Responses to Influenza Vaccine in Patients With Mitochondrial Disorders (MELAS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Responses to Influenza Vaccine in Patients With Mitochondrial Disorders (MELAS) (NCT01831934), a non-randomized phase 4 study. The primary outcome is Clinical Safety of TIV Vaccine.

2. Clinical Question

The study evaluated safety and metabolic responses to a licensed inactivated seasonal influenza vaccine, TIV, among volunteers with MELAS and controls. The clinical question represented by the primary outcome is whether participants experienced solicited local or systemic adverse events or serious adverse events during the stated follow-up period after immunization. The posted adverse-event counts distinguish serious events from other adverse events, but they do not provide a detailed account of each event’s type, timing, duration, severity, or relationship to vaccination.

The record describes a pilot study rather than a randomized comparison designed to isolate a vaccine effect. The observed event counts can therefore describe what was recorded in these groups, but they do not by themselves establish that vaccination caused an event or that a difference between groups reflects a difference in underlying risk.

3. Trial Design

The registry identifies this as a Phase 4, parallel, non-randomized study with no masking. Stanford University is listed as the sponsor. The title refers to responses to influenza vaccine in patients with mitochondrial disorders, and the official title describes metabolic and immune responses to TIV in patients with mitochondrial disease. The study’s brief summary characterizes it as a pilot evaluating safety and metabolic responses in MELAS volunteers and controls.

The registry enrollment is 22. The MELAS group is described as ages 13-60 years, and the Control Group as ages 18-65 years. Both groups received Fluzone®; the formula is listed as 2010-2011 or 2011-2012 depending on year. The record does not explain how the year or formula was assigned, or provide additional detail about how participants entered each group. Since allocation was non-randomized, group membership may reflect factors other than chance. The registry itself cautions that the arms are not a like-for-like control comparison.

The study is marked completed. Its recorded start is 2010-09 and primary completion is 2011-12. The primary outcome timeframe is Day 0 to Day28, with the description specifying solicited local and systemic adverse events and serious adverse events for 1 month following immunization. The posted safety counts use risk sets of 12 in the MELAS Group and 10 in the Control Group. The record does not explain how these risk-set counts relate to the enrollment figure, or why they differ from it.

The parallel arrangement permits a descriptive comparison of the groups, but the non-randomized allocation, absence of masking, and age-range differences limit what can be inferred from that contrast. Further details on recruitment, baseline characteristics, and group comparability are 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

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 Clinical Safety of TIV Vaccine, measured over Day 0 to Day28.

The primary endpoint is titled “Clinical Safety of TIV Vaccine” and is expressed as participants. Its description says the study would measure solicited local and systemic adverse events and serious adverse events for 1 month following immunization. The registry gives the timeframe as Day 0 to Day28. The posted outcome is a count of participants with an event, rather than a count of every episode or a measure of event duration.

Recording adverse events after immunization is a way to describe the safety experience observed during a specified follow-up period. Solicited events are actively sought, while serious adverse events are a separate category of particular clinical importance. These categories should not be treated as interchangeable: a count of participants with any other adverse event does not indicate how many had a serious event, and vice versa. In these posted figures, the serious-event counts and other-event counts are presented separately.

Participant counts are straightforward to interpret as observed counts within the risk sets, but they do not communicate uncertainty on their own. A proportion, confidence interval, event-specific description, or adjusted comparison could add different information, but such results are not reported in the registry record. The endpoint also does not, by itself, determine whether an event was caused by vaccination. The record does not give event-level assessments of causality, severity, or timing.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry presents the primary outcome as a count of participants with an event. This is a binary-outcome framework at the participant level: for the outcome being assessed, a participant either had a recorded event or did not. The posted results separate serious adverse events from other adverse events. They should not be read as counts of every symptom or episode, because the stated unit is participants.

What does a participant count tell us?

A count preserves the actual number of participants affected, which is useful when event counts are sparse. It does not, on its own, give a complete picture of frequency unless read alongside the number at risk. Nor does it express uncertainty. Statistical summaries for binary outcomes may include proportions and confidence intervals, but those are not reported for these results. A confidence interval is a statistical range intended to show the precision of an estimate under the assumptions of the chosen method. Wider intervals indicate less precision; with sparse events, the uncertainty can remain substantial even when the observed count is zero.

Why does the design matter for a group comparison?

In a randomized comparison, allocation is intended to make groups comparable in expectation with respect to factors that can affect outcomes. Here, allocation is non-randomized. Differences between the MELAS Group and Control Group may therefore reflect participant characteristics, selection, or other factors in addition to any effect associated with the intervention. The registry explicitly cautions that the arms are not a like-for-like control comparison. The age ranges differ, and the record does not provide enough baseline detail to evaluate group balance or adjust for possible differences.

