EPI-743 for Metabolism or Mitochondrial Disorders: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for EPI-743 for Metabolism or Mitochondrial Disorders (NCT01642056), a non-randomized phase 1, phase 2 study. The primary outcome is Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Part I-III, Baseline.

2. Clinical Question

3. Trial Design

This was a phase 1 and phase 2 study with non-randomized allocation, double masking and a crossover model. The registry lists enrollment of 20. The study is marked completed, with a start date of 2012-09-01 and a primary completion date of 2019-09-24.

The two recorded sequences were EPI-743 followed by placebo, and placebo followed by EPI-743. The brief study description says participants were to receive one treatment for the first 6 months, have a 1-month rest period, and then receive the other treatment for the next 6 months. It also describes seven inpatient study visits lasting 3- to 5-days, planned about 3 months apart, and says the study would last about 13 months. The registry does not report whether each participant completed every planned visit or treatment period.

In a crossover design, participants receive treatments in sequence, so outcomes may be considered across treatment periods. General statistical context: interpreting such a design can depend on changes over time, effects that persist after a treatment period, and differences between sequences. The registry record does not report analyses addressing these issues. It states that outcome measures were analyzed separately by arm and phase, rather than combining results across phases, because of the progressive nature of the underlying disease.

Non-randomized allocation limits what can be inferred from a comparison between arms. The registry explicitly notes that the arms are not a like-for-like control comparison. It does not report how participants were assigned to sequence or whether any adjustment was made for differences between groups.

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: 20 subjects were consented. One subject died during first intervention due to progression of disease. Three subjects did not complete the second intervention.

First Intervention

Second Intervention

Analysis population for the primary outcome, as defined in the registry: Participants who who had treatment intervention in phase I. The outcome measures were analyzed separately by arm and phase, not by combining results by intervention across phases, due to the progressive nature of the underlying disease.

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 Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Part I-III, Baseline, measured over Baseline - Day 0.

The primary outcome listed is the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS), Parts I–III, at baseline, with a timeframe of Baseline - Day 0. It is recorded as a mean on a scale, with standard error as the stated measure of dispersion. The registry describes the NPMDS as a semi-quantitative clinical rating scale that evaluates progression of mitochondrial disease in pediatric patients. Parts I–III are added to produce a score between 0 and 130, with higher scores representing more severe disease.

A clinical rating scale can provide a structured way to describe disease status using defined assessments. General statistical context: a baseline measure can characterize participants before treatment exposure and may be relevant when interpreting later measurements. However, a baseline score alone does not show whether a participant changed after treatment or whether any change differed between treatment periods.

The primary outcome title specifies baseline measurement, not a change-from-baseline endpoint. The registry record does not report the mean, standard error, or a treatment-effect estimate for this outcome. It also does not state a numerical follow-up comparison for NPMDS Parts I–III. Therefore, the endpoint description establishes what the scale measures, but the posted results do not allow assessment of the treatment-period outcome from this measure.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry classifies the primary measure as continuous and summarizes it using a mean and standard error. A mean describes the center of a set of numerical measurements. A standard error describes the estimated precision of that mean; it is not the same as the spread of individual participants’ scores. General statistical context: the standard error generally becomes smaller when a mean is estimated more precisely, but its interpretation depends on the analysis and the observations contributing to it. No mean or standard error is reported for the primary measure in the registry record.

A confidence interval, when reported, gives a range of estimates compatible with the data under the method used. Its width conveys precision: a narrower interval indicates greater precision than a wider one. A confidence interval is not a guarantee that the true value lies within the displayed range. The registry record does not report a confidence interval for the NPMDS outcome, and it does not give a treatment-effect estimate to which one could be attached.

The study is described as a crossover, with participants assigned to one treatment sequence and then the other. General statistical context: crossover analyses commonly need to distinguish treatment effects from period effects, because outcomes can change over time regardless of treatment. They may also need to consider carryover, meaning an effect of an earlier treatment that remains relevant in a later period. This is particularly important when a treatment sequence includes a rest period. The record describes a 1-month rest period but does not report whether or how period or carryover effects were assessed. It also does not report the model, test, or assumptions used for the outcomes.

The registry says results were analyzed separately by arm and phase, rather than combining results across phases, because the underlying disease is progressive. General statistical context: separating observations by phase can avoid treating measurements from different periods as directly interchangeable when time trends matter. It can also leave a treatment comparison less directly summarized unless an explicit analysis combines information in a way that accounts for those differences. No such treatment comparison or model description is reported.

