Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response (NCT02495883), a randomized phase 4 study. The primary outcome is Regions With fMRI Differences Between ET and Controls.

2. Clinical Question

The study is titled Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response. Its stated imaging outcome concerns regions with fMRI differences between the essential tremor group and controls. The outcome description counts statistically significant voxels in regions of differential activation and characterizes these as voxels seen in the essential tremor group but not in the healthy control group.

The registry summary presents questions about the neural networks associated with essential tremor and whether postural and kinetic tremors may arise through different neural mechanisms. Those are the scientific motivations described in the record, not reported findings. The primary outcome is an imaging measure rather than a direct measure of symptom improvement or treatment response. The registry record does not report numerical endpoint results, so the posted information cannot establish what regions differed or how large any differences were.

3. Trial Design

This is a phase 4 randomized, unmasked crossover study sponsored by the University of California, San Diego. The registry lists enrollment of 56 and a completed status. The recorded study dates are 2013-12 for the start and 2017-04 for primary completion.

People in the essential tremor group were randomized to start with one of two treatments: 50ml of 40% ethanol or Propranolol SR 60-120mg. The arm descriptions say that participants who received one treatment first would return for a second visit and receive the other treatment, and vice versa. This is the crossover feature: participants are scheduled to receive both treatments in a sequence, rather than remaining in only one treatment arm. The registry lists no masking.

Healthy volunteers form a separate group and are described as receiving no interventions. The primary imaging outcome compares essential tremor with healthy controls, while the crossover treatment sequence applies to the essential tremor group. The registry record does not fully describe the procedures, visit timing beyond the stated outcome timeframe, or how treatment-period data were incorporated into a particular analysis.

The primary outcome timeframe is “At visit 1 or 2 based on randomization table.” The posted record lists one outcome measure and no analyses. It does not report numerical primary-outcome results or a statistical comparison. The listed enrollment and the safety-group denominators describe different record elements; the registry record does not explain how those figures relate to the analyzed population. Details of sequence generation, handling of any period or carryover effects, and the protocol's rationale for the enrollment target are not reported in the registry record.

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 methodology of this trial utilizes functional MRI measures. In order to understand the significance of a group's unique brain responses, the data between the two groups (Essential Tremor vs. Healthy Controls) are statistically compared to derive regions that are unique. The output of the analyses show regions that are unique to ET. NOTE: Data structure cannot be provided separately for each group based on the experiment paradigm and analysis methods.

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 Regions With fMRI Differences Between ET and Controls, measured over At visit 1 or 2 based on randomization table..

The primary endpoint is titled “Regions With fMRI Differences Between ET and Controls.” Its unit is the number of activated voxels. According to the outcome description, the measure counts statistically significant voxels in regions that were differentially activated, representing voxels seen in the essential tremor group but not in the healthy control group. The stated timeframe is at visit 1 or 2 based on the randomization table.

In general, functional MRI provides a way to characterize patterns of brain activity, and a voxel is a unit of the image. Counting voxels meeting a statistical criterion can summarize the spatial extent of a detected activation pattern. It does not, by itself, describe the size of a clinical benefit, the severity of tremor, or whether an observed pattern causes tremor. Interpretation depends on the analysis choices used to define statistically significant voxels and regions.

The registry record gives the endpoint definition but does not report the resulting voxel counts, the regions identified, uncertainty estimates, or the statistical procedure used to identify significant voxels. Consequently, the endpoint's intended meaning can be described, but its observed value and precision cannot be evaluated from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted record establishes the broad design and endpoint but leaves many analysis details unspecified. It identifies a randomized crossover study with no masking, a primary imaging measure based on activated voxels, and a timeframe tied to visit 1 or 2. It does not report an analysis plan, numerical primary result, or analysis. The explanations below describe statistical concepts generally; they should not be read as claims about methods used in this trial.

What does randomization contribute?

In general, randomization assigns participants to treatment sequences by chance. It can reduce systematic differences between sequence groups, on average, but does not ensure that every characteristic is balanced in a particular study. Here, the registry says that participants with essential tremor were randomized to start with ethanol or propranolol and then receive the other treatment. It does not report how the randomization sequence was generated, whether assignment was concealed, or how sequence groups were analyzed.

How should a crossover design be understood?

