Non-invasive Intermittent Theta Burst Stimulation of the Dorsolateral Prefrontal Cortex in Functional Movement Disorders: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Non-invasive Intermittent Theta Burst Stimulation of the Dorsolateral Prefrontal Cortex in Functional Movement Disorders (NCT05155059), a randomized na study. The primary outcome is Change in S-FMDRS at 1 Month After Real iTBS vs Sham iTBS.

2. Clinical Question

The trial asks whether active intermittent theta burst stimulation of the dorsolateral prefrontal cortex is associated with a different change in functional movement disorder symptoms than sham stimulation. The primary comparison is the change in Simplified Functional Movement Disorders Rating Scale (S-FMDRS) scores at 1 month after stimulation. The registry describes the intervention as non-invasive transcranial magnetic stimulation and the control as sham stimulation using a sham coil.

The registry also lists secondary assessments of S-FMDRS at 2 and 6 months, Hospital Anxiety and Depression Scale scores at 1, 2, and 6 months, and Clinical Global Impression at 1, 2, and 6 months. Those listed outcomes give the study a broader set of questions about symptoms and related assessments over follow-up, but the posted primary result concerns the 1-month S-FMDRS comparison.

3. Trial Design

The registry describes a randomized, double-masked, parallel-group trial sponsored by the National Institutes of Health Clinical Center (CC). Its official title identifies it as a Phase II trial, while the registry phase field is listed as NA. The listed enrollment is 25, and the record status is active, not recruiting. The registry dates the study start to 2022-05-06 and primary completion to 2025-04-25.

Participants are assigned to active TMS or sham TMS. The active arm receives stimulation through an active coil; the sham arm uses a dummy coil that does not deliver stimulation. The design description says the initial visit includes a neurological examination, questionnaires, a urine test, and brain MRI, including responses to images while in the scanner. TMS is to begin within 2 weeks of baseline. The intervention schedule is described as 5 daily sessions, each with three 3-minute cycles and 20-minute breaks between cycles.

Follow-up assessments are planned at 1 month, 2 months, and 6 months after the last day of TMS. These visits can be in person or virtual and include evaluation of FMD symptoms and health questionnaires. The registry lists 11 participants in the Treatment arm and 12 in the Control arm for the posted primary outcome. The reason these outcome counts differ from the listed enrollment is not reported in the registry record.

The posted primary measure is change in S-FMDRS at 1 month after iTBS, expressed as percentage change of scores on a scale. The primary result is reported as a least-squares mean with standard error for each arm. The registry lists 5 outcome measures and 3 secondary outcomes, but the detailed posted results described in the primary comparison concern the 1-month measure.

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: Twenty-five participants consented to participate; one failed screening, and one was withdrawn prior to randomization due to newly identified exclusionary finding.

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 S-FMDRS at 1 Month After Real iTBS vs Sham iTBS, measured over 1 month after iTBS.

The primary endpoint is change in the Simplified Functional Movement Disorders Rating Scale (S-FMDRS) at 1 month after iTBS. The registry describes the outcome in terms of percentage change of scores on a scale. The scale evaluates abnormal movements in 7 body regions, as well as gait and speech. For each body region, symptom severity and duration are rated, and the ratings are added to form a total score. The total can range from 0 to 68, with higher scores representing worse outcomes.

A change score focuses on how a participant’s measured symptoms differ from baseline by the specified follow-up assessment. Comparing changes between randomized groups can distinguish the observed course in the active arm from the observed course in the sham arm, while retaining the trial’s assigned comparison. The registry’s stated primary time point is 1 month after iTBS; it should not be conflated with the separately listed 2- and 6-month S-FMDRS assessments.

Using a rating scale provides a structured way to summarize several movement-related features in a single outcome. That summary is useful for a group comparison, but it does not show every component separately. The posted primary result therefore speaks to the scale’s overall score change, not to a specific body region, gait, or speech component on its own.

7. Results Posted in the Registry

• Treatment: mean -48.08 versus -39.47 on control; difference -8.61 (95% CI -42.94 to 25.72), standardized effect d = -0.21; z-test p = 0.623.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it is a score-based percentage change, and the registry reports a mean for each randomized arm. For continuous outcomes, a mean summarizes the group’s average measured value. A mean difference compares the two group means on the same scale. Here, the reported comparison is the Treatment arm mean minus the Control arm mean, yielding -8.61 percentage points. The negative sign indicates that the Treatment arm estimate is lower on the change scale; because these are negative changes, it is more negative than the Control estimate.

What does a least-squares mean represent?

A least-squares mean is a model-based estimate of a group mean. It can account for terms in a statistical model, unlike a simple arithmetic mean calculated directly from all observed scores. The registry identifies the primary parameter as a least-squares mean but does not report the model specification, the variables included, or the exact method used to estimate it. It is therefore appropriate to describe the posted values as least-squares means without inferring which adjustments or modeling choices produced them.

