A Trial to Evaluate Safety, Tolerability and Efficacy of Elamipretide in Subjects With Barth Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Trial to Evaluate Safety, Tolerability and Efficacy of Elamipretide in Subjects With Barth Syndrome (NCT03098797), a randomized phase 2, phase 3 study. The primary outcome is Part 1: Distance Walked During the 6-Minute Walk Test (6MWT) by Visit.

2. Clinical Question

3. Trial Design

This was a randomized crossover trial of elamipretide and placebo in participants with Barth syndrome. The registry lists the study as Phase 2 and Phase 3, with enrollment of 12 and completed status. Its official title describes a Phase 2 randomized, double-blind, placebo-controlled crossover trial followed by open-label treatment. The registry’s masking field says quadruple masking. The record does not explain the difference in wording, so the masking details should be reported as listed rather than interpreted further.

In Part 1, participants were assigned to one of two treatment sequences. The elamipretide-then-placebo sequence received 40 mg of elamipretide by daily subcutaneous injection for 12 weeks, followed by 12 weeks of placebo. The placebo-then-elamipretide sequence received the treatments in the reverse order. Both sequences included a 4 week washout between periods. This arrangement allows each participant to receive both treatments, while randomizing which treatment comes first.

The registry also describes Part 2 as an open-label extension in which all participants would receive elamipretide. The available arm descriptions end before the full treatment details, and the extension duration is not reported in the registry record. The primary outcome is specifically labeled as a Part 1 measure. Some secondary outcomes are labeled Part 1 and others Part 2, including walking distance, fatigue, muscle strength, sit-to-stand performance, and balance assessments.

A crossover design can be informative because treatment outcomes may be compared within the same participants. In general, however, interpretation can depend on treatment order, changes over time, and whether effects persist into a later period. The registry record gives the sequence and washout but does not report how these design features were handled in an analysis. No analysis results are listed.

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.

First Intervention (12 Weeks)

Washout (4 Weeks)

Second Intervention (12 Weeks)

Part 2 Open Label Extension

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants for whom 6MWT was measured.

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 Part 1: Distance Walked During the 6-Minute Walk Test (6MWT) by Visit, measured over Pre-dose to Week 12 (end of treatment).

The primary endpoint was distance walked during the 6-Minute Walk Test, recorded in meters. The registry defines the measurement as the average distance walked during the test at the end of treatment: the end of Visit 5 at Week 12 for Period 1 and the end of Visit 10 at Week 12 for Period 2. Results were described as pooled for each 12 week period. The stated population was all participants for whom the test was measured.

As a continuous measure, walking distance retains gradations in performance rather than reducing the outcome to a simple yes-or-no category. In general, a timed walking test is used to assess functional performance over a defined task. The endpoint therefore provides a directly measured distance, while its interpretation remains specific to the test procedure and the trial population.

The registry identifies the intended summary as a mean with standard deviation. Those labels describe how numerical observations could be summarized: the mean gives a central value, while the standard deviation describes variability among measurements. The registry record does not report the actual means or standard deviations for either treatment period, nor does it provide a treatment contrast or confidence interval. The endpoint definition alone therefore does not establish the direction, size, or precision of any treatment difference.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is continuous: each 6-Minute Walk Test produces a distance in meters. The registry says the intended summary is a mean and standard deviation. In general, the mean describes the center of a set of measurements, while the standard deviation describes how spread out individual measurements are around that center. Neither summary, by itself, describes the uncertainty in a treatment comparison.

What would a treatment contrast represent?

In general, a treatment contrast compares the outcome under one treatment with the outcome under another. For a crossover trial, the observations are linked within participants because each participant receives both treatments. A suitable analysis would usually reflect that pairing rather than treating the observations as if they came from unrelated groups. The registry record does not report a treatment contrast or the model used to estimate one, so no particular analysis can be attributed to this trial.

The record states that results were pooled for each 12 week period. It does not explain whether pooling refers to a specific statistical model or how treatment sequence and period were incorporated. In a crossover trial, period effects can arise when outcomes change over time regardless of treatment. Sequence effects can arise when the order of treatments is relevant. Carryover is a further general concern if an effect from one period persists into the next. A 4 week washout is described, but the record does not report whether carryover was assessed or what assumptions supported the chosen analysis.

How should uncertainty be understood?

In general, a confidence interval gives a range of values compatible with the data and the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, while an interval spanning values on either side of no difference may leave the direction and size of a treatment contrast uncertain. The registry record does not report a confidence interval for the primary outcome, so its precision cannot be evaluated.