Allocation was non-randomized. General statistical context: random allocation can help balance measured and unmeasured factors between treatment groups on average. Without it, differences between groups can be entangled with treatment differences. Statistical adjustment can sometimes address measured differences, but cannot automatically remove bias from factors that were not measured or modeled. The registry record does not report how sequence assignment occurred or whether adjustment was used.

For planning, a sample-size calculation usually states the target effect, significance level, power, allocation, and assumptions about the outcome. The registry’s planning description specifies a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects defined as fractions of the observed effect. It identifies the calculations as planning illustrations, not as the trial’s own design. Such illustrations are not evidence that the study had a particular probability of detecting an effect, and they are not observed power. The registry record does not report the trial’s sample-size justification. Since no primary outcome effect is reported, the planning assumptions do not supply a treatment-effect estimate.

General statistical context: over-dispersion arises when variation in data exceeds what a chosen statistical model expects. It can make standard errors too small if the model does not account for the extra variability. This concept can matter for outcomes such as counts, but the primary outcome is described as a continuous scale score, and the record does not report an over-dispersion assessment or a model. No assumption about over-dispersion should therefore be attributed to this trial.

The registry lists four outcome measures and zero analyses. It does not report a statistical analysis plan, the handling of missing outcome observations, or methods for repeated measurements. Without those details and numerical results, the reader cannot reproduce an outcome analysis or evaluate its assumptions. The posted description supports explanation of the design and endpoint, but not reconstruction of an unreported treatment comparison.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("EPI-743, Then Placebo", "Placebo, Then EPI-743")
n   <- c(10, 10)
m   <- c(23.9, 20.4)
sp  <- c(2.8, 3.7)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  EPI-743, Then Placebo  10  23.900  8.854  17.566  30.234
CARM  Placebo, Then EPI-743  10  20.400  11.700  12.030  28.770

11. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures, but does not report a multiplicity plan. Multiplicity arises when several outcomes, time points, or comparisons are tested: the chance of at least one apparently notable result can increase as the number of tests grows. General statistical context: a prespecified strategy may define which outcome is primary and whether adjustments are needed for other tests. Although the NPMDS Parts I–III measure is labeled primary, the record does not describe any procedure for controlling multiplicity across the listed outcomes or analyses.

Missing-data methods are not reported in the registry record. The available description does not say how missing visits, incomplete scale assessments, withdrawals, or missed treatment periods were handled. General statistical context: the impact of missing observations depends partly on why data are missing and on the assumptions made by the analysis. Different approaches can produce different estimates when those assumptions do not hold.

The outcome population is described as participants who had treatment intervention in phase I, and the registry says outcomes were analyzed separately by arm and phase. It does not give a clear analysis-population definition for each outcome or report how many participants contributed measurements to each analysis. It also does not state whether analyses followed an intention-to-treat, per-protocol, or other population definition. With zero analyses listed and no numerical primary-outcome results, the record does not allow assessment of exclusions, missingness, or the effect of analysis-population choices.

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: hospitalisation (21.1%), hyperthermia (5.3%), respiratory tract infection (5.3%), blood creatine phosphokinase increased (5.0%), status epilepticus (5.0%).

The registry reports serious adverse events for the EPI-743 group and placebo group separately. In the EPI-743 group, 3 of 20 participants were affected by serious adverse events; in the placebo group, 4 of 19 were affected. The record also lists 17 other adverse events among 20 at risk in the EPI-743 group and 18 among 19 at risk in the placebo group. These are descriptive counts, not an adjusted comparison.

The record reports 1 death in the EPI-743 group and 0 in the placebo group. It does not report the cause, timing, relationship to treatment, or the treatment phase in which the death occurred. The serious event terms listed include Hospitalisation (21.1%), Hyperthermia (5.3%), Respiratory tract infection (5.3%), Blood creatine phosphokinase increased (5.0%), and Status epilepticus (5.0%). The record does not specify in that list which group each term or percentage refers to.

General statistical context: an adverse event occurring during a trial is not necessarily caused by the treatment. The listed counts do not establish causation or provide a like-for-like risk comparison, particularly given non-randomized allocation and the crossover design. Timing, exposure, seriousness definitions, and participant-level context would be needed for a fuller interpretation; these details are not reported in the registry record.

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

The registry record establishes that EPI-743 was studied against placebo in a completed, double-masked, non-randomized crossover trial involving children with metabolic or mitochondrial disorders. It identifies the intended treatment sequences, the NPMDS Parts I–III baseline measure, and some adverse-event counts. It does not report a numerical primary-outcome result or a treatment-effect estimate.