The arm-specific estimates are -48.08 for Treatment and -39.47 for Control. Their reported standard errors are 13.3 and 11.4. A standard error quantifies uncertainty in an estimated mean under the analysis model. It is distinct from a standard deviation, which describes variation among individual observations. The registry reports standard error as the dispersion measure for the arm results; it does not report individual-level outcome distributions in this result.

How should the mean difference be read?

The mean difference puts the arm comparison on the endpoint’s scale. The estimate of -8.61 is the observed contrast between the two posted least-squares means, not a difference in raw S-FMDRS points. The endpoint is specified as percentage change of scores on a scale, so the comparison is expressed in percentage points. The confidence interval from -42.94 to 25.72 describes uncertainty around this contrast. Since it extends across zero, the posted result does not rule out no mean difference, and it also permits estimates on either side of zero.

The registry reports an unadjusted p-value of 0.623. In general, a p-value evaluates how unusual data at least as discordant with a null model would be if that model and the test assumptions held. It does not say how likely the null hypothesis is, does not measure the probability that chance alone produced the result, and does not quantify clinical importance. Because the test details and any multiplicity strategy are not reported in the registry record, the p-value should be read as the unadjusted value reported for this comparison rather than as evidence about an undocumented analysis plan.

Why does uncertainty matter?

Any estimate from a sample has uncertainty. A confidence interval gives a range of values that are reasonably compatible with the data and the method used to construct it. In general, a wider interval indicates less precision. The interval for the primary mean difference is wide in relation to its point estimate and includes both negative and positive values. The data therefore do not pin down the direction or magnitude of the between-group difference with precision. A point estimate is one value within that uncertain range, not a guarantee that the underlying effect equals that value.

The registry’s sample-size illustrations use the observed effect as a planning reference and show hypothetical participant counts under stated assumptions. Such calculations are prospective planning illustrations, not a measure of the probability that the completed study found an effect. They also do not replace the trial’s actual analysis or explain why the trial enrolled its listed number of participants.

What is not specified about the analysis?

The registry record does not report the primary analysis model, its covariates, the precise construction of the change measure, or the handling of repeated observations. It does not report whether the primary comparison was adjusted for baseline score, how missing outcome values were handled, or which analysis population was used. The registry identifies randomization and double masking, but those design labels do not by themselves specify the analytic methods. No additional model or analysis details should be inferred from the least-squares mean label alone.

Likewise, the record lists additional outcome assessments but does not report a multiplicity adjustment or a hierarchy for interpreting them. It lists three secondary outcomes and reports no analyses for them. These omissions do not establish that a method was or was not used; they mean the method is not reported in the registry record. For interpretation, the posted primary estimate, standard errors, interval, and unadjusted p-value should be kept distinct from assumptions about unreported statistical procedures.

10. Confidence Intervals and Precision

The primary contrast is -8.61 percentage points, with a 95% confidence interval from -42.94 to 25.72. A confidence interval is a range generated by a statistical procedure to express uncertainty around an estimate. In general, a narrower interval indicates greater precision, while a wider interval leaves more uncertainty about the plausible value of the contrast. The interval reported for this result is wide and includes zero.

Because zero lies within the interval, the posted result is compatible with no between-arm mean difference at the primary time point. Values below zero are also compatible with the result, as are values above zero. The interval therefore does not determine the direction of the underlying difference. Its breadth also means that the point estimate of -8.61 should not be treated as an exact or highly precise estimate of the effect.

The registry reports standard errors of 13.3 for the Treatment mean and 11.4 for the Control mean. These quantities describe precision of the arm estimates under the analysis; they do not describe the range of individual participant scores. Outcome counts are 11 for Treatment and 12 for Control. The record does not provide a detailed account of how those counts relate to the listed enrollment of 25, and the reason is not reported in the registry record.

A confidence interval is not a guarantee that the true effect lies within its endpoints, nor is it a range of participant-level responses. It is also not an equivalence interval. No equivalence margin is reported, and the interval alone cannot establish that the arms are sufficiently similar. The posted estimate and interval should be read together: the estimate gives the direction and magnitude of the observed contrast, while the interval conveys substantial uncertainty around it.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effect, not the trial’s original design assumptions. The figures are participants per arm, not total events. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

For planning for 100% of the observed effect, the figures are 370 participants per arm for 80% power and 495 participants per arm for 90% power. For planning for 75% of the observed effect, the figures are 657 participants per arm for 80% power and 879 participants per arm for 90% power. For planning for 50% of the observed effect, the figures are 1,477 participants per arm for 80% power and 1,977 participants per arm for 90% power.

