A 24 Week, Multicenter, Open, Evaluation of the Clinical Effectiveness of the Once-daily 10 cm^2 Rivastigmine Patch Formulation in Patients With Probable Alzheimer's Disease (EXTRA): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A 24 Week, Multicenter, Open, Evaluation of the Clinical Effectiveness of the Once-daily 10 cm^2 Rivastigmine Patch Formulation in Patients With Probable Alzheimer's Disease (EXTRA) (NCT00622713), a na phase 4 study. The primary outcome is Percentage of Patients Who Achieved and Maintained the Maximum Dose of 10 cm^2 Rivastigmine Patch for at Least 8 Weeks During 24 Weeks Study.

2. Clinical Question

The study was designed to evaluate clinical effectiveness, tolerability, patient compliance, and caregiver satisfaction with the target patch in the community setting. The primary endpoint focuses specifically on reaching and remaining at the target dose for a minimum duration. It is therefore a measure of dose tolerance and persistence at that dose, rather than a direct measure of change in cognition or daily function.

The registry also names a physician-rated Clinical Global Impression of Change, changes in 4-IADL and MMSE scores, and change in the Mini-Zarit Inventory Score as secondary outcomes. Those measures address clinical status, instrumental activities of daily living, cognition, and caregiver burden. Their results are not reported in the registry record.

3. Trial Design

This was a completed, phase 4, multicenter, open, single-group study of rivastigmine transdermal patches. The study duration was 24 weeks, and the planned regimen targeted a once-daily patch size of 10 cm^2. The registry records enrollment of 228 and lists the study as completed. The start is recorded as 2008-01 and primary completion as 2009-01.

There was no randomized allocation or parallel control group: allocation is recorded as NA, masking as none, and the model as single group. Accordingly, the study describes outcomes observed among participants receiving the patch, rather than a randomized treatment contrast. Changes over time within a single group can be described, but without a control group they cannot isolate the effect of treatment from other explanations for change.

The primary endpoint was defined for an ITT population consisting of patients who received at least one dose of study medication and had at least one efficacy assessment. The enrollment figure and this analysis-population definition are different concepts; the registry record does not report the number meeting the ITT definition for the primary endpoint.

The registry lists five outcome measures, including the primary dose-tolerance measure and the secondary outcomes. It records 0 analyses. The statistical analysis plan, details of any interim analyses, and the rationale for the planned enrollment are not reported in the registry record. The sponsor is Novartis. The registry title identifies the study as EXTRA.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Intent-to-Treat (ITT) population was defined as all patients who were administered at least one dose of study medication and were assessed for efficacy at least 1 time.

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 Percentage of Patients Who Achieved and Maintained the Maximum Dose of 10 cm^2 Rivastigmine Patch for at Least 8 Weeks During 24 Weeks Study, measured over 24 weeks.

The primary endpoint is the percentage of patients who achieved and maintained the maximum dose of a 10 cm^2 rivastigmine patch for at least 8 weeks during the 24-week study. Its description frames the measure as the percentage able to tolerate and stay on the target patch size for that minimum period. The endpoint therefore combines reaching the target dose with maintaining it for a specified duration.

This kind of endpoint is used to describe whether participants can remain on a target regimen under the study conditions. It is distinct from an efficacy outcome such as a change in cognition or daily function: staying at a dose does not itself indicate the size or direction of a clinical change. Nor does this endpoint alone characterize every aspect of tolerability, patient experience, or adherence.

The registry record does not report the observed percentage or the number of patients who met the endpoint. It also does not report a confidence interval or a statistical test for this primary measure. Consequently, the endpoint's observed level and the precision of its estimate cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a percentage, so it is a binary outcome at the participant level: each participant either meets the stated target-dose and duration criterion or does not. General statistical interpretation of a binary percentage begins with the estimated proportion and its denominator. Both are important: the proportion describes the observed frequency, while the denominator indicates how much information supports that estimate. The registry defines an ITT population but does not report the primary endpoint's result or its analysis denominator.

What does a confidence interval add?

In general, a confidence interval communicates the precision of an estimate under a statistical model. A point estimate alone does not show how much uncertainty is associated with the observed data. For a proportion, the interval depends in part on the number of observations and the estimated event frequency. A narrow interval generally indicates greater precision than a wide one, but neither width nor statistical precision establishes clinical importance. The registry record does not report a confidence interval for the primary endpoint.

A hypothesis test and a confidence interval answer related but different questions. A test evaluates how compatible the data are with a specified null hypothesis under its assumptions. A confidence interval presents a range of parameter values compatible with the data and model at a stated confidence level. Neither method removes design limitations. In particular, statistical inference from a single group does not create a randomized comparison that the study did not have.

How does the design affect interpretation?

