ExAblate Transcranial MR Guided Focused Ultrasound for the Treatment of Essential Tremors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for ExAblate Transcranial MR Guided Focused Ultrasound for the Treatment of Essential Tremors (NCT01827904), a randomized na study. The primary outcome is Tremor Motor Score - Clinical Rating Scale for Tremor (CRST Part A (Upper Extremity) + Part B) Percent Change From Baseline.

2. Clinical Question

3. Trial Design

The registry identifies this as a prospective, randomized, double-blind, crossover, multi-site, two-arm study. The interventions were Transcranial ExAblate and Sham Transcranial ExAblate. The stated objective was to test treatment efficacy and further demonstrate safety in people with medication-refractory essential tremor. Phase is recorded as NA. The study status is completed; its recorded start was 2013-05 and its primary completion date was 2021-02-24.

Blinding is described specifically for subjects, the local site's blinded assessor, and Tremor Core Lab assessors. The registry's general masking field also identifies the study as double-blind. The available record does not specify which other study personnel, if any, were masked, or how the masking was maintained. It also does not give the crossover sequence, the timing of crossover, or the rationale for the design. These details should not be inferred from the design label alone.

The primary outcome is the percent change from baseline to Month 3 in treated-side upper extremity Tremor-Motor scores, using the sum of CRST Part A and Part B. The posted primary results give a mean and 95% confidence interval for each of the two listed arms. The primary outcome sample sizes shown in those results are 56 for Transcranial ExAblate and 20 for Sham Transcranial ExAblate. These are the arm-specific outcome counts, not a description of the full crossover sequence or of all analysis populations.

The record lists four secondary outcomes: CRST Part A and Part B tremor motor score change, CRST Part A posture score change, CRST Part C functional disability score change, and QUEST summary total change. It records six outcome measures and one analysis. The registry does not report how the secondary outcomes were ordered or incorporated into an inferential testing strategy. Nor does the record report detailed eligibility criteria, a sample-size justification, or the planned statistical analysis protocol.

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.

Main Study

Reasons for not completing this period:

Main Continuation / Crossover Phase

Reasons for not completing this period:

Long-term Annual Follow-up

Reasons for not completing this period:

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 Tremor Motor Score - Clinical Rating Scale for Tremor (CRST Part A (Upper Extremity) + Part B) Percent Change From Baseline, measured over Baseline, 3 Months post-treatment.

The primary endpoint is the percent change from baseline to Month 3 in treated-side upper extremity tremor-motor score. It combines the upper-extremity score from Clinical Rating Scale for Tremor Part A with Part B. The registry describes the score as ranging from 0-32 points and explains that individual scores at baseline and three months were used to calculate percent change before averaging across subjects. Higher percent change is defined as better, meaning improvement in the measured tremor.

This endpoint is used to quantify change in the treated side rather than to report a single follow-up score alone. Its clinical-rating scale basis makes the result an assessment of measured tremor-motor signs. The endpoint is not a direct measure of every aspect of essential tremor, daily functioning, or quality of life. The record lists functional disability and quality-of-life measures among the secondary outcomes, but those are separate outcomes and should not be treated as interchangeable with the primary tremor score.

The posted results report mean percent changes and 95% confidence intervals for each arm. The Transcranial ExAblate mean is 46.9, with a 95% confidence interval from 40.3 to 53.5. The sham mean is -0.1, with a 95% confidence interval from -9.6 to 9.5. These are arm-specific summaries; they are not a confidence interval for the between-arm difference. The registry does not post a between-arm effect estimate or its confidence interval for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a continuous primary outcome: percent change from baseline in a tremor-motor score. A continuous outcome can take values across a scale rather than being limited to categories such as yes or no. The record summarizes each arm with a mean. A mean describes the arithmetic center of the observed values, but does not show how individual participants' scores were distributed. The record does not post a standard deviation, range of observed values, or participant-level data for this endpoint.

What do the confidence intervals describe?

The posted intervals are identified as 95% confidence intervals. In general, a confidence interval represents uncertainty around an estimated quantity under a statistical procedure and its assumptions. Here, the quantities summarized are the arm-specific mean percent changes: 46.9 for Transcranial ExAblate and -0.1 for Sham Transcranial ExAblate. Their respective intervals are 40.3 to 53.5 and -9.6 to 9.5. The intervals are not ranges containing a stated proportion of individual participants' outcomes, and they are not a direct interval for the difference between arms.

