Respiratory Muscle Training (RMT) in ALS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Respiratory Muscle Training (RMT) in ALS (NCT04224961), a non-randomized na study. The primary outcome is Number of Participants With Safe, Well-tolerated Moderate Intensity Respiratory Muscle Training (RMT) as Measured by Rating of Perceived Exertion (RPE).

2. Clinical Question

3. Trial Design

This completed study, sponsored by Duke University, concerns moderate-intensity respiratory muscle training in ALS. The registry lists a non-randomized, parallel design with no masking. Enrollment is recorded as 9. The brief summary, however, describes a planned study of twelve adults, allocated by baseline inspiratory muscle strength into two groups of six. The reason for the difference between the planned number and the registry enrollment is not reported in the registry record.

The group definitions use maximum inspiratory pressure (MIP): minimal to no respiratory weakness is MIP ≥ 70% predicted, and mild to moderate inspiratory weakness is MIP 40-70% predicted. Both group descriptions specify a home-based RMT program and weekly web-based RMT therapy sessions. The brief summary describes four 3-week cycles of progressive RMT. MIP and maximum expiratory pressure (MEP) were to be measured weekly, with most measurements obtained through web-based telehealth visits.

The primary outcome is a count of participants who completed the study and met the registry’s definition of safe, well-tolerated moderate-intensity training, assessed in part by RPE over 12 weeks. Listed secondary outcomes are change in peak cough flow and change in sniff nasal inspiratory pressure. The registry lists 7 outcome measures but 0 analyses. Outcome results and a statistical analysis plan are not reported in the registry record.

Because the groups are based on baseline strength and there is no randomized control group, differences between them would not isolate the effect of training. Baseline respiratory status could be related to subsequent measurements or events. The record does not describe an untreated or alternative-treatment comparison.

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: Participants who completed the study.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Safe, Well-tolerated Moderate Intensity Respiratory Muscle Training (RMT) as Measured by Rating of Perceived Exertion (RPE), measured over 12 weeks.

The primary endpoint is the number of study completers meeting the registry’s definition of safe, well-tolerated moderate-intensity RMT, assessed in part using rating of perceived exertion (RPE), over 12 weeks. RPE is a self-rating of how hard a participant feels their body is working. The registry gives a scale from 0 = rest through 10 = maximal, with verbal anchors such as 4 = somewhat hard and 5 = hard. The stated criterion includes an RPE between 4-5 and <6.

A participant count is a direct way to describe how many completers met the specified criterion. It is not, by itself, a measure of the size of a change in respiratory function, nor does it establish that training caused the experience recorded. The endpoint’s interpretation depends on how the criterion was applied across sessions and participants. The registry description does not report those operational details, such as whether a participant had to meet the RPE criterion at every session or how missing session ratings were handled.

The endpoint population is participants who completed the study, rather than all enrolled participants. The number of completers meeting the criterion is not reported in the registry record, so the primary outcome cannot be quantified from the record. The record also does not report an uncertainty interval or inferential test for this count.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods are difficult to assess because the registry lists 0 analyses and does not report a statistical analysis plan. The following concepts are general explanations of how the listed outcomes and design are commonly interpreted; they are not claims about procedures used in this study.

Counts and denominators

The primary outcome is a count: the number of participants who completed the study and met a stated RPE-based criterion. A count is most interpretable alongside its denominator. Here the target population is described as study completers, but the number of completers and the number meeting the criterion are not reported in the registry record. Without both, readers cannot determine the observed frequency of meeting the criterion. A count also does not show whether participants met the criterion throughout training or only at particular assessments; that rule is not reported.

Adverse-event counts likewise need their at-risk denominators and group context. The registry reports both, but the denominators differ between the baseline-strength groups. In general, raw counts from groups of different sizes should not be read as directly comparable measures of risk. A formal comparison would also need an appropriate analysis plan and sufficient information about event timing, ascertainment, and participant follow-up. Those details are not reported in the registry record.

Repeated measurements

The brief summary describes weekly MIP and MEP measurement during four 3-week training cycles, with most measurements intended to occur in telehealth visits. Repeated observations from one participant are correlated: measurements from the same person tend to share characteristics and are not equivalent to measurements from separate people. General analyses of repeated measurements account for this dependence, for example by modeling participant-level trajectories or using methods that allow within-person correlation. Treating every weekly measurement as independent could make uncertainty appear smaller than it is.