In general, power is the chance that a planned study will detect an effect of a specified size under the assumed model and conditions. The 80% and 90% columns describe different target probabilities for detecting the selected effect if it is present; they are not probabilities that the treatment works. A higher target power generally requires more participants under otherwise unchanged assumptions. Smaller effects are harder to distinguish from random variation, so planning for a smaller fraction of the observed effect requires more participants per arm.

These values are not observed power. They are hypothetical sample-size estimates calculated from the observed effect under the stated planning assumptions. They should not be interpreted as the number enrolled, the number analyzed, or evidence about the probability that the completed trial detected an effect. The registry enrollment is 25, while the posted primary outcome counts are 11 and 12 by arm; the reasons for the difference are not reported in the registry record.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -8.610; pooled standard deviation σ = 41.755.
2. n = 2 × (1.96 + 0.842)² × 41.755² / -8.610² = 369.2, rounded up to 370 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -8.61                      # observed difference in means
sigma <- 41.7547373987443                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(5155059)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 370 (80% power), 495 (90% power)
 75% of observed effect: n per arm = 657 (80% power), 879 (90% power)
 50% of observed effect: n per arm = 1,477 (80% power), 1,977 (90% power)
power.t.test: 370.1 
Simulated power at n = 370 per arm: 0.799 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary S-FMDRS outcome at 1 month after real iTBS versus sham iTBS. It also lists secondary S-FMDRS assessments at 2 and 6 months, HADS assessments at 1, 2, and 6 months, and CGI assessments at 1, 2, and 6 months. The record lists 5 outcome measures and 3 secondary outcomes, but no analyses are posted for the secondary outcomes. The reported primary comparison should therefore be distinguished from the broader set of assessments named in the registry.

When a study evaluates multiple outcomes or time points, the chance of obtaining at least one apparently notable result can increase if each is tested separately. Statistical methods can address this multiplicity, for example by specifying a primary outcome hierarchy or adjusting inference across tests. That is general statistical context; the multiplicity approach for this trial is not reported in the registry record. The unadjusted p-value of 0.623 is the value posted for the primary comparison, and no adjustment should be assumed.

The registry record does not report the handling of missing outcome data, the number of participants with missing primary scores, or any imputation method or sensitivity analysis. It also does not report whether the primary analysis used an intention-to-treat population, a per-protocol population, or another analysis population. The outcome counts are 11 in Treatment and 12 in Control, but those counts alone do not identify why the counts differ from the listed enrollment of 25 or establish the analysis population.

The record identifies randomization and double masking, but does not report details of allocation concealment, who was masked, or whether masking was assessed. It does not report interim analyses, stopping rules, or the full statistical analysis plan. These items should be treated as unreported rather than presumed absent. The limitations affect how fully the posted result can be evaluated; they do not change the numerical estimate, confidence interval, or p-value recorded for the primary outcome.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

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 registry lists serious adverse events for 0 of 11 participants at risk in the Treatment arm and 0 of 12 participants at risk in the Control arm. It also lists 0 deaths in each arm. These are the posted serious-event and death figures for the listed groups and exposure counts.

For other adverse events, the registry lists 8 of 11 participants affected in Treatment and 3 of 12 in Control. These figures are counts of participants recorded as affected, not a description of event severity, timing, recurrence, or causal relationship. The registry does not provide the terms for the most frequent serious adverse events, consistent with no serious-event terms being listed in the posted record.

Zero recorded serious events or deaths in these groups does not establish that no such event could occur, and it does not by itself establish comparative safety. The counts are from a small trial, and the registry record does not report detailed event narratives, severity grading for other adverse events, attribution, or follow-up-specific event timing. The figures should be interpreted as the safety counts posted in the record, not as a complete characterization of risk.

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

The posted result describes the difference between the active and sham groups in S-FMDRS change at 1 month after iTBS. The mean difference was -8.61 percentage points, with a 95% confidence interval from -42.94 to 25.72 and an unadjusted p-value of 0.623. The estimate is in the negative direction, but the interval includes zero and permits a range of possible values in either direction. The comparison therefore remains uncertain rather than establishing a precise between-group difference.

The result does not establish that the groups are equivalent. A finding of no clear difference in this comparison is not the same as evidence that any true difference is negligible. An equivalence or non-inferiority conclusion requires a prespecified margin and a corresponding design and analysis; those details are not reported in the registry record. The result also does not establish that stimulation did or did not affect an individual participant, because the posted comparison is a group-level summary.

The endpoint is an overall S-FMDRS score change. It does not independently report changes in each body region, gait, or speech. The posted primary result concerns 1 month after treatment; although the registry lists follow-up assessments at 2 and 6 months, analyses for the listed secondary outcomes are not posted. No conclusions about later time points or the other listed measures follow from the primary estimate alone.