The sham interval extends across values below and above zero, while the active-arm interval runs from a positive lower endpoint to a positive upper endpoint. Zero represents no percent change. This description concerns the arm-specific intervals only. It does not replace the reported between-arm test, and it does not establish the size or precision of an arm contrast. The registry does not state the interval construction method, whether the intervals are adjusted, or whether the test and intervals use the same model.

What does the reported test say?

The registry reports a one-sided t-test for superiority with p < 0.001. A t-test is a general method for assessing evidence about a mean or a contrast involving means, under assumptions about the data and the test's sampling distribution. A one-sided test evaluates evidence in a prespecified direction rather than treating departures in either direction as the target. The record does not report the full hypothesis statement, the test statistic, the degrees of freedom, or detailed assumptions used for this analysis.

A p-value is a measure of how incompatible the observed data are with a specified null model, if that model and the test assumptions are used. It is not the probability that the null is true, and it does not state the probability that a future study will have the same result. The value p < 0.001 is the reported threshold, not an exact p-value. It does not quantify the treatment contrast or by itself indicate whether the contrast is important to patients.

Why does the design matter for the analysis?

Randomization is intended, in general, to support fair comparisons by assigning participants to study groups according to a chance process. Blinding can reduce some forms of influence on participants' reports or assessors' measurements. The registry identifies random allocation and describes blinding of subjects, the local site's blinded assessor, and Tremor Core Lab assessors. These design features are relevant context, but the record does not provide details of the allocation procedure, concealment, masking checks, or the handling of possible unblinding.

A crossover design generally involves participants receiving more than one study condition in different periods. In such designs, analysis may need to account for measurements from the same participant and for period or sequence effects. This is a general statistical point, not a description of the analysis used in this trial. The registry does not report the treatment sequence, period structure, washout details, or whether the posted primary comparison used a crossover-specific model. Consequently, the design label alone is not enough to reconstruct the statistical analysis.

What is the role of the planning illustrations?

The planning assumptions state that the illustrations use a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Such calculations are general planning exercises: they ask how many participants per arm would be needed under stated assumptions for a chosen power and target effect. They are not observed power, do not describe the trial's actual design rationale, and do not establish what sample size the investigators planned.

The registry record does not report a sample-size justification. The planning assumptions alone do not supply the trial's targeted effect, the anticipated variability, or a rationale for the enrollment. No planning result should be interpreted as evidence about the achieved precision or the probability that the trial detected an effect. Planning calculations concern hypothetical future or planned studies; the observed trial results are the arm estimates and reported test in the record.

What statistical details remain unavailable?

The record lists one analysis and gives the test type and p-value, but does not report a full statistical analysis plan. It does not specify how missing endpoint observations were handled, whether any participants were excluded from the primary analysis, or the analysis population definition. It also does not describe adjustment for baseline values, site, period, sequence, or other covariates. These details cannot be assumed from the study's randomized or crossover labels.

The record lists four secondary outcomes in addition to the primary endpoint. It does not report a multiplicity strategy, such as a testing hierarchy or adjustment across outcomes. In general, when multiple hypotheses are tested, the chance of at least one apparently unusual result can be affected by how many tests are considered and by their dependence. That general issue does not establish that any particular secondary result is significant or that an adjustment was or was not performed. The registry does not provide enough information to assess the treatment of multiplicity.

10. Analyses Reported by the Sponsor

The registry reports the sponsor's primary comparison as a one-sided t-test for superiority, with p < 0.001. It also posts the arm-specific mean percent changes and 95% confidence intervals. These results describe the reported test and the uncertainty around each arm mean; they do not provide a direct estimate or confidence interval for the between-arm difference.

No independently recalculated two-arm comparison is reported for this continuous endpoint in the registry record. The posted information therefore does not support a numerical comparison between a sponsor test and a separate recalculated estimate. It is possible to read the sponsor's reported result alongside the arm summaries, but the difference between those summaries should not be calculated or treated as though it were the test's effect estimate. The one-sided p-value does not supply the missing contrast or its precision.