The study is also unmasked. Masking can reduce the influence of expectations on some aspects of outcome assessment or reporting. For solicited events, the way questions are asked and responses are recorded can matter. The registry does not describe the event collection instruments, assessors, or procedures beyond stating that solicited local and systemic events and serious adverse events were to be measured. It is therefore not possible to assess from the record how consistently events were elicited or classified across the groups.

What does the follow-up timeframe define?

The safety outcome covers Day 0 to Day28, and the description refers to 1 month following immunization. This defines the period represented by the endpoint; it does not describe safety beyond that period. The registry does not report event-level timing, so the counts cannot show when within the follow-up an event occurred. They also do not establish whether events continued after follow-up or were judged related to vaccination.

How should statistical testing be understood?

The registry record lists 0 analysis entries. No test of the difference between groups, confidence interval, adjusted model, or statistical analysis plan is reported in the registry record. In general, statistical tests assess how compatible observed data are with a specified model or hypothesis; they do not repair limitations in study design. An adjusted model may address measured differences if suitable information is available, but cannot reliably resolve unmeasured confounding. No such model is reported.

For binary outcomes, methods may be chosen according to the number of events, group structure, and analysis objective. When counts are sparse, common approximations can perform poorly, and exact or other suitable methods may be considered. This is a general methodological point, not a description of an analysis used in this study. The registry does not report a method for testing the safety counts.

What do the planning assumptions mean?

The registry’s planning illustration is described as based on the observed effect, with two-sided significance level 0.05, equal allocation between arms, and a normal approximation. It considers detecting a stated fraction of the observed effect. Such a calculation is a hypothetical planning exercise: it estimates participant requirements under its assumptions, rather than measuring the study’s observed power. The illustration is not the trial’s own design justification. The registry record does not report the protocol’s sample-size justification or give enough analysis detail to assess whether the planning assumptions match the study’s conduct.

Overall, the methods that can be identified from the record are limited: a parallel, non-randomized, unmasked design; participant-count safety outcomes; and a defined follow-up period. Further statistical methods, including adjustment, uncertainty estimation, and the handling of incomplete observations, are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary safety description includes solicited local and systemic adverse events and serious adverse events. The posted figures distinguish serious events from other adverse events, but the registry does not report a statistical plan for testing these outcomes, defining a hierarchy among them, or controlling for multiple comparisons. Multiplicity refers to the increased chance of a misleading finding when many outcomes or hypotheses are examined. Whether and how it matters depends on the analysis plan and the claims being made; that plan is not reported in the registry record.

The registry lists 0 analysis entries. It does not provide an inferential analysis, adjusted estimates, or a description of which analysis population was used. The safety results identify risk sets of 12 for the MELAS Group and 10 for the Control Group, but inclusion rules and the relationship to the registry enrollment of 22 are not explained. The record does not state whether these counts represent all enrolled participants, participants with available follow-up, or another defined population.

Missing-data handling is not reported in the registry record. In particular, the record does not say whether all participants completed the stated follow-up, how incomplete event information was treated, or whether any imputation or sensitivity analysis was performed. The discrepancy between enrollment and the safety risk sets should not be resolved by assuming a particular reason for missing observations or exclusion. Without further documentation, the safest interpretation is to describe the posted counts with their stated risk sets and leave the analysis population and missing-data process unspecified.

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 serious adverse event counts are 0 in the MELAS Group among 12 participants at risk and 0 in the Control Group among 10 participants at risk. Deaths are recorded as 0 in each group. Separately, other adverse events affected 4 participants in the MELAS Group among 12 at risk and 0 in the Control Group among 10 at risk. The registry describes the outcome as counts of participants with an event, so these figures should not be interpreted as counts of every event episode.

A zero serious-event count means that none was recorded in the listed risk set during the stated outcome period. It does not mean the underlying risk is known to be zero. Likewise, the other-event counts describe what was recorded, not whether events were caused by vaccination. The registry does not provide event descriptions, severity details, timing, or individual causality assessments. Because the study was non-randomized and not a like-for-like control comparison, the group counts should not be treated as an estimate of a causal difference in safety.

The registry enrollment is 22, but the outcome risk sets are reported separately as 12 and 10. Why these figures differ is not reported in the registry record. They should be retained as stated rather than used to infer participant flow or missing follow-up.

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

The results establish a limited descriptive account of the safety events recorded for this pilot study’s participants during the stated follow-up. No serious adverse events or deaths are recorded in either group. Other adverse events are recorded for 4 participants in the MELAS Group and 0 in the Control Group, using the stated risk sets of 12 and 10. These counts are the central observations available for interpreting safety in the registry record.

