Effects of a Combined Transcranial Magnetic Stimulation (TMS) and Cognitive Training in Alzheimer Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effects of a Combined Transcranial Magnetic Stimulation (TMS) and Cognitive Training in Alzheimer Patients (NCT01504958), a randomized na study. The primary outcome is Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog).

2. Clinical Question

3. Trial Design

The registry describes a randomized, parallel-group study with triple masking and a placebo-controlled design. Its official title identifies it as a single-center study. The sponsor was Beth Israel Deaconess Medical Center, and the study status is completed. The record lists a start of 2010-12 and primary completion of 2015-05. The phase is listed as NA.

Participants were assigned to one of three listed conditions: active rTMS with real cognitive training, sham rTMS with real cognitive training, or sham rTMS with sham cognitive training. The stimulation descriptions identify the same set of brain regions across the conditions; the distinction is active versus sham stimulation. The cognitive training condition also differs between the two sham-stimulation groups. All participants were therefore not assigned to a single simple active-versus-control contrast.

Enrollment is reported as 22. For the primary outcome, the registry lists 10 participants in the active rTMS with real cognitive training group, 5 in the sham rTMS with real cognitive training group, and 6 in the sham rTMS with sham cognitive training group. Those outcome group counts should be read as posted, rather than assumed to represent every enrolled participant or the analysis population. The record does not explain how participants were allocated, how the masking was implemented, or whether all randomized participants were included in the outcome analysis.

The listed secondary outcomes are Clinical Global Impression of Change and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory. The registry record does not report additional details on the randomization procedure, masking roles, treatment adherence, or a prespecified statistical analysis plan.

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.

Population: Total number analyzed: 21 (1 enrolled was excluded from analysis) Real/Real: 10 Real/Sham: 5 Sham/Sham: 6

6. Primary Endpoint

The registry lists the primary outcome as Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog), measured over Pre treatment; 1 month post treatment.

The primary endpoint is the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), recorded as percentage change from baseline to 1 month post treatment. The measure is intended to assess severity across important symptoms of Alzheimer’s disease, including memory, language, praxis, and attention. The registry describes a total scoring range of 0-70, with 0 representing the least impairment and 70 the most severe impairment.

The posted outcome is a change score, calculated in the registry description as the 1 month score minus the baseline score. Under that definition, a positive change represents improvement. This direction is important because the interpretation of a change score depends on how it is defined; it should not be assumed that a positive value means worsening merely because some scales use higher scores to represent greater impairment.

A continuous endpoint such as this can be summarized using a mean and a measure of spread. The group means describe average changes, while the standard deviations describe variability among participant outcomes. The registry reports means and standard deviations for the listed groups. It does not report a comparative confidence interval or p-value for the primary outcome, so the posted summaries alone do not establish the precision or statistical significance of differences between groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a continuous outcome, the mean is the arithmetic average of the recorded values in a group. Here, the outcome is defined as percentage change in ADAS-Cog from baseline to 1 month post treatment, with positive change designated as improvement. The mean therefore describes the average change under that scoring convention. It does not describe every participant’s outcome, and it does not by itself quantify the difference between randomized groups.

What does the standard deviation describe?

The standard deviation summarizes how dispersed participant values are around their group mean. A smaller standard deviation indicates that observations are more concentrated around that mean; a larger one indicates more spread. It is a description of participant-level variability, not a measure of uncertainty in a treatment comparison. That distinction is important: the standard deviation concerns the distribution of observations, whereas a confidence interval for a mean or contrast concerns the precision of an estimated quantity.

The posted standard deviations are 3.6 in the active rTMS with real cognitive training group, 5.45 in the sham rTMS with real cognitive training group, and 2.91 in the sham rTMS with sham cognitive training group. The group counts differ, so the estimates also rest on different amounts of outcome information. The registry does not post confidence intervals for the means or for comparisons among these groups.

Why is a comparison needed?

Random assignment is intended to make assigned groups comparable on average, including with respect to factors that were not measured. But a randomized design does not mean that observed group averages will be identical apart from an intervention effect. Random variation can produce differences between group summaries. A comparative estimate, together with an uncertainty interval or an appropriate test, is needed to assess how compatible the observed contrast is with a range of possible underlying differences.

A confidence interval is a statistical range that conveys uncertainty around an estimated quantity under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, though interpretation also depends on the outcome and the clinical question. A p-value measures how unusual data at least as incompatible with a specified null hypothesis would be under the test’s assumptions. Neither quantity is posted for the primary group comparison in this registry record. Their absence means that the descriptive means and standard deviations cannot substitute for an inferential analysis.

How does the group structure affect interpretation?

