Electrophysiological Study of the Effects of Limb Cooling on Essential Tremor: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Electrophysiological Study of the Effects of Limb Cooling on Essential Tremor (NCT01093027), a randomized na study. The primary outcome is Tremor Amplitude.

2. Clinical Question

The study was designed to examine the effect of upper-limb forearm cooling on essential-tremor tremor using a practical cold-pack approach. The registry describes two visit sequences: 15 - 30 and 30 - 15. In each, the affected upper limb receives both water-temperature conditions, with the order differing by sequence. The primary measure is tremor amplitude, averaged across the Outstretched, Abducted, Nose, and Mug conditions of the Tremor Rating Scale test.

This is a question about a measured physiological outcome following cooling, not a question about long-term symptoms or daily function. The registry also lists the Tremor Rating Scale as a secondary outcome. It does not report the primary comparison, the result for the secondary outcome, or a numerical estimate of the difference between cooling conditions. Therefore, the clinical question can be described from the planned outcome and treatment sequences, but the record does not establish what the results were.

3. Trial Design

The study is registered as randomized, single-masked, and crossover, and its status is completed. The record lists enrollment of 20. It describes two sequences of cooling conditions. Participants assigned to 15 - 30 receive 15 degrees Celsius water for 10 minutes at Visit 1 and 30 degrees Celsius water for 10 minutes at Visit 2. Participants assigned to 30 - 15 receive the reverse order. Both sequences concern the upper limb with tremor.

In a crossover design, participants receive more than one condition in sequence, so the comparison can potentially use measurements from the same participant under each condition. That feature can reduce the influence of stable differences between participants, because each participant can serve as their own reference. This is a general property of crossover designs; the registry record does not say which statistical method was used to account for the within-participant structure.

The randomized allocation concerns the order of the two cooling conditions. The record identifies masking as single but does not state who was masked. It does not report details about sequence generation, allocation concealment, washout between visits, timing between visits, adherence, or whether the visit procedures were otherwise identical. These details matter when interpreting a crossover comparison, especially if an earlier condition could influence a later measurement.

The listed primary outcome is a continuous measure of tremor amplitude in cm/s^2, recorded after 10 minutes of limb cooling. Its stated summary parameter is the mean, with standard deviation as the dispersion measure. The registry lists the Tremor Rating Scale as a secondary outcome and indicates two outcome measures, but does not report their complete results. The study is completed, yet the analysis count is recorded as zero and no primary-outcome comparison is available 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.

Visit 1

Visit 2

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 Amplitude, measured over After 10 minutes of limb cooling treatment..

The primary endpoint is tremor amplitude, expressed in cm/s^2. The registry defines it as the average tremor amplitude during four Tremor Rating Scale test conditions: Outstretched, Abducted, Nose, and Mug. The measurement is specified for after 10 minutes of limb cooling treatment. The summary parameter is a mean, and standard deviation is the named measure of dispersion.

Amplitude provides a quantitative measure of the movement being studied. A mean can describe the central level of a continuous measurement across observations, while a standard deviation describes how spread out those observations are around the mean. These are general statistical interpretations of the selected summary measures; they do not indicate what values were observed in this study.

Using a defined set of test conditions gives the endpoint a consistent measurement context, and the continuous scale can represent variation in tremor amplitude rather than reducing it to a yes-or-no classification. The registry’s description does not specify whether the four condition-level measurements were averaged for each participant before analysis, or how observations from the two visits were combined. It also does not provide the observed means, standard deviations, effect estimate, or uncertainty interval for the primary endpoint. The endpoint is therefore clear as a planned measure, but its treatment comparison cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical methods that were actually used are not reported in the registry record. The record describes the design and the intended endpoint, but it does not give a model, a primary contrast, an analysis population, an uncertainty interval, or a hypothesis-test result. The explanations below are general statistical context, not claims about procedures used in this trial.

What does randomization address?