They do not show whether the vaccine caused any event. The study was non-randomized and unmasked, and the registry cautions that the groups are not a like-for-like comparison. Participant characteristics, event reporting, and other factors may differ between groups; relevant baseline details and event-level assessments are not reported. The comparison therefore cannot isolate a vaccine effect or establish that one group had a higher underlying risk.

The findings also do not show that serious adverse events are impossible or that the observed pattern would be the same in a larger or different population. Zero recorded serious events is compatible with the limited observation represented by this study, but the registry provides no confidence intervals or other uncertainty estimates. The count gives no information about events outside the Day 0 to Day28 period.

The record describes a pilot evaluation of safety and metabolic responses, but the posted figures concern adverse events. They do not answer broader questions about metabolic or immune responses. Nor do they provide a detailed clinical characterization of the other adverse events. The appropriate interpretation is correspondingly narrow: these are the recorded participant counts in the stated groups and timeframe, with important uncertainty about precision, group comparability, and the basis for the analysis population.

This statistical interpretation is not a recommendation about vaccination or clinical care. It separates the observed counts from causal claims that the study design and registry information do not support.

13. Why This Trial Matters Statistically

This study raises a useful statistical problem: how to interpret sparse safety counts when the comparison is non-randomized. The posted counts are easy to state, but their meaning depends on design, outcome definition, follow-up, and the people represented in each group. A zero count can sound definitive if treated as proof of no risk; statistically, it is only the count observed in a particular risk set over a particular period.

The registry’s warning that the arms are not a like-for-like control comparison is especially important. A numerical contrast between groups is not automatically a causal contrast. Random allocation is one way to reduce systematic group differences, but it was not used. The different age ranges and lack of reported baseline detail further limit assessment of comparability. These concerns remain even if a statistical test were available, because a test cannot make non-randomized groups equivalent.

The record also illustrates why denominators and analysis populations matter. Enrollment is listed as 22, while outcome risk sets are given separately for the MELAS Group and Control Group. The reason for this relationship is not described. Clear accounting of participant flow and outcome availability would help readers understand which observations contribute to the safety counts, without requiring them to infer how missing or excluded observations were handled.

Finally, the study distinguishes serious adverse events from other adverse events and specifies a follow-up period. That framing supports a focused description, but the absence of event-level information and uncertainty estimates constrains interpretation. The statistical value of this record is therefore not a definitive comparative conclusion; it is an example of why transparent reporting of denominators, follow-up, group formation, uncertainty, and analysis procedures is essential when clinical evidence is limited.

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 non-randomized allocation is a central limitation for interpreting group differences. The registry explicitly says the arms are not a like-for-like control comparison. The age ranges listed for the MELAS Group and Control Group differ, and other baseline characteristics are not reported in the registry record. Consequently, observed differences may reflect group composition or other factors rather than the intervention.

The study is unmasked. The record does not describe who elicited or assessed adverse events, how solicited symptoms were defined, or whether the same procedures were applied across groups. Such details matter when outcomes depend on participant reports or event classification. Event-level descriptions, severity, timing, duration, and causality assessments are also not reported.

The registry lists enrollment as 22, while the safety risk sets are 12 for the MELAS Group and 10 for the Control Group. The record does not explain this relationship. Participant flow, eligibility for the outcome analysis, completion of follow-up, and missing-data handling are not reported. It is therefore not possible to determine from the record why the outcome risk sets take these values.

The safety follow-up is limited to Day 0 to Day28, described as 1 month following immunization. The posted counts do not address events outside that period. No confidence intervals, inferential tests, adjusted comparisons, or statistical analysis plan are reported, and the registry lists 0 analysis entries. The record also does not provide a sample-size justification for the trial’s own design. These limitations constrain both precision and the strength of any comparative interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Responses to Influenza Vaccine in Patients With Mitochondrial Disorders (MELAS) — NCT01831934.
• Registry record last updated 2017-05-30; status last verified 2017-04.
• Results first posted 2017-04-21.
• 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

NCT01831934 is a completed Phase 4, parallel, non-randomized, unmasked pilot study sponsored by Stanford University. It evaluated safety and metabolic responses to Fluzone® in MELAS volunteers and controls. The MELAS group is described as ages 13-60 years, and the Control Group as ages 18-65 years; both received a seasonal formula listed as 2010-2011 or 2011-2012 depending on year.

The primary safety outcome covers solicited local and systemic adverse events and serious adverse events from Day 0 to Day28. Serious adverse events and deaths are recorded as 0 in both groups. Other adverse events affected 4 participants in the MELAS Group and 0 in the Control Group. The corresponding risk sets are 12 and 10. The registry does not explain how these counts relate to its enrollment of 22.

No analysis entries are listed. The non-randomized design, lack of masking, absence of reported uncertainty estimates, and unreported analysis and missing-data procedures limit the conclusions that can be drawn from the posted counts.