In general, a crossover design allows participants to receive more than one intervention in sequence. Comparing interventions within the same participant can account for stable characteristics shared across that person's treatment periods. But period effects, changes over time, and carryover from an earlier treatment can affect interpretation. A suitable analysis may need to account for the treatment sequence and period structure. The registry record does not report whether such effects were assessed, whether a washout period was used, or how the crossover data were modeled. Those details are not reported in the registry record, so they should not be assumed.

What does an activated-voxel count represent?

In general, voxel counts summarize how many image locations meet a statistical threshold or other defined criterion. The count depends on how the imaging data are processed, what comparison is made, and how statistical significance is defined. Spatial patterns may also depend on rules for grouping nearby voxels into regions. The registry describes the outcome as the number of statistically significant voxels in regions differentially activated between the essential tremor and control groups. It does not specify the threshold, processing decisions, or exact inferential procedure in the record.

Why does uncertainty matter?

In general, an estimate gives a point summary, while a confidence interval describes uncertainty around that estimate under a specified method. A p-value, when used, summarizes how compatible data are with a stated null model; it does not measure the probability that a hypothesis is true or the clinical importance of a result. For an imaging endpoint, interpretation also depends on the number and structure of the comparisons and on how the analysis accounts for searching across regions or voxels. The registry record does not report estimates, confidence intervals, p-values, thresholds, or a multiplicity procedure for the primary outcome.

What is over-dispersion, and is it relevant?

In general, over-dispersion occurs when observed variability in count data exceeds what a chosen statistical model expects. If present, it can make standard errors too small and tests too optimistic unless the model accounts for the extra variability. The endpoint is expressed as a count of activated voxels, but that description alone does not establish which model was used or whether over-dispersion was assessed. The registry record does not report a count model, a dispersion estimate, or a correction for over-dispersion.

How should the sample-size material be read?

The posted planning assumptions describe an illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The stated effect to detect is a fraction of the observed effect. These are planning assumptions, not a report of the trial's original design rationale. In general, an illustration of participants per arm for a chosen power describes a hypothetical planning requirement under its assumptions. It is not observed power and does not show that a completed study was adequately powered. The registry record does not report the original sample-size justification or the actual calculated illustration values in the registry record.

Because the registry lists no analyses and no numerical outcome results, none of these general concepts can be connected to a reported trial estimate. The record does not say which statistical tests or models were used, how the crossover was handled analytically, or how the imaging comparisons were adjusted. Those choices are essential context for interpreting any reported voxel findings, but they are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

Multiplicity, missing-data handling, and analysis populations are important for interpreting this imaging study, but the registry record does not describe them. It lists one primary outcome measure and no analyses. The outcome is based on regions with fMRI differences, and in general imaging analyses may involve many locations or comparisons. When multiple tests are conducted, the chance of at least one apparently significant result can increase unless the analysis accounts for multiplicity. The record does not state whether any correction, prespecified region selection, or other control was used.

The record does not report how missing scans, incomplete treatment periods, or participants without usable imaging data were handled. It also does not define an intention-to-treat, per-protocol, or other analysis population. Although enrollment is listed as 56, that figure alone does not reveal how many participants contributed to the primary analysis. The safety section separately lists 31 people at risk in the ET Group and 24 in Healthy Volunteers; the registry record does not explain these denominators in relation to enrollment or the analysis population.

In general, missingness can affect interpretation when the likelihood of missing data is related to participant characteristics or outcomes. Different handling methods rely on different assumptions, and the number and reasons for missing observations help readers judge those assumptions. Since these details are not reported in the registry record, the potential effect of missing data cannot be assessed.

11. 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.

The registry safety section lists the ET Group with 31 at risk and the Healthy Volunteers group with 24 at risk. For each listed group, it records 0 serious events, 0 other events, and 0 deaths. These are the figures reported for the groups in that section.

These counts should be read as descriptive entries in the registry record, not as proof that no adverse events occurred outside the reporting definitions or observation period. The record does not provide event definitions, follow-up duration, or further detail about how safety information was collected. It also does not report a statistical comparison between groups. The listed group denominators are not explained in relation to the enrollment of 56, so the record does not support reconstructing the safety analysis population.

In general, a count of zero in a group does not establish that the underlying risk is zero; the amount of information depends on the number observed, follow-up, and event ascertainment. These safety entries do not answer the imaging endpoint question and should not be interpreted as evidence about treatment effectiveness.