In a randomized comparison, allocation can support estimation of a treatment contrast by making groups comparable in expectation. This study has no randomized comparator: the allocation is recorded as NA and the model as single group. As a result, any observed outcome is a description of the treated study group. It cannot establish how outcomes would have differed for the same participants under an alternative condition. This limitation applies even if a within-group change were reported and statistically precise.

The study is open, with masking recorded as none. In general, lack of masking can matter when outcomes involve judgment, self-report, or knowledge of treatment. The physician-rated global-change outcome is one of the listed secondary measures; the record does not report a masking procedure or other safeguards that would permit further assessment of this issue. The registry also does not report the detailed methods used to analyze any outcome.

What does the ITT definition mean?

The registry defines the ITT population as patients who received at least one dose and were assessed for efficacy at least once. This is the record's stated analysis-population definition; it is not a report of the number included in an endpoint analysis. The registry does not report how participants with no post-baseline assessment, incomplete follow-up, or missing endpoint information were handled. It also does not report whether other analysis populations were used.

Missing observations can affect an estimate if the participants without recorded outcomes differ systematically from those with outcomes. General approaches to missing data make assumptions about why observations are missing and how that relates to the unobserved outcome. Without the amount, pattern, and handling of missing data, readers cannot assess the sensitivity of the primary estimate to these assumptions. Those details are not reported in the registry record.

What is multiplicity?

Multiplicity arises when several outcomes or hypotheses are tested: conducting multiple tests can increase the chance of at least one apparently notable result under a set of null hypotheses. Statistical plans sometimes identify a primary outcome, order tests, or adjust significance thresholds. The registry identifies a primary endpoint and lists secondary outcomes, but the multiplicity strategy and statistical analysis plan are not reported in the registry record. The record lists five outcome measures and 0 analyses; it does not report inferential results for the secondary measures.

General sample-size calculations depend on assumptions such as the target effect, variability or event frequency, significance level, power, and allocation. The registry's planning description specifies a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and detection of a stated fraction of the observed effect. It describes planning illustrations rather than the trial's own design. The single-group design does not have equal allocation between two arms. Sample-size illustrations are not observed power, and they do not substitute for estimates and uncertainty from actual trial data.

Over-dispersion is a general concern when the variability in data exceeds what a statistical model assumes, which can make standard errors too small and intervals too narrow. It is relevant in some clustered or count-data settings. The registry does not report an analysis model for the listed outcomes, so whether an over-dispersion adjustment was relevant or used is not reported in the registry record. No recalculated estimates are available from the reported details, and no adjusted or unadjusted analysis result is posted.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Rivastigmine Transdermal Patch")
n      <- c(218)
events <- c(154)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Rivastigmine Transdermal Patch  218  154  70.6  64.1  76.6  64.3  76.3  64.3  76.3

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary endpoint and lists secondary outcomes: physician-rated Clinical Global Impression of Change, mean change in 4-IADL, mean change in MMSE, and mean change in the Mini-Zarit Inventory Score. It lists five outcome measures in total and 0 analyses. The statistical analysis plan and any multiplicity strategy are not reported in the registry record. Without that information, readers cannot determine whether secondary outcomes were treated as exploratory, whether testing followed a planned order, or whether adjustments were used to account for multiple comparisons.

The registry's ITT definition includes patients who received at least one dose and had at least one efficacy assessment. It does not report the number included in the primary endpoint analysis, the number with missing endpoint data, or how missing data were handled. Details such as reasons for missing assessments, assumptions used in an analysis, and sensitivity analyses are not reported in the registry record. These omissions limit assessment of how representative the analyzed patients were of the population defined by the study.

The record also does not report whether analyses used additional populations, whether an interim analysis was conducted, or whether the primary analysis was adjusted for other variables. These details should not be inferred from the stated ITT definition or the list of outcomes. The posted record therefore supports description of the design and outcome definitions, but not reconstruction of the analysis plan or its implementation.

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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fall (2.3%), bradycardia (0.9%), lymphadenopathy (0.5%), acute coronary syndrome (0.5%), cardiac arrest (0.5%).

For the rivastigmine transdermal patch group, the registry lists 218 at risk for serious adverse events and a serious-event affected count of 21. It lists 218 at risk for other adverse events and an affected count of 13. These are descriptive counts for the study group, not a comparison with another treatment. The registry does not report deaths.

The listed serious adverse-event terms and percentages are FALL, 2.3%; BRADYCARDIA, 0.9%; LYMPHADENOPATHY, 0.5%; ACUTE CORONARY SYNDROME, 0.5%; CARDIAC ARREST, 0.5%; and NAUSEA, 0.5%. The denominator used for these term percentages is not reported in the registry record. The listed terms should not be added together to infer an overall rate: a participant may be represented in more than one event term, and the record does not explain the overlap or the event-counting convention.