Random allocation is intended to make the assigned treatment order independent of participant characteristics, on average. In this study, the sequence labels specify which cooling temperature is used at Visit 1 and which is used at Visit 2. Randomizing order can help avoid systematically giving one temperature first to participants with particular characteristics. It does not guarantee that every source of bias is removed, and it does not establish that the measurements were analyzed correctly. The registry says the study was randomized but does not describe how the sequence was generated or concealed before assignment.

How does a crossover comparison work?

In a crossover design, participants receive multiple conditions over time. A comparison can then use measurements from the same participant under each condition. As a general principle, within-participant comparisons may be more precise than comparisons between unrelated groups when measurements from one person are correlated and stable participant differences are substantial. The analysis should account for that correlation rather than treating all measurements as independent. The registry does not say whether the reported analysis, if any, used a paired method or another approach.

Crossover studies also raise questions about period and carryover. A period effect is a change associated with the visit or time of measurement rather than the treatment itself. Carryover means an earlier condition may continue to affect observations taken after a later condition begins. A suitable design and analysis may need to consider these possibilities. Here, visit order is described, but washout timing, any assessment of carryover, and methods for handling visit effects are not reported in the registry record. It would be inappropriate to assume that these factors were absent or that a particular adjustment was made.

What do mean and standard deviation describe?

The endpoint is continuous and the registry names the mean as its parameter and standard deviation as its dispersion measure. In general, the mean conveys the central level of a set of measurements. The standard deviation describes the spread of the observations around that mean, rather than the precision of the estimated mean. Precision is commonly conveyed by a standard error or confidence interval, but neither is reported for this outcome. The registry does not provide the endpoint values needed to interpret even the stated mean and standard deviation summaries.

The endpoint description refers to an average across the Outstretched, Abducted, Nose, and Mug conditions. A statistical analysis would need a defined unit of analysis and a clear account of how these condition-level measurements contribute to each participant’s endpoint. The record does not explain whether the condition measurements were first combined within participant, analyzed separately, or handled another way. It also does not say whether all four conditions were assessed at each visit.

What would an effect estimate and interval add?

As a general matter, an effect estimate quantifies the contrast between conditions on the chosen scale. A confidence interval conveys uncertainty about that estimate under the model and sampling assumptions. The interval is not a guarantee that the true value lies within its limits; it is a procedure with a repeated-sampling interpretation. A narrow interval generally indicates greater precision than a wide interval, while the meaning of the estimate still depends on the outcome scale and design. No effect estimate or confidence interval is reported, so the magnitude and precision of the primary comparison cannot be evaluated.

A p-value, if reported, would address compatibility of the observed data with a specified null model under stated assumptions. It would not measure the size or clinical importance of an effect. The registry record provides no primary-outcome p-value and no stated hypothesis test. It also does not report whether any test was one-sided or two-sided. The general sample-size assumptions mention a two-sided significance level of 0.05, but that planning assumption does not establish the test used for the completed study.

Why can dispersion and model assumptions matter?

For continuous outcomes, variability affects how precisely a mean or contrast can be estimated. A model that assumes a particular distribution or variance structure may be inappropriate if the measurements depart substantially from those assumptions. In general, over-dispersion means that observed variability is greater than a model expects; accounting for it can affect standard errors and uncertainty intervals. The endpoint is continuous, and the registry names standard deviation, but it does not report a distributional assessment, variance model, transformation, or robust method. No assertion about over-dispersion or model fit can be made for this study.

Because the outcome is measured in a crossover design, correlation between a participant’s repeated measurements is also relevant. Ignoring such correlation can lead to incorrect uncertainty estimates. Appropriate methods vary with the design, outcome distribution, and estimand. The registry does not identify the estimand, such as whether the intended contrast was an average within-participant temperature difference or another summary. It does not provide enough information to reconstruct a valid analysis.

How should planning illustrations be read?

The registry describes sample-size planning illustrations based on a fraction of the observed effect, using a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. In general, a planning calculation estimates the number of participants per arm that might be needed under its assumptions to detect a specified effect with a chosen power. It is not a measure of the power achieved by a completed trial, and it does not demonstrate that the planned effect was observed. The record’s own sample-size justification is not reported in the registry record. Since a single primary comparison was not derived from the outcome with several categories or time points, planning values should not be treated as if they correspond to a fully specified primary contrast.

