Mexiletine for the Treatment of Muscle Cramps in ALS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Mexiletine for the Treatment of Muscle Cramps in ALS (NCT01811355), a randomized phase 4 study. The primary outcome is Daily Muscle Cramps.

2. Clinical Question

The clinical question is framed around a patient-recorded symptom: how often muscle cramps occur in the preceding 24 hours. This measure focuses on frequency rather than cramp intensity, duration, or broader effects on daily life. The record does not describe those other outcomes as primary endpoints.

Because the study is registered as a crossover trial, participants were assigned to a treatment sequence rather than only to one permanently assigned parallel group. The record identifies mexiletine and placebo but does not report the treatment sequence, the timing of each treatment period, or whether a washout interval was used. Those details matter for interpreting within-participant comparisons, so they should not be inferred.

The registry record identifies the purpose and endpoint, but does not provide a treatment-effect estimate, confidence interval, or hypothesis-test result for daily cramps. It therefore does not establish from the recorded primary-outcome results whether cramp frequency differed between treatments or how precisely any difference was estimated.

3. Trial Design

This was a randomized, quadruple-masked, Phase 4 crossover study of mexiletine and placebo for muscle cramps in ALS. The registry lists an enrollment of 23 and a completed study. The start is recorded as 2013-05, and primary completion as 2016-03. The listed sponsor is Bjorn Oskarsson, MD.

Random allocation means that assignment to a treatment sequence was determined by chance, rather than being selected solely by participants or clinicians. In a crossover design, participants receive more than one study treatment over the course of the study. This design can allow comparisons within the same participant, which may reduce the influence of stable differences between people. That is a general property of crossover trials, not a claim about the analysis used in this study.

The record labels masking as quadruple, but does not identify which specific roles were masked or describe how masking was maintained. It also does not report the treatment sequence, period-specific schedule, washout arrangements, or whether any carryover assessment was planned. These are important details for understanding how a crossover comparison was conducted.

The intervention descriptions specify mexiletine as a 150mg capsule taken orally twice daily for 14 days and placebo as a capsule taken orally twice daily for 14 days. The registry record does not give further details about placebo composition or explain how the dose and treatment schedule were selected.

Although the study is marked Phase 4 and completed, the record does not provide a complete analysis plan, a sample-size justification, or a single primary-outcome treatment contrast. It states that the primary measure covers a 6 week period and that 20 patients had outcome data available for analysis after one of the 21 completers did not return the diary. These record details describe the design and recorded outcome availability; they do not by themselves establish the treatment effect.

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: Of 28 patients who signed consent, 5 did not meet inclusion criteria because of past myocardial infarction (n=1), long QT syndrome (n=1), AV block (n=1), no muscle cramps (n=1), and hospitalization during the screening period that resulted in inability to complete a screening diary and follow-up (n=1) .

First Dose

Washout

Second Dose

Analysis population for the primary outcome, as defined in the registry: Among the 21 patients who completed the study, 1 patient did not return the outcome diary, which resulted in 20 patients available for analysis.

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 Daily Muscle Cramps, measured over 6 weeks.

The primary endpoint is Daily Muscle Cramps, expressed as cramps per 24 hours. It is described as the average of daily recordings of the number of muscle cramps that occurred in the last 24 hours, over a 6 week period. This is a continuous outcome summarized as a mean, with standard deviation identified as the dispersion measure.

A daily symptom count can capture how frequently cramps occur over time, rather than relying on a single recollection at the end of treatment. Repeated diary entries may describe variation from day to day; averaging them provides a summary of typical frequency across the specified observation period. This is a general explanation of the measurement approach. The registry record does not give the diary format, the rules for handling incomplete diary days, or the exact averaging procedure.

Cramp frequency is relevant to the stated study purpose because the trial concerns treatment of muscle cramps. However, frequency alone does not describe cramp severity, duration, disruption, or a participant’s overall assessment. The record does not identify those aspects as components of the primary endpoint.

The stated timeframe is 6 weeks, while each intervention description specifies 14 days of dosing. The record does not explain the relationship between the dosing periods and the full endpoint timeframe. Nor does it provide a single primary-outcome comparison, endpoint means, standard deviations, or an estimated treatment effect. The endpoint definition is therefore available, but the posted registry information does not permit a numerical assessment of the primary result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas are relevant to understanding this study, even though the registry record does not list the specific analysis method or a primary-outcome result. The explanations below are general and should not be taken as a description of methods that the study actually used.

What does a mean represent?

The primary endpoint is described as a mean of daily cramp counts. A mean is an average that summarizes the observed values in a set of measurements. For a diary-based symptom, it can represent average recorded frequency over the observation period. A mean alone does not show whether observations were tightly clustered or widely varied; the record identifies standard deviation as the measure intended to describe dispersion. The endpoint description does not give the actual mean or standard deviation for either treatment.