The study has three listed treatment conditions rather than a single active and a single control condition. Active rTMS with real cognitive training and sham rTMS with real cognitive training differ in stimulation condition while sharing active training. The sham rTMS with sham cognitive training condition differs from the active-training sham condition in training, and from the active-rTMS condition in both listed components. Those comparisons answer different questions. A statistical plan would ordinarily specify which contrast is primary and how the multiple comparisons are handled. Such a plan is not reported in the registry record.

The study is described as parallel-group, meaning the listed conditions are separate groups rather than a sequence in which each participant receives each condition. This matters because the group summaries represent different participants. The registry identifies randomization and triple masking, but does not report implementation details, such as the allocation procedure, who was masked, or whether masking was assessed.

What does the planning illustration mean?

The record describes planning illustrations using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes the effect to detect as a stated fraction of the observed effect. In general, a sample-size calculation combines an assumed effect, outcome variability, a significance criterion, and a desired probability of detecting the assumed effect if it exists. Changing the assumed effect or other inputs can change the resulting planning estimate.

These calculations are planning illustrations, not observed power. Observed power is not a substitute for a confidence interval or a treatment-effect estimate. The illustrations also do not show what assumptions the investigators used when designing the completed trial. The registry record does not report a sample-size justification, and it does not post the comparative analyses needed to evaluate the primary result.

Why can variability matter?

Standard statistical methods often rely on assumptions about the distribution of outcomes or the behavior of estimates. In general, over-dispersion means that observed variability is greater than a model assumes. If a model understates variability, uncertainty can be understated and tests or intervals can be misleading. This is a general statistical concern, not a finding reported for this study. The registry summaries do not provide enough information to assess distributional assumptions, outliers, or whether an alternative model was used.

In this record, the appropriate reading is therefore limited to what is reported: group means, standard deviations, and outcome counts. A full evaluation would require details of the planned analysis, participant-level or sufficiently detailed summary data, and comparative estimates with uncertainty. Those details are not reported in the registry record.

10. Confidence Intervals for Each Arm

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

R code and output

arm <- c("Active rTMS With Real Cognitive Training", "Sham rTMS With Real Cognitive Training", "Sham rTMS With Sham Cognitive Training")
n   <- c(10, 5, 6)
m   <- c(1.79, -0.2, -0.66)
sp  <- c(3.6, 5.45, 2.91)
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  Active rTMS With Real Cognitive Training  10  1.790  3.600  -0.785  4.365
CARM  Sham rTMS With Real Cognitive Training  5  -0.200  5.450  -6.967  6.567
CARM  Sham rTMS With Sham Cognitive Training  6  -0.660  2.910  -3.714  2.394

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary ADAS-Cog outcome and two secondary outcomes: Clinical Global Impression of Change and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory. When a study examines multiple outcomes or multiple contrasts, the chance of at least one apparently notable result can increase if each is tested separately without accounting for the multiplicity. Statistical approaches can address this issue, but the choice depends on which outcomes and comparisons were planned and on the analysis strategy.

The registry record does not report a multiplicity adjustment, a hierarchy of outcomes, or a prespecified method for choosing among comparisons. It also reports zero analyses for the posted outcome results, so there is no set of inferential results from which to determine whether multiplicity was addressed in practice.

Missing-data handling and analysis populations are not reported in the registry record. In particular, the record does not state whether analyses followed intention-to-treat principles, how missing outcome measurements were handled, or whether participants were excluded from the primary analysis. Enrollment is reported as 22, while the primary outcome groups list counts of 10, 5, and 6. The registry does not explain the relationship between those figures. It would be inappropriate to infer a reason for the difference or to assume a particular missing-data method.

The registry record also does not report a statistical analysis plan, interim analyses, or the sample-size justification used for the trial. The planning illustration described in the record is not evidence about the investigators’ actual design assumptions or analysis decisions.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: rib fracture (16.7%).

The safety record reports serious adverse events separately from other adverse events. For active rTMS with real cognitive training, serious adverse events affected 0 of 10 participants at risk; other adverse events affected 5 of 10. For sham rTMS with real cognitive training, serious adverse events affected 0 of 6 participants at risk; other adverse events affected 5 of 6. For sham rTMS with sham cognitive training, serious adverse events affected 1 of 6 participants at risk; other adverse events affected 0 of 6.

Rib fracture is listed as the top serious adverse event term at 16.7%. The registry record does not establish from these summaries whether an event was caused by an intervention. Counts in small groups can be sensitive to individual events, and these data should be read as event reporting rather than as a comparative safety analysis. The record does not report deaths; the death fields are not reported in the registry record.

The serious-event count and the count of participants affected by other adverse events are distinct categories. They should not be added or treated as if they represented the same outcome. The registry record does not provide further event detail or a statistical comparison of adverse-event rates.