Recalculation from summary statistics would also require reported numerical summaries and a defined contrast. The registry does not report the necessary primary-outcome values or an analysis. There is therefore no basis for a numerical reanalysis or for comparing a recalculated result with a sponsor analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures and names the Tremor Rating Scale as a secondary outcome. It does not report a multiplicity strategy, such as a prespecified hierarchy or adjustment across outcomes or comparisons. Multiplicity matters in general when several outcomes, conditions, or time points are examined, because the chance of obtaining an apparently notable result can depend on how many analyses are considered. The record does not state which outcomes were treated as confirmatory or how multiple tests were interpreted.

The registry specifically notes that the primary outcome has several categories or time points and was not reduced to one comparison. Without a clearly defined primary contrast, a reader cannot identify a single estimate as the decisive test of the primary question. The registry records zero analyses, and it does not provide numerical primary or secondary outcome results.

Missing-data handling is not reported in the registry record. There is no description of participants with unavailable measurements, reasons for missingness, imputation, or sensitivity analyses. The analysis population is also not stated: the record does not say whether all randomized participants, participants completing both visits, or another group was included in an analysis. Enrollment of 20 and completed study status do not answer those questions.

The sequence descriptions do not establish whether every participant attended both visits or contributed measurements under both conditions. Such details are important in a crossover study because incomplete sequences can affect which within-participant comparisons are available. The registry does not report adherence or visit completion data. Consequently, the effect of missing observations, the analysis population, and the robustness of any outcome conclusion cannot be assessed.

11. 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.

The registry reports serious adverse events by sequence group. For 15 - 30, zero participants with a serious adverse event are listed among 10 at risk. For 30 - 15, zero are listed among 10 at risk. These are the counts recorded for the two sequence groups; they should not be added to infer a total number of distinct participants, particularly because this is a crossover study. The registry also lists zero participants with other adverse events among 10 at risk in each sequence group.

The death counts are not reported in the registry record. No serious adverse event terms are listed. The figures describe the registry’s event counts and denominators, not the completeness of event surveillance or the certainty that no event occurred. The record does not provide definitions, collection procedures, timing, severity details, or an explanation of how events were attributed to treatment conditions.

Zero events recorded in these groups cannot establish that a cooling condition is risk-free. These counts are descriptive safety information, and the registry record does not provide an analysis comparing adverse-event risk between temperatures. In a crossover design, the sequence-level safety entries also do not by themselves identify which condition preceded an event or how exposure time was handled. The counts should therefore be read narrowly as the posted adverse-event figures, without a broader safety conclusion.

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

The study record describes a practical question: whether upper-limb tremor amplitude differs after cooling with 15 degrees Celsius or 30 degrees Celsius water for 10 minutes. It also describes how randomized order was organized across two visits. Those design details clarify the intended comparison and the measurement context.

They do not provide the comparison’s result. The registry does not report observed tremor-amplitude means, a difference between conditions, an uncertainty interval, or a test result. It does not report the result for the Tremor Rating Scale secondary outcome either. As a result, the posted record cannot establish whether the measured amplitude was higher, lower, or similar under either temperature condition, or how precise any such estimate would be.

The absence of a reported result should not be interpreted as evidence that the conditions have identical effects, nor as evidence that one condition is superior. Equivalence or absence of an important difference would require a defined margin and an analysis designed to assess it; neither is reported. Likewise, statistical significance, even if available, would not alone establish clinical importance. The registry record does not provide an estimate that could be considered in either way.

The randomized crossover design may support a within-participant comparison in principle, but interpretation depends on the actual analysis and on factors such as visit order, period effects, carryover, and missing measurements. Those details are not reported. The record also does not identify an analysis population or a single primary contrast, noting that the primary outcome has several categories or time points and was not reduced to one comparison.

The narrow conclusion is therefore about what the registry records: a completed randomized crossover study with a defined cooling sequence and a specified continuous primary endpoint, but without a reported primary-outcome analysis. The adverse-event counts are descriptive and limited to the entries recorded. Neither efficacy nor a definitive safety conclusion can be drawn from these registry entries alone.