A mean comparison would need to define which observations are being compared. In a crossover study, participants receive both treatments at different times. A comparison may therefore use each participant’s outcome under one treatment relative to that same participant’s outcome under the other treatment. This can account for stable participant characteristics, but it does not remove the need to consider treatment order, changes over time, or possible carryover from an earlier period. The registry record does not state how these issues were handled.

Why does the crossover design matter?

General statistical methods for crossover trials distinguish treatment effects from period effects and sequence effects. A period effect is a change associated with when an outcome is measured, whether or not it is caused by the treatment. A sequence effect can arise when participants receive treatments in different orders. Carryover refers to effects of an earlier treatment that persist into a later period. Appropriate interpretation depends on the design and analysis addressing these possibilities. The record does not report the sequence, period structure, washout arrangements, or an analysis of carryover.

Measurements from the same participant are related rather than independent. A method that treats every daily diary entry as if it came from a different person would not reflect that dependence. General approaches can model repeated measurements or summarize outcomes within participant and period before comparing treatments. The record identifies a daily measure and a crossover design, but does not state which approach was used, how diary records were aggregated, or how correlation among repeated measurements was handled.

What would uncertainty intervals tell a reader?

In general, a confidence interval describes a range of effect estimates compatible with the data and the assumptions of the statistical method. Its width communicates precision: a narrower interval indicates greater precision, while a wider interval indicates less. A confidence interval is not posted for this primary endpoint in the registry information. Without an estimate and its uncertainty interval, readers cannot judge the size or precision of a treatment difference from this record.

A hypothesis test, when used, addresses whether the observed data are inconsistent with a specified null hypothesis under a statistical model. A p-value does not measure the probability that a treatment works, nor does it indicate the clinical importance of an effect. The registry record does not report a p-value or a single primary comparison. It would therefore be inappropriate to infer a test result from the design description, outcome definition, or adverse-event counts.

Why do analysis populations and missing observations matter?

The record says that 21 patients completed the study, one did not return the outcome diary, and 20 patients were available for primary-outcome analysis. These statements describe participant and diary availability. They do not specify whether the analysis followed randomized assignment, included only participants with complete data, or used another population definition. Nor do they describe whether missing diary days occurred among participants with returned diaries.

General missing-data methods rely on assumptions about why observations are absent. If missingness is related to symptoms or treatment experience, an analysis limited to observed diary values may not represent the full set of outcomes as intended. Alternative methods can address some patterns of missingness, but their appropriateness depends on details not reported. The registry record does not describe imputation, sensitivity analyses, or missing-data assumptions.

Why is a single comparison important?

The registry indicates that the primary outcome has several categories or time points and was not reduced to one comparison. When outcomes are assessed at multiple times or in multiple ways, it is important to define which contrast is primary. Otherwise, readers may not know which estimate is intended to answer the principal question. Considering many comparisons can also increase the chance of finding an apparently notable result by chance. General methods for addressing multiplicity include prespecifying a primary contrast or adjusting the interpretation of multiple tests. The record does not report such a plan or an adjustment method.

The registry also lists no analyses. This means it does not contain a reported analysis from which the primary treatment effect can be evaluated. It does not establish that no analysis was conducted outside the registry. Any analysis method, planned or completed, is not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry record indicates that the primary outcome has several categories or time points and was not reduced to one comparison. It also lists zero analyses. As a result, the record does not identify a single primary contrast, provide an outcome estimate, or describe how multiple possible comparisons were handled. In general, when several outcomes, time points, or contrasts are considered, prespecifying the principal comparison can help readers distinguish the main question from additional analyses. Adjustment methods may also be used to account for multiple testing. The record does not report whether either approach was used.

For outcome availability, the record states that 21 patients completed the study; one patient did not return the outcome diary, leaving 20 patients available for analysis. This does not describe whether the returned diaries were complete across the entire observation period. It also does not state how missing diary entries were treated, whether any observations were imputed, or whether sensitivity analyses were conducted. Those decisions can affect the interpretation of a diary-based average, particularly if the chance of missing an entry is related to symptom experience.

The analysis population is not described beyond the number available for the primary outcome. The registry does not report whether analyses followed randomized assignment, included only participants with observed outcome data, or used another definition. It also does not report a protocol-based analysis population or the handling of participants who did not complete the study.

These omissions limit assessment of multiplicity and missing-data assumptions. They do not show that the study’s analysis was invalid, but they mean the registry record does not provide enough detail to evaluate those choices or their influence on the primary result.

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.

Most frequent non-serious adverse event terms

The registry lists serious adverse events and other adverse events separately for mexiletine and placebo. For mexiletine, serious adverse events are recorded as 0 among 23 at risk, and other adverse events as 9 among 23 at risk. For placebo, serious adverse events are recorded as 0 among 21 at risk, and other adverse events as 3 among 21 at risk. Deaths are recorded as 0 for each listed group. No serious adverse-event terms are listed.

These are descriptive registry counts. They do not, by themselves, establish whether an event was caused by a treatment, how severe the other events were, or whether the groups differed in risk. The study is registered as a crossover trial, and the record does not explain how participants’ treatment exposure was represented in these adverse-event entries. The group counts should therefore not be interpreted as a simple parallel-group comparison.