That means the posted data do not establish whether NPMDS scores changed during either treatment period, how any changes compared across treatments, or how precise a comparison would be. The baseline endpoint description alone cannot answer those questions. The record also does not provide an analysis method, confidence interval, or statistical test for the primary outcome.

The safety figures describe events recorded in each group, but they do not establish that EPI-743 caused or prevented an event. The groups were not formed through random allocation, and the registry cautions that they are not a like-for-like control comparison. The counts should therefore be read as descriptive information rather than a causal estimate.

General statistical context: a completed trial is not necessarily a trial whose results are fully posted in the registry. Completion status describes the study’s recorded status, while the presence and detail of results determine what can be evaluated from that record. Here, the registry’s limited numerical outcome reporting constrains the conclusions that can be drawn. The available information supports understanding the planned design and measurement, but does not support a conclusion about the magnitude or direction of an NPMDS treatment effect.

14. Why This Trial Matters Statistically

This trial is statistically notable for combining a crossover structure with non-randomized allocation and a progressive underlying condition. Those features make careful separation of treatment, time and group differences important. The registry itself notes that outcomes were analyzed separately by arm and phase because of disease progression, and cautions that the arms are not a like-for-like control comparison.

General statistical context: crossover designs can make within-participant comparisons informative because each participant receives more than one treatment. But interpretation depends on the quality and completeness of period-specific measurements and on assumptions about changes over time and lingering treatment effects. Non-randomized assignment introduces a separate concern: sequence groups may differ for reasons unrelated to treatment. The registry record does not report analyses addressing these issues.

The record also illustrates why endpoint definitions and results are both necessary for statistical interpretation. It explains what the NPMDS measures and how higher scores are interpreted, but gives no numerical primary-outcome result. Without an estimate and its uncertainty, readers cannot judge the size or precision of a treatment comparison. The serious adverse-event counts add descriptive safety information, but do not resolve the absence of efficacy results or establish causality.

For clinical researchers, this is a reminder to distinguish study completion, outcome specification and posted analysis. Each conveys different information. A well-described design can clarify what investigators intended to study; only reported results and methods show what was estimated and how reliably. The registry record leaves those outcome-analysis details unavailable.

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 main limitation of the registry record for interpreting this trial is the absence of numerical primary-outcome results. The NPMDS is identified at baseline, but no mean, standard error, follow-up score, treatment contrast, confidence interval, or test is reported. Although four outcome measures are listed, the record reports zero analyses.

The record does not describe how non-randomized allocation to treatment sequence occurred. It therefore does not establish whether the groups were comparable at baseline, beyond identifying the baseline endpoint. It also does not report statistical adjustment for group differences. The registry’s own note cautions that the arms are not a like-for-like control comparison.

For the crossover, the record describes the sequence and rest period but does not report the analysis method, handling of period effects, assessment of carryover, or completeness of treatment-period measurements. It does not give missing-data methods, outcome-specific analysis populations, or participant counts contributing to each outcome analysis. These omissions prevent assessment of how the design was implemented and analyzed.

The safety information is also limited: event timing, relationship to treatment, and the group attribution of the listed serious event terms and percentages are not specified. The record does not state the trial’s sample-size justification or a multiplicity strategy. Together, these gaps mean the registry supports a description of the planned study and recorded adverse-event counts, but not a detailed evaluation of its treatment-effect estimates.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: EPI-743 for Metabolism or Mitochondrial Disorders — NCT01642056.
• Registry record last updated 2021-04-14; status last verified 2019-12-09.
• Results first posted 2021-04-14.
• 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

The registry identifies NCT01642056 as a completed phase 1 and phase 2 study of EPI-743 for metabolism or mitochondrial disorders. It lists non-randomized allocation, double masking, a crossover model, and enrollment of 20. The recorded sequences were EPI-743 followed by placebo and placebo followed by EPI-743.

The primary outcome is baseline NPMDS Parts I–III, a continuous scale measure of mitochondrial disease progression. Higher scores indicate more severe disease. The record lists four outcome measures but zero analyses and does not report numerical results for the primary measure.

Serious adverse-event counts are reported by group, alongside other adverse-event counts and a list of serious event terms. These figures are descriptive; the record does not provide the detail needed to infer causality or make a like-for-like comparison. Overall, the registry describes the study design and outcome definition, but does not provide a numerical primary treatment-effect result.