To interpret change over time, readers would need the observed values, the timing and number of measurements, and a definition of the contrast being estimated. A change from baseline, a trend over sessions, and a difference in trajectories between groups are distinct questions. The record does not report estimates or a model for these outcomes, and it does not state how incomplete measurement series were handled.

Non-randomized group comparisons

The two groups are stratified by baseline MIP, and both are described as receiving RMT. In general, stratification by a baseline characteristic can help describe participants with different starting respiratory strength, but it does not create a randomized control condition. Group comparisons may reflect baseline differences or other factors associated with group membership. Randomization is one way to balance such factors on average; this study is listed as non-randomized. The registry does not report an adjusted group analysis, so no adjustment should be presumed.

Masking is listed as none. For outcomes that include participant ratings, such as RPE, knowledge of the training experience may influence reporting. This is a general consideration, not evidence that ratings in this study were biased. The registry does not report procedures intended to limit or assess measurement bias.

Uncertainty and statistical significance

A confidence interval is a general statistical tool for expressing the precision of an estimate. A narrow interval indicates greater precision under the model used; a wide interval indicates greater uncertainty. For a participant count or proportion, an interval would need a defined denominator and a statistical method. No interval for the primary outcome is reported in the registry record. A p-value, if reported, would address compatibility of the data with a specified statistical hypothesis under stated assumptions; it would not by itself measure clinical importance or prove causation. No p-value or inferential test is listed.

Planning illustrations

The registry describes sample-size calculations as planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It states that the effect to detect is a specified fraction of the observed effect. Such illustrations are not observed power and are not evidence that an outcome was detected. They depend on the assumptions and on the effect estimate used. The registry does not report the numerical illustrations or the observed primary outcome result in the record. The sample-size justification used when the study was designed is not reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Minimal to No Respiratory Weakness")
n      <- c(7)
events <- c(4)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Minimal to No Respiratory Weakness  7  4  57.1  18.4  90.1  25.0  84.2  24.5  84.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 outcome measures, including a primary outcome and named secondary outcomes of change in peak cough flow and change in sniff nasal inspiratory pressure. It lists 0 analyses. A complete statistical analysis plan would ordinarily clarify which outcomes are primary or secondary, the specific contrasts and time points, the models used, and how multiple testing is handled. Those analysis details are not reported in the registry record.

Multiplicity arises when several outcomes, time points, or comparisons are tested. In general, considering many tests can increase the chance that at least one appears statistically notable by chance. Analysis plans may address this through a prespecified hierarchy, adjusted significance thresholds, or a clear distinction between confirmatory and exploratory results. No multiplicity approach is reported, so it is not possible to determine whether any outcome testing was adjusted or how results were intended to be prioritized.

The primary endpoint is defined among participants who completed the study. The number of completers is not reported, and the registry does not describe how participants who did not complete or who had missing RPE observations were handled. It also does not report missing-data assumptions, imputation, sensitivity analyses, or rules for excluding observations. These omissions matter because an analysis limited to completers can differ from one that includes all enrolled participants, particularly if completion or missingness is related to health status or training experience. No analysis population beyond the stated completer population is 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: respiratory decline (100.0%).

The registry reports serious adverse events separately for the two baseline-strength groups. In the minimal to no respiratory weakness group, 0 serious adverse events are listed among 8 participants at risk. In the mild to moderate inspiratory weakness group, 1 is listed among 1 participant at risk. Deaths are listed as 0 in both groups. The registry’s top serious adverse event term is respiratory decline, listed at 100.0%.

Other adverse events are reported for 5 of 8 participants in the minimal to no respiratory weakness group and 1 of 1 in the mild to moderate inspiratory weakness group. These are counts from small and unequal groups. They should be read as descriptive registry data, not as a reliable comparison of event risk or evidence that group membership or training caused an event. Because the study has no randomized control group, the figures do not distinguish events related to training from events related to ALS or other circumstances.

The registry does not report event timing, severity details beyond the serious-event classification, participant-level context, or a causal attribution assessment. The 100.0% listing for respiratory decline identifies the top serious-event term in the registry; it does not by itself provide a complete account of all safety outcomes or their relationship to RMT.

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

The registry record establishes that a completed, non-randomized study examined moderate-intensity RMT in ALS. It describes home-based training with weekly web-based sessions, planned repeated measurement of MIP and MEP, two baseline-strength groups, and a primary outcome based in part on perceived exertion. It also reports adverse-event counts. These details help define what the investigators intended to study and the context in which the results would need to be interpreted.

