Mann-Whitney). In general, this is a rank-based method for comparing observations across two groups. It uses the ordering of values rather than relying on a comparison of means alone. The method’s result is not automatically a test of a difference in means; its interpretation depends on the assumptions and the pattern of the group distributions. Here, the record also labels the reported parameter “Mean Difference (Final Values),” so the relationship between the named test and the stated parameter is not fully explained in the registry record. The record does not report additional analysis details that resolve this distinction.

The registry record reports p = 0.836 and no confidence interval. In general, a p-value measures the compatibility of the data with a null hypothesis under the test’s assumptions. It does not express the probability that a treatment effect is absent. A confidence interval, when reported, gives a range of values compatible with the data and statistical procedure, and conveys uncertainty about an estimated effect. No interval is posted for the reported analyses, and a two-arm recalculation is not estimable from the available summary values. Consequently, the precision of a between-arm effect cannot be described from these results.

Why does variation matter?

The arm-level standard deviations are large relative to the scale of the reported means, but no new comparison should be inferred from that observation alone. In general, greater variability makes it harder to estimate a group contrast precisely, especially when there are few observations. A distribution may also include unusual values or be asymmetric. Rank-based methods can be useful in some settings where distributional assumptions for mean-based methods are questionable, but the choice and interpretation of a test should follow the planned analysis and endpoint structure. The statistical plan and rationale for this test are not reported in the registry record.

Over-dispersion is a general concept in which observed variability exceeds what a chosen model expects. When present, it can make standard errors too small if a model fails to account for the extra variation. The registry record does not report a model-based analysis or evidence of over-dispersion for this endpoint, so this is general context rather than a claim about this trial. More broadly, variability and sample size affect precision, while the reported group summaries do not reveal the full distribution of individual changes.

How should planning illustrations be read?

General sample-size planning uses assumptions about the effect to detect, variability, significance level, allocation, and statistical method. The registry record’s planning description specifies a two-sided significance level of 0.05, equal allocation, and a normal approximation; it describes the target effect as a stated fraction of the observed effect. These are planning illustrations based on the observed effect, not evidence about the trial’s original design. They should not be interpreted as observed power. No numeric planning estimates are stated in this explanation, and the record does not report the original sample-size justification or design assumptions.

Randomization is intended in general to make treatment groups comparable in expectation, while masking is intended to reduce the influence of treatment knowledge on care or measurement. These design features do not remove uncertainty, guarantee balance in a small trial, or replace clear reporting of analysis methods. The record identifies randomized, double-masked, parallel allocation, but does not describe the implementation details needed to assess those procedures further.

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("Placebo", "Active")
n   <- c(6, 8)
m   <- c(-22.5, -31.71)
sp  <- c(78.7, 90.6)
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  Placebo  6  -22.500  78.700  -105.091  60.091
CARM  Active  8  -31.710  90.600  -107.453  44.033

11. Analyses Reported by the Sponsor

The registry record reports the sponsor’s analyses using the method label Wilcoxon (Mann-Whitney), the parameter label “Mean Difference (Final Values),” and p = 0.836. It also posts the arm-level means and standard deviations for change from baseline. These items do not form a complete reported between-arm estimate with a confidence interval: the posted analyses are listed for individual groups, and the required two-arm comparison is not estimable from the available summary statistics.

Accordingly, there is no recalculated two-arm result to compare directly with the sponsor’s reported analysis. The registry record does not provide enough detail to reconcile the analysis labels with the arm-level change summaries or to derive an uncertainty interval for the contrast. The reported p-value remains the available inferential result in the registry record, but it should be read alongside the absence of a clearly reported between-arm effect estimate and confidence interval. The record does not flag a discrepancy between a sponsor result and a recalculation.

12. Multiplicity, Missing Data and Analysis Populations

The registry record lists four outcome measures and eight analyses. The primary endpoint is change in cerebrospinal fluid Aβ42 from baseline to month 4. Three secondary outcomes are listed: change in cerebrospinal fluid ACE levels, flow-mediated vasodilation, and augmentation index. The record does not report how the analyses were grouped into the total number of analyses or which tests were planned for each outcome.

When several outcomes or analyses are examined, the chance of at least one apparently notable result can increase. Statistical approaches to multiplicity may adjust how evidence is evaluated or prioritize a primary outcome. This is general statistical context. The registry record does not report a multiplicity adjustment, a hierarchy for secondary outcomes, or a prespecified strategy for interpreting multiple analyses. The absence of that information does not establish that no such plan existed; it means the plan is not reported in the registry record.

The record lists an enrollment of 14, with 6 participants in the placebo arm and 8 in the active arm for the posted primary endpoint summaries. It does not report whether every randomized participant had both required cerebrospinal fluid measurements, how missing measurements were handled, or whether any participants were excluded from the analysis. The analysis population and missing-data methods are not reported in the registry record. No imputation approach, sensitivity analysis, or participant flow details are stated in the registry entries.

These gaps matter because the analysis population and handling of incomplete observations can affect estimated results and their uncertainty. The available record also does not report an interim analysis plan, a statistical analysis plan, or the original sample-size justification. Those methods should not be inferred from the posted p-value or from planning illustrations based on the observed effect.

13. 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.

The posted safety figures report zero serious adverse events among 6 participants at risk in the placebo group and zero among 8 participants at risk in the active group. The record also reports zero other adverse events among 6 and 8 participants at risk, respectively. These figures describe the adverse-event counts recorded for the stated groups; they do not show that the possibility of adverse events is absent.