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

The registry record describes a study designed to examine functional MRI differences between people with essential tremor and healthy controls, with a primary outcome based on the number of activated voxels. It also describes a randomized crossover sequence of ethanol and propranolol for the essential tremor group. These details establish the questions the study set out to address, not the findings.

The record does not report numerical results for the primary endpoint and lists no analyses. It therefore does not show whether any regions differed, how many voxels were involved, or how precise any estimate might be. It also does not report an outcome comparing ethanol with propranolol. The study description's hypotheses about tremor circuits and postural and kinetic tremors are motivations, not results reported in this record.

In general, an imaging difference is a statistical observation whose meaning depends on the methods used to process and analyze the images. It does not automatically demonstrate a causal mechanism, a clinically meaningful change, or a treatment effect. A statistical count of voxels is not interchangeable with a measure of symptoms or quality of life. Here, without a posted estimate and analysis, even the presence and direction of a statistical difference cannot be assessed.

The zero event counts in the safety listing describe the entries recorded for the groups and do not establish absence of all possible harms. Similarly, the sample-size material is described as a planning illustration based on an observed effect, rather than observed power. It cannot fill the gap left by unreported endpoint results. The appropriate reading is that the registry provides design and outcome definitions, but not the results needed to judge the imaging question or treatment response.

13. Why This Trial Matters Statistically

This trial is statistically interesting because its questions span different kinds of comparison. The treatment sequence is a crossover within the essential tremor group, while the primary endpoint is described as an fMRI comparison between essential tremor and healthy controls. Keeping those comparisons distinct is necessary: a design detail about receiving both treatments does not itself establish that the primary imaging outcome compares those treatments.

The endpoint also illustrates how a statistical measure can be narrower than the scientific motivation. Counting activated voxels can summarize a detected imaging pattern, but the count alone does not identify a biological cause or quantify a clinical outcome. In general, spatial analyses require choices about thresholds, regions, and multiple comparisons. Those methodological choices affect the interpretation of a count, yet they are not reported in the registry record.

The study record also demonstrates why outcome definitions and outcome results must be distinguished. The primary outcome is named and described, and the study status is completed, but the registry record lists no analyses or numerical primary results. Without those results, readers cannot evaluate the size or precision of an observed difference. The sample-size material is a planning illustration, not a substitute for those estimates.

Finally, the design requires clear reporting of how crossover periods, sequences, and missing observations are handled. Such information supports an assessment of whether the statistical analysis matches the design. The record does not report these details. The statistical importance of the study therefore lies both in the questions it poses and in the limits of what can be inferred from the posted record.

14. 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 does not report numerical results for the primary fMRI endpoint or any analyses. This is the central limitation for interpreting the study: readers cannot identify the observed regions, voxel counts, direction of differences, or uncertainty from the posted information. The record defines the outcome but does not provide the values needed to evaluate it.

The available design description is incomplete for assessing the crossover analysis. It states that people with essential tremor were randomized to start with ethanol or propranolol and later receive the other intervention, but does not report the sequence-generation method, washout details, treatment-period analysis, or handling of possible period and carryover effects. The registry record does not report whether the imaging endpoint was analyzed by treatment period or by group comparison independent of treatment.

Important imaging-analysis details are also absent. The record does not describe image-processing methods, the significance threshold, region definition, or adjustment for multiple comparisons. It does not explain how missing scans or incomplete observations were handled, or define the analysis population. The relationship between the enrollment figure and the safety denominators is not reported.

These omissions mean that the record supports description of the planned scientific questions and recorded safety counts, but not an independent assessment of the primary statistical finding. The sponsor's original sample-size justification, detailed statistical plan, and reasons for any missing data are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response — NCT02495883.
• Registry record last updated 2020-12-02; status last verified 2020-12.
• Results first posted 2020-12-02.
• 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.

18. Record Summary

This is a completed phase 4 randomized, unmasked crossover study sponsored by the University of California, San Diego. The registry lists enrollment of 56 and study dates of 2013-12 to 2017-04.

Participants with essential tremor were randomized to start with 50ml of 40% ethanol or Propranolol SR 60-120mg and were scheduled to receive the other treatment at a second visit. Healthy volunteers received no interventions. The primary outcome measures the number of activated voxels in regions with fMRI differences between the essential tremor group and controls, at visit 1 or 2 based on the randomization table.

The registry record lists one outcome measure and no analyses. It does not report numerical primary-outcome results. The safety listing records zero serious events, zero other events, and zero deaths in each listed group.