NAD+ and Exercise in FA: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for NAD+ and Exercise in FA (NCT04192136), a randomized na study. The primary outcome is Within-Participant Change in Peak V02 (Maximal Oxygen Uptake on Cardiopulmonary Exercise Testing).

2. Clinical Question

3. Trial Design

This was a completed, randomized trial with a 2x2 factorial design and quadruple masking. The registry record lists 75 participants as enrolled and Children's Hospital of Philadelphia as the sponsor. The condition studied was Friedreich Ataxia 1. The listed start date is 2020-09-03, and the primary completion date is 2025-02-07. The phase is recorded as NA.

The registered interventions were nicotinamide riboside, placebo, and exercise. The four outcome groups were NR, placebo, exercise with NR, and exercise with placebo. This arrangement represents the combination of the supplement assignment and exercise assignment. A factorial design can estimate the separate effects of each factor and assess whether their joint effect differs from what would be expected from their separate effects. Whether and how those effects were tested is not reported in the registry record.

The exercise description specifies at-home aerobic sessions on a bike trainer and resistance exercise using bands. The NR description identifies the supplement as nicotinamide riboside. The full dosing details and full intervention descriptions are not available in the registry record information. The record describes placebo as matched to the supplement.

The primary outcome was within-participant change in Peak VO2, measured in L/min from baseline to 12 weeks. One person in the placebo group did not attempt the week-12 cardiopulmonary exercise test because of an intercurrent foot injury and did not contribute to the main outcome analysis. The outcome results list 17 participants for NR, 16 for placebo, 16 for exercise with NR, and 16 for exercise with placebo. Analysis populations and the handling of other missing measurements 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.

Before assignment: Once consent was obtained, participants were reviewed for eligibility and inclusion in the trial. Individuals meeting criteria were randomized. In total, 75 participants signed informed consent. There was 1 withdrawal of consent prior to in-person screening (ankle injury). 74 completed in-person screening. 8 were considered ineligible after screening due to: not reaching cadence during CPET (7) and not able to complete blood draw (1)

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: One individual in the Placebo group did not attempt a CPET at week 12 because of an intercurrent foot injury, and thus did not contribute to the analysis for the main outcome

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.

Population: Data not collected for non-randomized participants

6. Primary Endpoint

The registry lists the primary outcome as Within-Participant Change in Peak V02 (Maximal Oxygen Uptake on Cardiopulmonary Exercise Testing), measured over Baseline to 12 Weeks.

Peak VO2 is the maximum oxygen uptake measured during cardiopulmonary exercise testing. In this trial, participants completed an incremental, symptom-limited exercise stress test on a recumbent leg-cycle ergometer. The outcome is defined as the change in Peak VO2 from baseline to 12 weeks, measured in L/min. The registry description states that a higher change indicates greater oxygen uptake.

Peak VO2 is used as a measure of aerobic capacity because it reflects oxygen uptake during demanding exercise. In general, an exercise-based measure can capture functional capacity that may not be represented by a resting measurement. This is a general explanation of the type of measure, not an additional finding from this trial.

The posted arm-level values are described as medians. They are 0.06 L/min for NR, -0.06 L/min for placebo, 0.1 L/min for exercise with NR, and 0.03 L/min for exercise with placebo. The lower and upper limits are also posted for each arm, but the registry record information does not identify their coverage level or explain how they were calculated. No interquartile ranges are posted in the results, despite the outcome description specifying median and inter-quartile range.

The outcome is a change within each group. Those group summaries alone do not establish the size or precision of a treatment contrast between groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a median summarize?

A median is the middle value in an ordered set of observations. It describes a typical position without being pulled as strongly by extreme observations as a mean can be. For clinical outcomes, reporting a median can be useful when values are skewed or when unusually large or small observations would distort an average. This is a general explanation; the registry record does not state why the median was selected for Peak VO2 change.

The outcome description specifies the inter-quartile range as the measure of dispersion. In general, an inter-quartile range describes the span between the middle half of observations and gives information about variation within a group. The results do not include an inter-quartile range for any arm. The posted lower and upper limits are not identified as inter-quartile limits, confidence limits, or another interval type, so their meaning cannot be inferred from the record.

Why distinguish changes from treatment contrasts?

A within-participant change compares a person's measurement at follow-up with that person's baseline measurement. A group median of those changes describes the distribution of changes among participants in that arm. A treatment contrast instead compares outcomes between randomized groups. That contrast is the quantity needed to estimate how outcomes differed by assigned intervention, subject to the assumptions of the analysis.