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

The posted results describe average change in ADAS-Cog for participants in each listed group, alongside the standard deviation and the number of participants reported for that outcome. Under the registry’s scoring convention, the mean of 1.79 for active rTMS with real cognitive training is in the improvement direction, while the means of -0.2 and -0.66 for the sham-stimulation groups are in the negative direction. These figures are descriptive; they are not a reported test of whether the groups differ.

The data do not establish how precise the group contrasts are because the registry record does not provide comparative confidence intervals or p-values. Nor do the group means alone determine whether a difference is attributable to rTMS, cognitive training, their combination, or other sources of variation. The treatment conditions permit several distinct comparisons, and the record does not report a statistical analysis specifying or estimating those contrasts.

The trial’s completed status and randomized, masked design are relevant features of the study, but they do not replace results from a reported analysis. Likewise, the sample-size planning illustration is not evidence of observed power and does not establish that the trial could reliably detect a particular effect.

The appropriate conclusion is limited to the registry’s descriptive summaries and safety counts. The record does not report a formal comparative result for the primary endpoint, does not describe how missing outcome data were handled, and does not state the analysis population. No conclusion about treatment efficacy or lack of efficacy should be drawn from these summary values alone.

14. Why This Trial Matters Statistically

This trial illustrates why reading a group mean is only the beginning of a statistical interpretation. The primary outcome is continuous, and the registry reports both mean change and standard deviation. Those summaries convey the average direction of change and the spread of participant outcomes, but they are not a substitute for a between-group estimate with uncertainty.

The multi-group design also makes the clinical question more specific than a simple active-versus-placebo contrast. One comparison keeps cognitive training active while changing the stimulation condition; other comparisons also differ in training condition. Without a reported analysis plan and comparative results, the reader cannot tell which contrast was prioritized or how the separate components were evaluated.

The record’s planning illustration offers a further statistical distinction: sample-size assumptions are not the same as trial results. A planning estimate based on an observed effect does not supply an analysis, establish observed power, or reveal the design rationale used by investigators. Likewise, enrollment and outcome counts need to be read as separate reported quantities unless the registry explains their relationship.

Finally, the safety summaries show why event categories and denominators matter. Serious adverse events and other adverse events are reported separately, and counts should be interpreted with the relevant group at-risk figures. These descriptive safety results do not constitute a formal comparison. Taken together, the study is a useful example of the difference between a randomized design and a fully reported statistical result: design features frame interpretation, while estimates and their uncertainty are needed to evaluate comparative evidence.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record leaves several limitations specific to interpreting this study. Although the title identifies a randomized, double-blind, placebo-controlled study and the record lists triple masking, it does not describe the randomization procedure, allocation concealment, who was masked, or how masking was maintained. These details cannot be inferred from the design labels alone.

The primary endpoint is described as percentage change, but the record does not explain the exact calculation underlying that term beyond defining the change as the 1 month score minus baseline. It does not report participant-level data, comparative estimates, confidence intervals, or p-values. As a result, the precision and statistical significance of group differences cannot be evaluated from the posted summaries.

Outcome counts are listed as 10, 5, and 6, while total enrollment is 22. The record does not explain these counts, whether all randomized participants contributed outcome data, or how any missing observations were handled. The analysis population is not reported in the registry record.

The registry lists two secondary outcomes but does not report their results in the registry record for the primary endpoint, nor does it report a multiplicity strategy. It also does not state a sample-size justification or provide a statistical analysis plan. The study is identified as single-center, so the record does not establish how well results would generalize beyond its study setting. These reporting gaps limit what can be concluded from the posted material, without establishing that any particular method was or was not used.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Effects of a Combined Transcranial Magnetic Stimulation (TMS) and Cognitive Training in Alzheimer Patients — NCT01504958.
• Registry record last updated 2017-07-02; status last verified 2017-06.
• Results first posted 2017-06-05.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT01504958 is a completed, randomized, parallel-group study of rTMS and cognitive training in people with Alzheimer’s disease. The record describes triple masking, a single-center setting, and enrollment of 22 participants. The primary outcome is ADAS-Cog percentage change from baseline to 1 month post treatment, with positive change defined as improvement.

Three groups are listed: active rTMS with real cognitive training, sham rTMS with real cognitive training, and sham rTMS with sham cognitive training. Their posted primary outcome means are 1.79, -0.2, and -0.66, with standard deviations of 3.6, 5.45, and 2.91. The registry reports zero analyses for these results, and comparative estimates with uncertainty are not reported. Two secondary outcomes are listed: Clinical Global Impression of Change and ADCS-ADL.

Safety summaries report serious and other adverse events separately. The record does not report a formal comparative efficacy or safety analysis, the analysis population, missing-data methods, or the trial’s sample-size justification.