Safety and Efficacy of Clenbuterol in Individuals With Late-onset Pompe Disease and Receiving Enzyme Replacement Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Clenbuterol in Individuals With Late-onset Pompe Disease and Receiving Enzyme Replacement Therapy (NCT01942590), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants With a Change in Creatine Kinase (CK) Reflecting Worsening of Muscle Involvement.

2. Clinical Question

The study asked about safety and efficacy of clenbuterol on motor function in people with late-onset Pompe disease receiving enzyme replacement therapy. The primary outcome, however, was a count based on a creatine kinase threshold, rather than a direct motor-function measurement. The registry also lists secondary outcomes involving walking, pulmonary function, a urinary biomarker, and motor-function assessments.

The primary counts describe whether participants crossed the stated laboratory threshold during follow-up. They do not by themselves establish a difference between the treatments. The registry record does not report a statistically estimated treatment effect or a confidence interval for this outcome, and it does not report the analysis details needed to assess the precision of a comparison. The question can therefore be framed as a comparison of the posted event counts, while keeping the uncertainty around that comparison explicit.

3. Trial Design

The registry identifies this as a randomized, quadruple-masked, parallel trial in phase 1 and phase 2. Randomization is a design method intended to reduce systematic differences between treatment groups; it does not ensure that all prognostic characteristics are balanced, especially in a small study. The registry record does not report the randomization sequence method, allocation concealment details, or the identities of the people covered by quadruple masking.

In a parallel design, participants are assigned to a group and followed within that group rather than switching between study treatments. The listed interventions were clenbuterol and placebo. Both arm descriptions give an escalating schedule, with increases conditional on tolerability, and describe treatment through week 52. The record does not report whether participants who could not tolerate an increase continued at a lower dose or how dose changes were handled analytically.

The registry lists enrollment of 17 and a primary completion date of 2016-09-02. The primary outcome counts are reported for 8 participants in the clenbuterol arm and 5 in the placebo comparator arm. These posted outcome denominators are not a complete account of participant flow: reasons for any difference between enrollment and the outcome counts, withdrawals, and analysis-set membership are not reported in the registry record. The record lists the study status as completed.

The clinical question concerns use of clenbuterol in people already receiving enzyme replacement therapy. The record does not specify further eligibility criteria, the underlying enzyme replacement regimens, or whether these were stable during the trial. It lists 13 outcome measures, 11 posted secondary outcomes, and 30 analyses. Those counts indicate that results span more than the primary endpoint; the statistical plan for choosing or interpreting analyses is 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:

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 a Change in Creatine Kinase (CK) Reflecting Worsening of Muscle Involvement, measured over Any point up to week 52.

The primary endpoint is the number of participants whose creatine kinase change reflected worsening muscle involvement at any point up to week 52. The registry defines worsening as a greater than 3-fold increase in creatine kinase from baseline that is also greater than 2-fold the upper limit of normal. The endpoint is thus a threshold-based binary outcome: each participant either met the definition or did not, as captured in the posted counts.

Creatine kinase is a laboratory measure used to characterize muscle involvement. A threshold can make an outcome rule explicit and can focus attention on marked changes rather than small fluctuations. At the same time, converting a continuous laboratory value into a yes-or-no classification loses information about the size and timing of changes that do not cross the threshold. The posted endpoint does not describe each participant’s creatine kinase trajectory or the number and duration of measurements.

The endpoint is not itself a direct measure of walking, strength, or daily function. The registry’s secondary outcomes include change in the 6 Minute Walk Test, Forced Vital Capacity, urinary Glc4, GSGC, and the Quick Motor Function Test. Those outcomes address other aspects of health and function, but they should not be conflated with the primary laboratory threshold. The record does not report why this particular threshold was selected or how it was expected to relate to clinically meaningful change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is this? The primary measure is binary at the participant level: a person either meets the creatine kinase definition of worsening or does not. The registry reports counts, with 1 event among 8 participants in the clenbuterol group and 0 among 5 in the placebo comparator group. For binary outcomes, the count and its denominator are both essential. A count without its denominator cannot describe how common the event was in the group, and a denominator without the count cannot show how many events were observed.

Why does a small count need careful interpretation? When event counts are sparse, the observed pattern can be highly sensitive to individual outcomes. Standard approximations used for some statistical tests or confidence intervals may be unreliable when there are few events or an empty cell. Exact methods or other approaches designed for sparse data may be considered in general, but the statistical method used for the sponsor’s analysis is not reported in the registry record. No inferential method should be attributed to the study without that information.

A confidence interval, in general, gives a range of values that are compatible with the data under a specified statistical model and method. It communicates uncertainty in an estimate; it is not a guarantee that the true value lies in that particular interval. No confidence interval for the primary two-arm comparison is reported in the registry record. Because the registry states that a two-arm comparison was missing or not estimable, the raw counts should not be converted into a claim of statistical significance or certainty.

What does randomization contribute? In general, random assignment helps make groups comparable with respect to both measured and unmeasured baseline factors over repeated use of the same design. In any particular trial, chance imbalances can remain, and randomization does not correct problems caused by missing outcomes, nonadherence, or biased measurement. The record labels the trial randomized but does not report the sequence-generation method, allocation concealment, baseline characteristics, or balance assessment. The label alone does not answer those questions.