Comparing the arm medians by eye is not equivalent to estimating a treatment contrast. A valid contrast may use a model that accounts for the trial design, baseline values, or other prespecified features, but the statistical plan and analysis model are not reported in the registry record. In a factorial trial, separate estimates for the supplement factor, exercise factor, and interaction may be relevant. The record does not report these estimates or explain which factorial terms were included in an analysis.

What do interval limits convey?

In general, an interval around an estimate communicates statistical uncertainty or data spread, depending on how it was constructed. A confidence interval, for example, is designed to express uncertainty about a population parameter under a specified method and its assumptions. The interpretation depends on the interval type, the model, and the confidence level. Because the registry record does not identify the type or coverage of the posted limits, they cannot be interpreted as confidence intervals with a known level. The limits can be quoted as posted, but no inferential meaning beyond that is established by the record.

Intervals also do not replace the actual treatment contrast. An interval for a group-specific median is not an interval for the difference between randomized groups. To assess the primary question, readers would need the contrast estimate and an appropriate uncertainty measure from the comparative analysis. Those are not reported in the registry record.

Why does factorial structure matter?

A factorial design assigns participants across combinations of intervention factors. It can allow researchers to estimate the effect of each factor using information across more than one group, as well as to examine whether the effect of one factor depends on the other. That possible efficiency depends on the analysis being appropriate to the design and on assumptions about the interaction. It should not be assumed that the effects of NR and exercise are additive or that an interaction was tested. The registry record confirms the factorial design but does not report the analysis plan or factorial estimates.

Here, the four registered groups are NR, placebo, exercise with NR, and exercise with placebo. Their outcome summaries are useful descriptions of the observed changes in each group. They do not separately identify the main effects or interaction without the relevant comparative model and estimates.

What can be learned from the sample-size illustrations?

Planning calculations based on an observed effect are illustrative, not evidence of the trial's original design rationale. The stated planning assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is described as a fraction of the observed effect. Such calculations can show how sample-size requirements vary under selected assumptions. They do not report the trial's observed power, and they do not establish that the study was designed around those assumptions. The trial's sample-size justification and specific planning values are not reported in the registry record.

More generally, sample-size planning depends on the chosen outcome, target contrast, variability, error rate, allocation, and analysis. In a factorial design, the assumptions for main effects and interaction effects may differ. These are general statistical considerations; the registry record does not say which assumptions guided this trial's enrollment target.

Why can variability matter?

Variability affects how precisely a group estimate and a between-group contrast can be estimated. Over-dispersion is a general situation in which the data vary more than a statistical model assumes. If a model fails to account for that extra variation, uncertainty can be understated. The registry record does not report a model or a dispersion assessment for the primary outcome, so over-dispersion cannot be evaluated from the posted summaries. For continuous change measurements such as Peak VO2, appropriate modeling depends on the distribution of the observed data and the estimand being targeted.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome, within-participant change in Peak VO2, and one secondary outcome, within-participant change in whole-body insulin sensitivity (Si). The primary outcome timeframe is baseline to 12 weeks. The record does not report a multiplicity strategy for interpreting more than one outcome or any additional comparisons. It also does not report which tests, if any, were planned for the factorial effects, combinations, or subgroup analyses.

Multiplicity is a general statistical concern when several hypotheses are tested: the chance of at least one apparently notable result can increase as the number of tests grows. Approaches to handling it depend on the research questions and analysis plan. No correction, hierarchy, or other multiplicity procedure is reported in the registry record, so none should be presumed.

The record notes that one participant in the placebo group did not attempt CPET at week 12 because of an intercurrent foot injury and did not contribute to the main outcome analysis. The outcome groups list 17 participants for NR, 16 for placebo, 16 for exercise with NR, and 16 for exercise with placebo. No further account of missing primary outcome data is reported. In particular, the record does not describe imputation, sensitivity analyses, reasons for any other missing measurements, or whether the analysis included all randomized participants.

Analysis populations such as intention-to-treat or per-protocol are not reported in the registry record. The record also does not describe exclusions after randomization or deviations from assigned intervention. These omissions matter because the analyzed population and missing-data approach can affect the interpretation of randomized comparisons. The available arm summaries should therefore be treated as descriptive results for the listed participants, not as a complete account of the analysis population or missing-data strategy.