The record does not report additional test details such as a test statistic, degrees of freedom, or full model specification. Nor does it describe whether the analysis accounted for crossover periods, baseline scores, or other factors. Those omissions limit independent verification and interpretation of the sponsor's inferential analysis. The information available supports reporting what the registry states, without inferring the underlying analysis beyond the named t-test and its stated direction.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and four secondary outcomes. It also records six outcome measures and one analysis. The listed secondary measures include tremor-motor score, posture score, functional disability score, and a quality-of-life questionnaire summary. The presence of multiple outcomes raises a general multiplicity question: if several hypotheses are tested, the interpretation of individual p-values can depend on whether and how the testing strategy accounts for the collection of outcomes. The registry record does not report a multiplicity adjustment, hierarchy, or other strategy, so no particular approach should be presumed.

The record does not explain how missing primary outcome values were handled. It does not describe imputation, complete-case analysis, sensitivity analyses, or the reasons that the outcome sample sizes differ between the arms. A listed outcome count is not enough to determine whether participants were excluded, lacked a measurement, or were analyzed under another rule. The record also does not define whether the primary analysis followed an intention-to-treat principle, a per-protocol principle, or another population definition.

These gaps matter because analysis choices can affect which observations contribute to an estimate and how uncertainty is assessed. In general, an analysis that uses only observed measurements can be affected if missingness relates to outcome values or treatment experience. This is a general concern, not a claim that missing observations caused bias in this trial. The registry record does not provide the information needed to assess that possibility.

The crossover label raises additional questions about the analytic population and repeated measurements. The record does not specify whether the primary result is based on a first treatment period, all periods, or another defined set of observations. It does not provide a sequence-specific or period-specific analysis in the posted primary result. These missing details prevent reconstruction of the analysis plan and limit assessment of how well the reported test reflects the design.

Accordingly, the primary result can be described, but the record does not permit a complete assessment of missing-data handling, analysis populations, or multiplicity. Those items are not reported in the registry record.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: tia (3.6%), embolic stroke (1.8%), numbness and tingling (1.8%), atrial fibrillation (1.8%), syncopal episode (1.8%).

The posted safety results distinguish serious adverse events from other adverse events and list groups for Transcranial ExAblate, Sham Transcranial ExAblate, and Crossover Transcranial Exablate. The serious adverse event counts are 6 among 56 at risk in the Transcranial ExAblate group, 0 among 20 at risk in the sham group, and 0 among 21 at risk in the crossover treatment group. Deaths are recorded as 0 in each group. The record also reports other adverse events affecting 49 among 56, 6 among 20, and 19 among 21, respectively.

These are descriptive counts by the registry's safety groups. They should not be added together or interpreted as counts of distinct participants across the full crossover study. The record does not explain the relationship among the safety groupings, the duration each group was observed, or whether the groups overlap. It also does not provide a causal assessment for individual events. The counts alone cannot show that a particular event was caused by the intervention.

The listed serious adverse event terms include TIA at 3.6%, Embolic Stroke at 1.8%, Numbness and Tingling at 1.8%, Atrial fibrillation at 1.8%, Syncopal episode at 1.8%, and Breast cancer at 1.8%. The registry labels these as top serious terms; it does not provide further event-level context in the information summarized. Percentages and counts should be read as posted and should not be combined into a rate without knowing the definitions and observation periods.

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

The primary result is a group-level summary of change in treated-side tremor-motor score from baseline to three months. The Transcranial ExAblate arm has a positive mean percent change, and the sham arm mean is close to zero. The registry defines higher percent change as better. Its one-sided superiority test reports p < 0.001. Together, these statements describe the posted primary outcome and its reported inferential result; they do not, on their own, communicate every aspect of the treatment effect or its clinical importance.

The test result is not a direct measure of how large the between-arm difference is. The registry does not post that difference or its confidence interval. The arm-level confidence intervals indicate uncertainty around the means, not a range for individual responses and not an interval for the contrast. A complete assessment of the magnitude and precision of the comparison would require the estimated contrast, an appropriate interval, and fuller analysis details.

The outcome captures rated tremor-motor signs on the treated side. It is not a complete measure of function, quality of life, or all consequences of essential tremor. The record lists functional disability and quality-of-life measures as secondary outcomes, but those should be interpreted separately. This summary does not make a treatment recommendation or establish what an individual should expect.

The registry identifies randomization and blinding, but some design and analysis details are absent. The crossover sequence, missing-data handling, primary analysis population, and multiplicity strategy are not reported. The safety record lists adverse event counts in several groups, but does not supply enough context to determine attribution or compare exposure periods. These limitations place boundaries around what can be concluded from the posted results.