A p-value, in general, describes how compatible the observed data are with a specified null hypothesis under an analysis model. It does not measure the probability that a treatment works, and it does not convey the size or clinical importance of an effect. No primary-outcome p-value is reported in the registry record. The listing of zero analyses means there is no reported inferential result to interpret.

What does the outcome population mean?

The registry describes the primary population as all participants for whom the 6-Minute Walk Test was measured. This wording identifies a measurement-based population, but it does not specify how many participants had measurements at each time point or how missing observations were handled. In general, excluding participants without measurements can affect interpretation if the reasons for missingness are related to outcome or treatment. The record does not provide enough detail to assess that issue.

The sample-size assumptions described for planning illustrations are not a report of the trial’s design justification. The record does not report the trial’s sample-size rationale, a target effect used to plan enrollment, or a statistical power calculation for the trial. Any planning illustration based on an observed effect is not observed power and should not be treated as evidence that the trial was adequately or inadequately powered.

For continuous outcomes, over-dispersion is not the central issue in the same way it can be for count outcomes. In general, the relevant questions include the distribution of the measurements, their variability, the paired structure, and whether the analysis accounts for the trial periods and sequences. Those details are not reported in the registry record. Without the outcome values and analysis specification, it is not possible to reproduce or evaluate a treatment-effect estimate.

The statistical description is therefore limited to the outcome definition, its planned mean and standard-deviation summary, and the crossover schedule. The record does not report model terms, covariate adjustment, confidence intervals, hypothesis tests, or sensitivity analyses. General explanations of these concepts do not imply that a particular method was used in this trial.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures, including the primary 6-Minute Walk Test outcome and secondary outcomes involving walking distance, fatigue, muscle strength, sit-to-stand performance, and balance. Several outcomes are described across visits or as changes from baseline. When a study examines multiple outcomes, time points, or comparisons, the chance of finding at least one apparently unusual result can increase. In general, a statistical plan may address this through a defined hierarchy or an adjustment strategy. Such a multiplicity plan is not reported in the registry record.

The record lists zero analyses, so it does not provide an inferential result for the primary or secondary outcomes. It also does not report a prespecified analysis plan, hypothesis-testing sequence, or adjustment for multiple comparisons. The absence of these details does not show that no plan existed; it means the registry record does not report one.

The stated primary-outcome population includes participants for whom the 6-Minute Walk Test was measured. The number with measurements at each visit, reasons for missing measurements, and methods for handling missing data are not reported in the registry record. In general, missing-data methods can affect estimates and their uncertainty, particularly when the likelihood of missingness is related to participants’ outcomes or treatment experience. No specific missing-data method can be inferred.

The record also does not describe an intention-to-treat, per-protocol, or other analysis population for the primary comparison. The measured-outcome population definition should not be taken as a full account of the analysis set or as evidence about how participants with incomplete data were treated. These reporting gaps limit assessment of the statistical interpretation of the trial outcomes.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumothorax (20.0%), mucositis (20.0%), costochondritis (20.0%), abscess of right axilla (20.0%), gastroenteritis (20.0%).

The registry reports serious and other adverse events separately for Part 1 and the open-label extension. For Part 1, the record lists 0 serious adverse events among 12 participants at risk in the elamipretide group and 0 among 12 at risk in the placebo group. Other adverse events were listed for 12 of 12 participants at risk in each group. The record lists no deaths in either group.

For the open-label extension, the sequence AB group lists 1 of 5 participants at risk as affected by a serious adverse event, and the sequence BA group lists 4 of 5. Other adverse events were listed for 5 of 5 participants at risk in each sequence. No deaths were listed in either extension group. These group counts should be read within their stated treatment period and sequence; they are not a single combined comparison.

The registry lists Pneumothorax, Mucositis, Costochondritis, Abscess of Right Axilla, and Gastroenteritis among the top serious adverse event terms, each at 20.0%. These term percentages do not by themselves provide the full event context, timing, severity detail, or treatment attribution. The record does not establish that any listed event was caused by elamipretide or placebo. The counts are descriptive safety information, not comparative evidence of a causal effect.

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

The registry record establishes that this was a randomized crossover trial of elamipretide and placebo in participants with Barth syndrome, with an open-label extension described after Part 1. It specifies the primary outcome as distance walked during the 6-Minute Walk Test at the end of each 12 week period. It also reports enrollment of 12 participants and selected adverse-event counts.

Those details do not establish the size or direction of a treatment effect. The registry record does not report the primary outcome means, standard deviations, treatment contrast, confidence interval, or p-value. It lists zero analyses. The posted information therefore cannot show whether measured walking distances were higher in one treatment period, whether any difference was precise, or whether it was compatible with chance under a statistical model.