13. Why This Trial Matters Statistically

This study is statistically interesting because its crossover design matches a question in which each participant may be measured under both cooling conditions. In general, repeated measurements within a person can help separate treatment-related variation from stable differences between people. That potential advantage depends on measuring and analyzing the repeated observations appropriately. The registry identifies the crossover structure but does not report the analysis used to handle it.

The order of conditions is also central. The two sequences reverse which water temperature is given at Visit 1 and Visit 2, and randomization is recorded. In general, distributing treatment order through randomization can reduce systematic order imbalance. However, crossover interpretation can still depend on period effects, carryover, and missing visits. The record does not report washout information or methods for assessing these issues, so readers cannot judge how they were addressed.

The primary endpoint is continuous, has a stated unit, and is linked to defined test conditions. Such detail helps clarify what the outcome is intended to represent. At the same time, the record says the primary outcome has several categories or time points and was not reduced to one comparison. Defining a primary contrast is statistically consequential: it tells readers which estimate directly addresses the main question and how uncertainty should be interpreted. That contrast is not available in the registry record.

The record also illustrates why study completion and outcome reporting are distinct. A completed status and an enrollment entry do not substitute for a numerical result, an analysis population, or a description of missing data. Without those elements, neither the direction nor precision of the comparison can be evaluated, and planning assumptions cannot serve as trial findings. The main statistical contribution of the available record is therefore the description of a design and measurement plan, rather than evidence quantifying a cooling-condition effect.

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 most consequential limitation for interpreting this trial record is the absence of a reported primary-outcome comparison. The registry gives no observed mean tremor amplitudes, standard deviations, effect estimate, confidence interval, or test result. The record therefore does not support a quantitative assessment of the direction, size, or precision of any difference between cooling conditions.

The primary outcome is described as involving several categories or time points, and it was not reduced to one comparison. The registry does not identify which contrast was intended to answer the primary question. It records two outcome measures and names the Tremor Rating Scale as secondary, but the result for that secondary measure is also not reported. A multiplicity plan is not reported in the registry record.

Important analytical details are absent. The statistical model, within-participant correlation method, treatment of sequence and visit effects, assessment of carryover, analysis population, and missing-data procedures are not reported. Although the design is crossover and randomized, the registry does not provide enough information to determine how incomplete visits or measurements were handled. Single masking is recorded, but who was masked is not specified.

The record describes two 10-minute cooling visits and the corresponding sequence order, but does not report washout timing, adherence, visit completion, or the timing between visits. These omissions limit assessment of whether order-related effects could influence the endpoint. The enrollment entry of 20 does not show how many participants contributed to each outcome analysis, and the analysis count is recorded as zero.

Safety entries list zero serious and zero other adverse-event participants in each sequence group, but event definitions and surveillance details are not reported. Death counts are not reported in the registry record. These entries should not be taken as a complete characterization of safety. Finally, the trial’s own sample-size justification is not reported, and planning assumptions cannot replace outcome results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Electrophysiological Study of the Effects of Limb Cooling on Essential Tremor — NCT01093027.
• Registry record last updated 2012-12-19; status last verified 2012-12.
• Results first posted 2012-04-03.
• 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

The registry record identifies NCT01093027 as “Electrophysiological Study of the Effects of Limb Cooling on Essential Tremor,” sponsored by Mayo Clinic. It lists the study as completed, with a start date of 2010-03 and primary completion date of 2011-12. Enrollment is recorded as 20, and phase is listed as NA.

The study is randomized, single-masked, and crossover. Its two sequences apply 15 degrees Celsius and 30 degrees Celsius water cooling in opposite visit orders, with each treatment lasting 10 minutes. The primary outcome is mean tremor amplitude in cm/s^2 after cooling, averaged across four Tremor Rating Scale test conditions. Tremor Rating Scale is listed as a secondary outcome.

No primary-outcome analysis or numerical treatment comparison is reported. The record notes that the primary outcome has several categories or time points and was not reduced to one comparison. The adverse-event entries list zero affected participants in each sequence group; death counts are not reported in the registry record.