The record does not provide event descriptions for the other adverse events, timing, duration, or a statistical comparison. A count of zero serious adverse events in the posted entries is not proof that no serious event could occur, and the listed counts do not describe safety beyond the recorded study information.

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

The registry record establishes that a randomized, quadruple-masked crossover study evaluated mexiletine and placebo for muscle cramps in ALS. It describes daily cramp frequency as the primary endpoint and gives the broad study population and intervention schedules. It also reports that 21 patients completed the study and that 20 were available for the primary-outcome analysis after one patient did not return the diary.

What the record does not establish is the primary treatment effect. It contains no single primary-outcome comparison, no treatment estimate, no uncertainty interval, and no hypothesis-test result. Consequently, it cannot show from the posted primary-outcome information whether cramp frequency was higher, lower, or similar under mexiletine and placebo, or how precise a comparison would be.

This absence of a reported estimate should not be interpreted as evidence of no difference or equivalence. Establishing that treatments are sufficiently similar would require a defined comparison and an analysis designed to assess equivalence or another stated margin; such information is not reported in the registry record. Likewise, the study’s completed status does not substitute for posted outcome results.

The adverse-event counts offer a descriptive account of events recorded under the two treatment labels, but they do not support a causal conclusion. The crossover design, lack of event details, and lack of a reported safety analysis all matter when interpreting those counts.

In general, a clinical trial result is best understood through the estimated effect, its uncertainty, the analysis population, and the assumptions behind the method. Here, the registry supports a description of the question and design, but not a quantitative conclusion about the primary outcome. Any more specific claim about efficacy, precision, or the comparative safety of the treatments would go beyond what is reported.

13. Why This Trial Matters Statistically

This trial is statistically notable because it combines a crossover design with a symptom outcome collected through daily recording. In general, crossover designs can compare treatments within the same participant, while repeated diary measurements can describe symptoms across time rather than relying only on a single retrospective assessment. Both features also require careful analysis: measurements within a person are related, and treatment order or period effects may affect interpretation.

The registry record makes clear that the intended primary endpoint is a mean daily cramp count over a 6 week period, but it does not provide the treatment comparison or analysis result. This illustrates why a clearly stated outcome definition is not enough to evaluate a trial’s primary finding. Readers also need the actual estimate, its uncertainty, the analysis population, and information on how the design was reflected in the method.

The record’s note that the primary outcome has several categories or time points and was not reduced to one comparison also highlights the importance of specifying a primary contrast. Without a single reported comparison, the principal statistical answer to the study question is not available in the registry record. The record lists no analyses, so it cannot show whether multiplicity, repeated observations, or missing diary data were addressed in a particular way.

These are broader lessons in clinical-trial interpretation, not findings that a specific method was or was not used outside the registry. The study description is useful for understanding what was intended, but statistical conclusions depend on the results and analysis details that are not reported.

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.

A central limitation of the registry information is the absence of a reported primary-outcome comparison. Although the endpoint is defined and the record describes outcome availability, it does not give treatment-specific means, a treatment-effect estimate, a confidence interval, or a test result. The note that the outcome was not reduced to one comparison further prevents a direct statistical interpretation of the primary question.

Important crossover details are also not reported in the registry record. The treatment sequence, period structure, washout arrangements, and handling of possible carryover are not described. The record labels the study quadruple-masked but does not specify which roles were masked or how masking was maintained.

The primary outcome relies on daily diary recordings. The record does not describe the diary’s administration, the rules for incomplete days, or the method for averaging observations. Although one of the 21 patients who completed the study did not return the diary and 20 were available for analysis, the completeness of the returned diaries and the handling of other missing entries are not reported. The analysis population and missing-data methods are also not described.

Finally, the adverse-event entries lack event descriptions and a comparative analysis. The registry gives counts for serious and other adverse events and deaths, but does not explain how crossover exposure was accounted for. These limits concern what is documented in the registry; they do not establish whether additional design or analysis details exist elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Mexiletine for the Treatment of Muscle Cramps in ALS — NCT01811355.
• Registry record last updated 2017-08-28; status last verified 2017-07.
• Results first posted 2017-06-27.
• 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 describes a completed Phase 4, randomized, quadruple-masked crossover study of mexiletine versus placebo for muscle cramps in ALS. Enrollment is listed as 23. The study start is recorded as 2013-05, with primary completion in 2016-03.

The primary endpoint is average daily muscle cramps, measured as cramps per 24 hours over a 6 week period. The intervention descriptions specify mexiletine 150mg orally twice daily for 14 days and placebo orally twice daily for 14 days. The record states that 21 patients completed the study; one did not return the outcome diary, leaving 20 available for primary-outcome analysis.

The registry does not report a single primary-outcome comparison or listed analysis results. Serious adverse events and deaths are recorded as 0 in both listed groups; other adverse events are recorded as 9 for mexiletine and 3 for placebo. These entries are descriptive and do not establish comparative treatment effects.