The record does not list any top serious adverse-event terms. Death counts are not reported in the registry record. The safety information is limited to the counts and group sizes posted; details such as event definitions, collection procedures, duration of safety follow-up, and participant-level event information are not reported in the registry record. With a small number of participants, zero recorded events should be interpreted as an observation in this trial rather than as a precise estimate of safety in a broader population.

These safety counts are separate from the primary biomarker outcome. They do not establish whether ramipril is safe or unsafe, and they do not determine the meaning of the cerebrospinal fluid result. They are descriptive registry figures, subject to the reporting details available in the record.

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

The primary endpoint concerns change in cerebrospinal fluid Aβ42 from baseline to month 4. The registry record reports mean changes and standard deviations for each arm, as well as a p-value of 0.836 for analyses labelled Wilcoxon (Mann-Whitney). It does not provide an estimable recalculated two-arm comparison or a confidence interval for the treatment-group contrast. The posted data therefore do not give a precise estimate of how the groups differed on the primary endpoint.

The endpoint is a biomarker, not a direct measure of Alzheimer’s disease onset or memory loss. Although the registry summary explains why beta-amyloid is of interest, this trial’s posted primary outcome cannot establish whether ramipril prevents Alzheimer’s disease, changes future risk, or improves memory and thinking. The study also lists vascular-function and other biomarker outcomes, but their results are not included in the registry entries for this analysis.

In general, a non-small p-value does not prove that groups are equivalent or that an effect is absent. It can reflect many factors, including imprecision, variability, and the amount of information available. The small enrolled sample and missing between-arm estimate limit the conclusions that can be drawn from the posted result. Without an uncertainty interval and fuller reporting of the analysis population and missing data, the range of effects compatible with the data cannot be assessed from the registry record.

The most defensible reading is therefore descriptive: the record reports arm-level biomarker changes and a sponsor-reported p-value, but does not provide enough information for a precise independent estimate of the randomized comparison. The result should not be extended beyond the measured biomarker and follow-up period.

15. Why This Trial Matters Statistically

This trial illustrates a common distinction in clinical research: a biologically motivated biomarker is not the same as a clinical outcome. The registry record focuses on cerebrospinal fluid Aβ42 over baseline to month 4, while its summary describes broader interest in Alzheimer’s disease risk, memory, and thinking. Keeping those questions separate prevents a short-term biomarker result from being interpreted as evidence about disease prevention.

It also shows why an arm-level mean and a p-value are not a substitute for a clearly reported treatment-group contrast. The record gives group means, standard deviations, and a p-value, but not an estimable recalculated two-arm effect with a confidence interval. Without that contrast and its precision, readers cannot tell from the posted summaries how large a difference between groups is compatible with the data. This is especially important in a trial enrolling 14 participants.

Finally, the record illustrates the value of reporting an analysis plan, outcome hierarchy, analysis population, and missing-data handling. Such information helps readers understand how results were selected and interpreted, particularly when several outcomes and analyses are listed. These details are not reported in the registry record, so conclusions must remain bounded by the posted summaries and their limitations.

16. 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 main limitation for interpreting the primary endpoint is that the registry record does not provide an estimable two-arm comparison from the posted summary statistics. It reports means and standard deviations by arm and a p-value, but no confidence interval for a between-arm effect. The analysis entries are associated with individual groups, and the record does not explain how the method label and parameter label relate to the primary endpoint’s change-score summaries.

The enrollment was 14, with arm-level endpoint summaries based on 6 participants in the placebo arm and 8 in the active arm. The record does not report whether those were all randomized participants or how incomplete baseline or month 4 measurements were handled. It also does not report the analysis population, missing-data methods, or sensitivity analyses. These omissions prevent assessment of whether the posted summaries represent all randomized participants or a subset.

The record lists multiple outcomes and analyses but does not report a multiplicity strategy, the full analysis plan, or the original sample-size justification. It also does not report interim analyses. The stated planning illustrations are based on the observed effect and should not be confused with the trial’s original design or with observed power. The short timeframe and biomarker focus further restrict interpretation: the primary outcome is change in Aβ42 through month 4, not a direct clinical outcome of Alzheimer’s disease onset or memory loss.

Safety reporting is also limited to posted counts; event definitions, collection details, and death counts are not reported in the registry record. These trial-specific reporting gaps mean that the results should be treated as limited descriptive evidence rather than a complete account of efficacy, safety, or longer-term outcomes.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Studying the Effects of Antihypertensives on Individuals at Risk for Alzheimer's — NCT00980785.
• Registry record last updated 2020-08-25; status last verified 2020-08.
• Results first posted 2020-08-25.
• 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.

20. Record Summary

NCT00980785 is a completed Phase 4 randomized, double-masked, parallel-group study sponsored by the University of Wisconsin, Madison. The registry record lists 14 participants and compares ramipril 5mg/day with matching placebo. The primary endpoint is change in cerebrospinal fluid Aβ42 from baseline to month 4, measured in pg/ml. The record also lists secondary outcomes involving cerebrospinal fluid ACE levels, flow-mediated vasodilation, and augmentation index.

For the primary endpoint, arm-level means and standard deviations are posted for 6 placebo participants and 8 active-arm participants. The registry reports p = 0.836 but no confidence interval, and a recalculated two-arm comparison is not estimable from the posted summaries. The record does not report a statistical analysis plan, analysis-population details, or missing-data methods. The biomarker result does not directly answer whether ramipril prevents Alzheimer’s disease or affects memory.