More broadly, a statistically significant result is not equivalent to proof of a particular mechanism, a guarantee of benefit for every participant, or a complete characterization of safety. The primary outcome provides evidence from the specified score and follow-up, while unanswered questions remain about the analysis and the broader outcomes. Interpretation should stay tied to the population, endpoint, comparator, and observation described in the registry.

14. Why This Trial Matters Statistically

This trial is statistically informative because its primary endpoint is a defined continuous measure, reported as percent change from baseline, and the registry provides both arm-specific means and confidence intervals. Those summaries allow readers to see the direction and precision of each arm's average change rather than relying only on a p-value. The reported one-sided superiority test adds an inferential result, while the absence of a contrast estimate illustrates why a p-value alone is not a complete account of a comparison.

The randomized and double-blind labels are relevant design features for a study involving a measured tremor outcome. The record identifies which groups were compared and specifies blinding of subjects and assessors involved in outcome evaluation. At the same time, the crossover label makes detailed reporting of sequence, periods, and analysis especially important. Without those details, readers cannot establish how the design was represented in the primary comparison.

The trial also illustrates the difference between a primary endpoint and a broader set of outcomes. The registry lists measures of tremor, posture, function, and quality of life. Each can answer a different question, and their presence makes the unreported multiplicity strategy relevant to interpretation. In addition, the safety group counts show why outcome findings should be read with safety reporting rather than as an isolated efficacy test.

Finally, the record distinguishes observed results from planning assumptions. Sample-size illustrations can inform hypothetical planning, but they are not observed power and do not substitute for the trial's unreported design justification. Keeping estimates, tests, planning calculations, and safety descriptions separate is central to a careful statistical reading of this study.

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 posted primary results do not include a direct estimate of the difference between Transcranial ExAblate and sham, or a confidence interval for that difference. The reported arm means and intervals cannot be used as a substitute for that contrast. The inferential result is a one-sided t-test with p < 0.001, but the test statistic, degrees of freedom, and detailed model specification are not reported.

The outcome counts are 56 in the active arm and 20 in the sham arm. The record does not explain why the counts differ or how participants with unavailable measurements were handled. It does not report the primary analysis population, missing-data methods, or sensitivity analyses. Therefore, the analysis cannot be independently reconstructed from the posted summary statistics.

Although the study is identified as crossover, the record does not provide the treatment sequence, period structure, timing, or analytical handling of crossover. It is not possible to determine whether the posted comparison uses only one period or multiple periods, or how any within-participant dependence was addressed. This is a limitation of the available reporting, not evidence that the analysis was necessarily inappropriate.

The registry does not report the sample-size justification or a multiplicity strategy for the primary and secondary outcomes. The secondary outcome listings do not establish which analyses were confirmatory or how their interpretation was controlled. The method used to construct the 95% confidence intervals is also not specified in the posted results.

Safety counts are presented across three groups, including a crossover treatment group, but the record does not explain overlap, observation duration, or event attribution. These limitations prevent a full comparative safety interpretation. Further details are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: ExAblate Transcranial MR Guided Focused Ultrasound for the Treatment of Essential Tremors — NCT01827904.
• Registry record last updated 2024-08-27; status last verified 2024-03.
• Results first posted 2024-03-13.
• 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

The registry describes a completed, prospective, randomized, double-blind, crossover, multi-site, two-arm study of Transcranial ExAblate versus Sham Transcranial ExAblate for medication-refractory essential tremor. Phase is recorded as NA. Enrollment is 76. The study start is recorded as 2013-05 and primary completion as 2021-02-24.

The primary endpoint is percent change from baseline to Month 3 in treated-side upper extremity tremor-motor score, combining CRST Part A and Part B. The reported mean is 46.9 (95% confidence interval 40.3 to 53.5) for Transcranial ExAblate and -0.1 (95% confidence interval -9.6 to 9.5) for sham. The sponsor's reported one-sided t-test for superiority has p < 0.001.

The record lists four secondary outcomes and safety results for active, sham, and crossover treatment groups. It does not report the between-arm effect estimate and confidence interval, detailed crossover analysis, missing-data handling, analysis population, sample-size justification, or multiplicity strategy. These omissions limit independent assessment of the posted comparison.