The trial’s crossover design means that treatment order and within-participant comparisons are relevant to interpretation. The registry describes the two sequences and a 4 week washout, but it does not report the analytical treatment of period, sequence, or possible carryover effects. It also does not report the missing-data approach or a multiplicity strategy for the listed outcome measures.

The adverse-event counts provide a record of events by group and period, but they do not demonstrate causation. The extension was open label, and its sequence-specific counts should not be interpreted as if they were a randomized, blinded comparison of elamipretide against placebo. The record’s listed serious-event terms and percentages also do not replace a full assessment of event details or comparative risk.

Accordingly, the registry record is informative about the trial structure, endpoint definition, and reported safety counts, but it is not sufficient to assess the primary efficacy result or its statistical precision. The absence of a result in this record should not be translated into a finding of no effect; it means the comparative outcome estimate is not reported in the registry record.

13. Why This Trial Matters Statistically

This trial illustrates why study design and outcome definitions need to be read separately from outcome results. The registry identifies a randomized crossover comparison and specifies how the primary walking-distance measure was collected. These details clarify the intended question and the data structure, but they do not supply the estimate needed to answer the question statistically.

The crossover arrangement is particularly relevant for biostatistical interpretation. Since participants were assigned to sequences that included both treatments, observations are not simply independent parallel-group measurements. General crossover methods need to account for within-participant association and may consider treatment period, sequence, and carryover. The record describes the sequence and washout, but does not report the analysis methods or results needed to assess those features.

The endpoint is a continuous distance measure summarized in the registry as a mean and standard deviation. That choice can convey both the typical measured distance and the spread of participant values, but treatment comparison requires more: an estimated contrast and an indication of its uncertainty. Neither is reported in the registry record. This distinction prevents the outcome definition from being mistaken for evidence of a treatment effect.

The record also lists a range of secondary measures across trial parts and visits. Without a reported multiplicity plan, missing-data approach, and analysis population, readers cannot determine how those outcomes were prioritized or how incomplete observations were handled. The registry’s safety counts add descriptive context but cannot substitute for the missing primary efficacy analysis.

Statistically, the trial is therefore notable for the questions its design raises and for the limits of what its registry record can answer. Its public record supplies the design framework, but not the numerical primary-outcome comparison or uncertainty needed for a complete assessment.

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 important trial-specific limitation of the registry record is that it does not report numerical results for the primary outcome. Although the outcome definition and summary type are specified, the period means, standard deviations, treatment contrast, and inferential results are not reported in the registry record. The record lists zero analyses, which prevents assessment of the estimated effect and its precision.

Enrollment was 12 participants. That is a small trial enrollment figure, but the record does not give the number with primary outcome measurements at each period or visit. It is therefore not possible to determine the analyzed sample for the endpoint from the enrollment figure alone. The record also does not describe missing-data handling or give reasons for any unmeasured outcomes.

The crossover schedule is described, including reversed treatment sequences and a 4 week washout. However, the analysis of period, sequence, within-participant correlation, and possible carryover is not reported in the registry record. The primary endpoint is said to have pooled period results, but the meaning of that pooling and the statistical method are not specified.

The trial also has multiple listed outcomes, including measurements across visits and outcomes in both Part 1 and Part 2. A multiplicity plan and analysis hierarchy are not reported. The open-label extension is described incompletely in the available arm details, so its full treatment duration is not reported in the registry record. Finally, the adverse-event counts are descriptive and do not establish causality or provide a complete comparative safety analysis.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Trial to Evaluate Safety, Tolerability and Efficacy of Elamipretide in Subjects With Barth Syndrome — NCT03098797.
• Registry record last updated 2024-04-16; status last verified 2024-03.
• Results first posted 2024-04-16.
• 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 describes a completed randomized crossover trial of elamipretide and placebo in participants with Barth syndrome, with enrollment of 12 and listings for Phase 2 and Phase 3. Part 1 used two treatment sequences: 12 weeks of elamipretide at 40 mg by daily subcutaneous injection followed by 12 weeks of placebo, or the reverse sequence, with a 4 week washout. An open-label extension with elamipretide is also described.

The primary outcome was distance walked during the 6-Minute Walk Test, measured in meters at the end of each 12 week period. Numerical primary results and inferential analyses are not reported in the registry record. Safety listings include serious and other adverse events by group and period, and no deaths are listed. The record does not report the analysis plan, missing-data methods, or multiplicity approach.