How should masking be understood? The record labels masking as quadruple. Masking is generally intended to reduce the influence of knowledge of assigned treatment on participant experience, care, outcome assessment, or reporting. The record does not identify which roles were masked, whether masking was maintained, or whether treatment assignment was guessed. Those details matter particularly for subjective outcomes, while the primary endpoint is based on a laboratory threshold. The record does not report procedures for laboratory measurement or review.

What are the limits of a threshold outcome? A binary threshold simplifies interpretation by classifying whether the stated event occurred. But it discards variation in the continuous measure: participants just below the criterion are grouped with those showing little change, while people who cross the criterion are counted together despite potentially different magnitudes. General statistical practice may also examine continuous change, repeated measurements, or time patterns when those data and analyses are available. The registry record does not report such primary-outcome analyses, the underlying creatine kinase values, or the timing of any qualifying event beyond the window up to week 52.

What does the sample-size illustration represent? The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning calculations, not observed power and not evidence that the trial was designed with those assumptions. For non-time-to-event outcomes, the described output is participants per arm for 80% power or another stated power level; time-to-event calculations are described in terms of total events. The record does not report a trial-specific sample-size justification. Since the primary binary comparison is described as not estimable, the illustration should not be treated as a reliable design recommendation for this endpoint.

Why might over-dispersion matter in general? Over-dispersion occurs when observed variation exceeds what a chosen statistical model expects. It can make standard errors too small if not accounted for, leading to overly narrow intervals or optimistic tests. This is a general issue for some count and clustered data analyses; the registry record does not state that over-dispersion was assessed or that it applies to this trial’s primary binary outcome. It should not be presented as a finding about this study.

What is missing for a fuller statistical assessment? The registry record does not report the sponsor’s statistical model, test, confidence interval, adjustment variables, handling of missing data, or analysis population. It also does not report whether the primary outcome definition or analysis changed, whether interim analyses occurred, or what rules governed multiplicity. These omissions prevent reconstruction of a complete inferential analysis from the posted counts. A simple recalculation from group summaries, if undertaken, would be unadjusted and should not be confused with the sponsor’s analysis.

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("Clenbuterol", "Placebo Comparator")
n      <- c(8, 5)
events <- c(1, 0)
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  Clenbuterol  8  1  12.5  0.3  52.7  2.2  47.1  2.8  48.2
ARM  Placebo Comparator  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9

11. Multiplicity, Missing Data and Analysis Populations

The record lists 13 outcome measures, 11 posted secondary outcomes, and 30 analyses. Several secondary outcome names appear more than once in the registry listing. With multiple outcomes and analyses, a chance finding can become more likely if each result is examined separately without a prespecified strategy. In general, multiplicity methods can control error rates or prioritize outcomes, but the choice depends on the study’s aims and analysis plan.

The registry record does not report whether the primary endpoint was formally prioritized for hypothesis testing, whether secondary outcomes were treated as exploratory, or whether any multiplicity adjustment was planned or used. It also does not report interim analyses or stopping rules. No conclusion about the handling of multiple comparisons can therefore be drawn from the list of outcomes and analyses alone.

Missing-data handling is similarly unclear. The primary outcome counts are reported for 8 participants in the clenbuterol arm and 5 in the placebo comparator arm, while enrollment is listed as 17. The record does not provide participant flow, reasons for missing outcomes, the number of randomized or treated participants in each analysis, or an imputation or sensitivity-analysis method. These details matter because the interpretation of an observed event count depends on which participants contributed data and how unavailable measurements were treated.

The record does not identify an intention-to-treat, per-protocol, safety, or other analysis population for the primary result. It also does not describe protocol deviations or treatment discontinuations. Consequently, the posted counts cannot be assigned to a particular analysis population beyond the arm denominators shown.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fall (12.5%).

The serious adverse event figures list 1 participant affected among 8 at risk in the clenbuterol group and 0 among 5 at risk in the placebo comparator group. The listed top serious-event term is “fall,” with 12.5% recorded. The record does not provide enough detail to determine from that term alone how the event relates to the participant-level serious-event count, and it does not report the event narrative or timing.

The registry also reports 0 deaths in each group. Other adverse events affected 8 participants among 8 at risk in the clenbuterol group and 5 among 5 at risk in the placebo comparator group. These categories should not be conflated: the record distinguishes serious adverse events from other adverse events. The presence of an adverse event does not, by itself, establish that the intervention caused it.

These counts are descriptive. They do not give a precise estimate of comparative safety, and a zero count in a group does not demonstrate that the underlying risk is zero. The registry record does not report event severity beyond the serious-event classification, exposure-adjusted rates, duration, attribution details, or a statistical comparison. The small listed groups and limited event information warrant a cautious reading rather than a broad safety conclusion.

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

The posted primary result records a creatine kinase threshold event in 1 participant receiving clenbuterol and none in the placebo comparator group. This describes what was counted under the registry definition during the stated follow-up window. It does not, on its own, show that clenbuterol caused the event or that the groups differ reliably. The record provides no comparative estimate or uncertainty interval for this endpoint.