The posted record does not report the primary endpoint count, the number of study completers, or results for the listed secondary outcomes. It therefore does not show how many participants met the RPE criterion or what changes occurred in respiratory measures. It also provides no confidence interval or statistical test for the primary outcome. Without those results, the magnitude and precision of any observed outcome cannot be assessed.

The group structure does not support a randomized comparison of training with no training: both groups are described as receiving RMT, and allocation is based on baseline inspiratory strength. Differences between groups would not by themselves show that training caused a difference. The design can describe experiences within the study groups, but a causal claim would require a suitable comparison and an analysis that addresses the study design and its limitations.

The adverse-event counts are descriptive, with few participants and different group denominators. They should not be treated as comparative estimates of safety. Nor should the registry’s completed status be taken to mean that every planned measure or analysis is reported. In short, the record describes the study question and design, but does not report the outcome data needed to quantify the primary result or evaluate the planned respiratory measures.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of how a study question, its endpoint, and its design must be considered together. The primary question is framed as a participant count based on perceived exertion, while the study also planned repeated physiological measurements. These outcomes answer different questions: an RPE-based count describes participants’ reported training intensity and tolerability under the stated criterion, whereas repeated MIP and MEP measurements would describe respiratory pressure over time.

The non-randomized grouping is important to interpretation. Participants are separated by baseline inspiratory strength, while both groups receive the described program. That arrangement can make the groups useful for describing training in different baseline-strength categories, but it does not create a control group. A statistical contrast cannot remedy the absence of randomized allocation simply by producing a p-value.

The record also illustrates why enrollment, completion, and analysis populations should be distinguished. Enrollment is recorded as 9, while the brief summary describes twelve planned participants in two groups of six. The primary endpoint concerns completers, but their number and the outcome count are not reported. Without clear denominators and outcomes, readers cannot evaluate the endpoint’s precision or assess how missing observations might affect interpretation.

Finally, listing multiple outcome measures without reporting analyses leaves uncertainty about how results were to be prioritized and how repeated measurements or multiple tests were handled. These are not merely technical details: they determine what an estimate means and how confidently it can be interpreted. The registry record makes the intended question visible, but the absence of outcome results and analysis details limits statistical conclusions.

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 registry reports enrollment of 9, whereas the brief summary describes twelve planned participants, split into two groups of six. The reason for the discrepancy is not reported in the registry record. The number who completed the study is also not reported, even though the primary outcome population is defined as completers. This prevents reconstruction of the primary outcome denominator.

The primary endpoint result is not reported in the registry record. Neither the number meeting the RPE criterion nor the handling of repeated ratings is stated. Results for the other listed outcome measures are also not reported. The registry lists 7 outcome measures but 0 analyses, and does not report estimates, confidence intervals, or statistical tests.

The study is non-randomized, unmasked, and has no described control group. The two groups are defined by baseline MIP and receive the same described intervention, limiting interpretation of between-group differences. The record does not report an adjustment strategy for baseline differences or other potential confounding.

The group denominators in the adverse-event record are small and unequal. Event timing, detailed ascertainment procedures, and causal attribution are not reported. The record also does not report how missing observations, withdrawal, or deviations from the training schedule were handled. In addition, the sample-size justification and the statistical analysis plan are not reported in the registry record. These limitations constrain both quantitative interpretation and assessment of the study’s intended analysis.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Respiratory Muscle Training (RMT) in ALS — NCT04224961.
• Registry record last updated 2026-01-29; status last verified 2026-01.
• Results first posted 2026-01-29.
• 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

NCT04224961 is a completed, non-randomized, unmasked, parallel study of respiratory muscle training in ALS, sponsored by Duke University. Registry enrollment is 9. The brief summary describes twelve planned adults, divided into two groups based on baseline MIP; the difference between planned and recorded enrollment is not explained in the registry record.

The described intervention is home-based RMT with weekly web-based therapy sessions. The brief summary describes four 3-week training cycles and weekly MIP and MEP measurement. The primary outcome is a count of completers meeting an RPE-based moderate-intensity criterion over 12 weeks. Peak cough flow and sniff nasal inspiratory pressure are named secondary outcomes.

The record lists 7 outcome measures and 0 analyses. It does not report the primary endpoint result, results for the secondary outcomes, a statistical analysis plan, or a sample-size justification. Adverse-event counts are recorded for both baseline-strength groups, but the non-randomized design and small, unequal groups limit comparative interpretation.