The safety counts report no serious adverse events and no deaths in either listed arm, alongside other adverse events affecting 8 participants in Treatment and 3 in Control. These counts do not alone establish that an intervention is safe or unsafe. Interpretation is limited by the small posted outcome groups and by the absence of detailed event descriptions and other safety-analysis information.

Overall, the registry record provides a primary estimate and an uncertainty interval, but does not report enough analysis detail to reconstruct the full statistical approach. Missing-data handling, analysis populations, multiplicity procedures, and the original sample-size rationale are not reported in the registry record. Those omissions limit the scope of conclusions that can be drawn from the posted result.

16. Why This Trial Matters Statistically

This trial illustrates why a point estimate should not be read in isolation. The observed mean difference is -8.61 percentage points, but its 95% confidence interval extends from -42.94 to 25.72. The interval includes zero and spans effects in both directions. The point estimate supplies a direction and scale for the observed contrast; the interval shows that the contrast is not estimated precisely.

The comparison is randomized and double-masked according to the registry, which defines the intended trial structure for comparing active and sham stimulation. However, design labels alone do not reveal the details of the analysis. The record identifies least-squares means and standard errors but does not report the statistical model, missing-data procedures, or analysis population. Evaluating a result involves both the estimate and the transparency of the methods used to obtain and interpret it.

The planning illustrations further demonstrate the consequences of imprecision. Under the listed assumptions, the participant counts required per arm rise as the planning effect becomes a smaller fraction of the observed effect, and a higher target power requires larger counts. These are planning illustrations rather than observed power, and they do not explain the trial’s original enrollment target. The original design assumptions are not reported in the registry record.

Multiplicity and follow-up also matter. The registry lists several additional outcomes and time points, but only the primary comparison has posted analysis results in the record described. Without a reported strategy for handling multiple comparisons, and without analyses for the secondary measures, the primary result should not be generalized to every outcome the study planned to assess.

For clinical researchers and statisticians, the central lesson is to separate what is numerically reported from what remains uncertain or undocumented. The registry supports a careful description of the 1-month group comparison. It does not support a definitive claim about equivalence, a full account of longer-term outcomes, or reconstruction of unreported analytical decisions.

17. 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 counts are 11 for Treatment and 12 for Control, while the registry lists enrollment as 25. The record does not explain the relationship between these figures. It does not report how many participants completed each follow-up visit, whether any participants withdrew, or the reasons for any differences between enrollment and outcome counts. The effect of any missing observations on the posted estimates cannot be assessed from the registry record.

The registry does not report the statistical model underlying the least-squares means, the covariates included, the precise method for calculating percentage change, or the assumptions used for the confidence interval and p-value. It does not identify the analysis population, describe missing-data handling, or report sensitivity analyses. These gaps limit independent assessment of how robust the primary estimate is to alternative analysis choices.

The record identifies a randomized, double-masked, parallel design but does not provide detailed information about allocation procedures, masking of specific roles, or assessment of masking. It also does not report interim analyses, stopping rules, or the statistical analysis plan. Those matters should be regarded as unreported in the registry record, not presumed to have been absent from the conduct of the trial.

Only the primary outcome comparison has posted numerical analysis results in the record described. Although secondary outcomes and later assessments are listed, their results are not posted. The safety information gives group counts but does not provide detailed descriptions of the other adverse events, their severity or timing, or attribution. These limitations restrict interpretation to the outcomes and details actually reported.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Non-invasive Intermittent Theta Burst Stimulation of the Dorsolateral Prefrontal Cortex in Functional Movement Disorders — NCT05155059.
• Registry record last updated 2026-08-12; status last verified 2026-07.
• Results first posted 2026-08-12.
• 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.

21. Record Summary

The registry record for NCT05155059 describes a randomized, double-masked, parallel-group trial of active versus sham intermittent theta burst stimulation for functional movement disorders. The official title identifies a Phase II trial, while the registry phase field is NA. The listed enrollment is 25, and the record status is active, not recruiting.

The primary endpoint is change in S-FMDRS at 1 month after iTBS. The posted Treatment and Control least-squares means are -48.08 and -39.47. The mean difference is -8.61 percentage points, with a 95% confidence interval from -42.94 to 25.72 and an unadjusted p-value of 0.623. The interval includes zero and indicates substantial uncertainty around the estimated difference.

The registry lists secondary S-FMDRS, HADS, and CGI outcomes, but their analyses are not posted. It lists no serious adverse events or deaths in either arm and reports other adverse events affecting 8 participants in Treatment and 3 in Control. Details about the analysis model, missing data, analysis populations, multiplicity, and the trial’s original sample-size assumptions are not reported in the registry record.