In general, adverse-event counts describe events recorded under a study's definitions and observation period; they do not by themselves establish that treatment caused an event. The open, single-group design provides no concurrent comparison for judging relative event frequency. Further detail on event severity beyond the serious/other categories, exposure duration by participant, and attribution is not reported in the registry record.

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

The registry record defines a study of whether participants could achieve and maintain the target 10 cm^2 rivastigmine patch for at least 8 weeks during a 24-week study. It also identifies secondary measures of global clinical change, daily function, cognition, and caregiver burden. However, the primary endpoint result and secondary outcome results are not reported in the registry record. The intended clinical question is clear, but the record does not provide the outcome estimates needed to answer it.

Even if a primary percentage were available, it would describe the observed proportion in this open, single-group study. It would not, by itself, show how that proportion compares with a different treatment or with no treatment. The design has no randomized control group, so a causal treatment contrast cannot be estimated from the stated design. The absence of a reported confidence interval also means the precision of the primary estimate cannot be assessed.

The safety counts and listed serious-event terms provide descriptive information about events recorded in the study group. They do not establish whether an event was caused by the patch or whether its frequency differs from another treatment. The registry does not report deaths, the denominator for the listed term percentages, or a comparative safety analysis.

These limitations do not make the study question meaningless. They define the scope of interpretation: the registry gives the design, intended outcomes, and some safety counts, but not the efficacy estimates, uncertainty intervals, or analysis details needed for a fuller statistical assessment. No conclusion about clinical benefit or lack of benefit can be drawn from outcome definitions alone.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of the distinction between a single-group tolerability outcome and a comparative treatment effect. Its primary endpoint asks whether participants achieved and stayed at a target dose for a minimum duration. That is a practical, participant-level outcome, but it is not a randomized comparison and is not itself a direct measure of clinical change.

The registry also makes the analysis-population definition explicit: patients had to receive at least one dose and have at least one efficacy assessment. That definition helps readers understand who was intended to contribute to efficacy analyses, while the absent endpoint denominator and missing-data details show why an analysis-population label alone does not complete the statistical account.

The study lists outcomes across several domains, including cognition, daily function, physician-rated change, and caregiver burden. Considering multiple outcomes raises questions about which results were primary, how secondary tests were interpreted, and whether multiplicity was addressed. The registry identifies the primary outcome but does not report the analysis plan or multiplicity strategy.

Finally, the record illustrates that a completed study status is not the same as a complete statistical report. The design and outcome definitions are available, along with selected adverse-event counts, but the primary result and uncertainty are not reported in the registry record. A reader can assess the limits imposed by the design and reporting, but cannot infer the missing efficacy results.

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 main trial-specific limitation is the absence of the primary endpoint result. The registry defines the percentage endpoint but does not report its estimate, analysis denominator, confidence interval, or test result. Without these, neither the observed frequency nor its precision can be assessed. Results for the listed secondary outcomes are also not reported in the registry record.

The open, single-group design has no randomized comparator. It can describe outcomes in the treated group but cannot estimate a contrast against another treatment. The lack of masking may be relevant to outcomes involving assessment or report, including the physician-rated global-change measure; further safeguards are not reported in the registry record.

The record defines an ITT population but does not report how many patients met that definition for the primary outcome. It does not describe missing data, withdrawals, endpoint analysis methods, or sensitivity analyses. The statistical analysis plan, multiplicity strategy, sample-size justification, and interim analyses are not reported in the registry record. The absence of these details prevents a reader from assessing whether the analyses followed a prespecified approach.

Safety reporting is also limited for interpretation: the record lists affected counts and selected serious-event terms, but deaths are not reported, the denominator for term percentages is not reported, and there is no comparison group. Event attribution and additional details about exposure and event handling are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A 24 Week, Multicenter, Open, Evaluation of the Clinical Effectiveness of the Once-daily 10 cm^2 Rivastigmine Patch Formulation in Patients With Probable Alzheimer's Disease (EXTRA) — NCT00622713.
• Registry record last updated 2011-07-26; status last verified 2011-06.
• Results first posted 2011-07-26.
• 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

NCT00622713 is a completed, phase 4, multicenter, open, single-group study of once-daily rivastigmine transdermal patches in probable Alzheimer's disease. The target patch size was 10 cm^2, and the study lasted 24 weeks. The registry records enrollment of 228, a start of 2008-01, and primary completion of 2009-01.

The primary endpoint was the percentage of patients who achieved and maintained the target dose for at least 8 weeks. The registry defines an ITT population, lists secondary outcomes, and reports selected adverse-event counts. The primary and secondary outcome results, analysis details, and deaths are not reported in the registry record. With no randomized comparator, the design is descriptive rather than a randomized treatment comparison.