The trial was designed to investigate safety and efficacy on motor function in people with late-onset Pompe disease receiving enzyme replacement therapy. The primary endpoint is a laboratory threshold, while the secondary outcomes listed include functional and pulmonary measures. A finding on the primary laboratory endpoint cannot substitute for results on those other outcomes. Their numerical results are not included in the registry record for this interpretation.

The record does not establish whether the observed event pattern is compatible with a meaningful difference, no meaningful difference, or a range of possibilities between those. Lack of a reported comparison is not proof that the groups are equivalent, just as the observed count in one group is not proof of a treatment effect. Precision is particularly important when the event counts are sparse, and a confidence interval or other uncertainty measure is not reported.

The safety figures likewise do not establish a complete comparative safety profile. One serious adverse event was recorded in the clenbuterol group and none in the comparator group, while other adverse events were recorded in both groups. The record does not describe causality, event course, or all clinical context needed to interpret these observations. No treatment recommendation follows from these registry counts.

The study’s randomized, masked design is relevant context, but important implementation and analysis details are not reported. Participant flow, missing-data methods, analysis populations, and the complete statistical plan are not available in the registry record. Accordingly, the results should be read as limited descriptive evidence about the recorded outcomes, rather than as a definitive estimate of treatment effect.

14. Why This Trial Matters Statistically

This trial raises several statistical issues that are common in small clinical studies. The primary outcome is binary and its posted event counts are sparse, including a group with no recorded event. Such data call for careful attention to the method used for estimation and inference. A raw count pattern can be informative descriptively, but it does not reveal how uncertain a treatment comparison is.

The contrast between the endpoint and the study’s stated motor-function purpose is also important. A laboratory threshold can capture a particular type of change, while walking tests, pulmonary function, and motor-function assessments address different dimensions. Multiple outcomes can provide a broader view, but they require clear prioritization and transparent reporting. The registry lists numerous outcomes and analyses, while its multiplicity strategy is not reported.

Trial registration offers key design information: randomization, quadruple masking, a parallel model, phase 1 and phase 2, and the treatment schedules. Yet a registry record is not necessarily a complete statistical report. In this case, the sponsor’s inferential method, missing-data approach, analysis population, and participant flow are not reported. Those omissions limit the ability to judge precision and robustness from the posted primary counts.

The sample-size assumptions also illustrate a distinction between planning and evidence. A calculation based on an observed effect is a planning illustration, not observed power and not proof that a study was adequately sized. For a sparse binary outcome whose two-arm comparison is listed as not estimable, a planning number derived from the observed effect would require especially cautious interpretation. Clear reporting of the outcome definition, denominators, uncertainty, and analysis decisions is central to making a small trial statistically interpretable.

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 primary outcome is reported as counts without a comparative estimate, confidence interval, or p-value. The registry explicitly notes that values were missing or not estimable for a two-arm comparison of this binary endpoint. As a result, the strength and precision of any treatment-group contrast cannot be assessed from the posted primary result.

The primary endpoint uses a threshold for creatine kinase change. The record does not report participant-level values, the number of measurements, the timing of measurements, or how repeated results were summarized. The binary classification also does not show the degree of change among participants who did not meet the worsening definition.

Enrollment is listed as 17, but the posted primary outcome denominators are 8 and 5. Participant flow, reasons for absence from the outcome counts, missing-data handling, and the analysis population are not reported in the registry record. This limits assessment of whether the counts represent all randomized participants and whether missing outcomes could affect interpretation.

The registry lists multiple secondary outcomes and analyses, but does not report the statistical analysis plan, multiplicity approach, interim analyses, or the sponsor’s method for the primary comparison. Further trial-specific details are also absent, including the randomization procedure, masking roles, baseline characteristics, and the basis for the primary threshold. The record does not report secondary outcome results in the registry record considered for this interpretation. These limitations constrain conclusions about efficacy, safety, and generalizability beyond the descriptive results recorded.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Clenbuterol in Individuals With Late-onset Pompe Disease and Receiving Enzyme Replacement Therapy — NCT01942590.
• Registry record last updated 2019-07-02; status last verified 2019-06.
• Results first posted 2017-10-23.
• 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

NCT01942590 is a completed randomized, quadruple-masked, parallel phase 1/phase 2 trial of clenbuterol versus placebo in individuals with late-onset Pompe disease receiving enzyme replacement therapy. Enrollment is listed as 17, and the primary completion date is 2016-09-02. The primary outcome counted participants with creatine kinase worsening, defined by the stated thresholds, at any point up to week 52.

The posted primary counts are 1 participant in the clenbuterol group and 0 in the placebo comparator group. The registry notes that a two-arm comparison for this binary endpoint was missing or not estimable. It lists secondary measures covering walking, pulmonary function, urinary Glc4, gait and related motor tasks, and the Quick Motor Function Test. The registry record does not report the primary comparison’s inferential method, confidence interval, missing-data approach, analysis population, or multiplicity strategy.