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 non-serious adverse event terms

The adverse-event record separates serious adverse events from other adverse events and reports counts of participants affected within each group. No serious adverse events were recorded among participants at risk in any of the four groups: NR, placebo, exercise with NR, and exercise with placebo. The record lists zero deaths in each group.

For other adverse events, the record lists 17 of 17 participants affected in the NR group, 17 of 17 in the placebo group, 16 of 16 in the exercise-with-NR group, and 14 of 16 in the exercise-with-placebo group. These are participant counts, not counts of individual event episodes. The registry record does not provide serious adverse-event terms, and no top serious-event terms are listed. It also does not provide event-level descriptions in the information.

These counts describe what was recorded during the trial; they do not establish whether an event was caused by an intervention. The absence of recorded serious events in these groups should not be interpreted as proof that an intervention has no serious risks. The record does not report further details about event severity, timing, relatedness, or follow-up duration for safety outcomes, so those aspects cannot be assessed from these figures.

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

The posted primary outcome data describe within-participant change in Peak VO2 over baseline to 12 weeks in four randomized groups. The median changes are 0.06 L/min for NR, -0.06 L/min for placebo, 0.1 L/min for exercise with NR, and 0.03 L/min for exercise with placebo. The registry also posts lower and upper limits for each arm, but does not explain their statistical interpretation. Taken together, these data describe the observed group summaries; they are not a direct estimate of the effect of NR, exercise, or their combination.

The trial's primary objective concerned combined NR and exercise. The record does not report the comparative estimate needed to evaluate that question, nor an uncertainty measure for such a contrast. It also does not report separate factorial effects or an interaction estimate. The arm-level summaries therefore cannot establish the size, direction, or precision of the randomized treatment comparisons.

The secondary outcome is change in Si, but results are not reported in the information. The record lists no reported analyses. Consequently, the available results do not support an inferential conclusion about either the primary or secondary objective. The number enrolled, 75, is not itself evidence of precision or of adequate statistical power; the trial's design justification and analysis plan are not reported in the registry record.

In general, a treatment result is best understood by considering the estimated contrast, its uncertainty, the analysis population, missing data, and the prespecified analysis plan. These are not fully available for this trial in the registry record. The appropriate interpretation is limited to the reported arm summaries and safety counts. They should not be translated into a claim that a treatment is effective or ineffective, and they do not resolve whether the observed group differences could reflect chance, measurement variation, or other influences.

13. Why This Trial Matters Statistically

This trial is statistically notable because it uses a factorial design to study a supplement and an exercise program in Friedreich's ataxia. Factorial designs can address more than one intervention factor within the same trial structure. They also require careful interpretation: arm-level descriptions alone do not reveal the separate effects of each factor or whether their combination behaves differently from the factors considered individually.

The primary endpoint is a continuous physiological measure, Peak VO2, assessed as change from baseline to 12 weeks. The registry gives median changes by group, but does not report a direct comparison for the primary question. This distinction is important for clinical researchers: a set of group summaries can show what was observed in each arm while still leaving the randomized contrast unanswered.

The record also illustrates why outcome precision and analysis transparency matter. It posts lower and upper limits without describing their type or coverage level, and it does not provide the specified inter-quartile ranges. A reader cannot safely assign a familiar interpretation to unlabeled interval limits. Likewise, a factorial design's potential analytical benefits depend on reporting the corresponding estimates and methods.

Finally, missing outcome data are relevant even when one reason is documented. The record explains that one placebo participant did not attempt the week-12 test because of an intercurrent foot injury, but does not give a full missing-data strategy or analysis population. These features do not invalidate the descriptive values; they define the limits of what can be inferred from the registry results.

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 primary limitation of the available results is the absence of a reported comparative analysis for Peak VO2. Although arm medians and lower and upper limits are listed, the registry record does not identify the interval type, report a direct treatment contrast, or provide a p-value or model-based estimate. The record therefore does not show the precision of the randomized comparisons that address the primary objective.

The posted outcome information also lacks the inter-quartile ranges specified in the endpoint description. The analysis method, handling of the factorial structure, and use of baseline measurements are not reported in the registry record. Without these details, the arm summaries cannot be used to reconstruct the intended analysis.

One participant in the placebo group did not attempt the week-12 CPET because of an intercurrent foot injury. The record does not explain the handling of other missing data, identify the analysis population, or provide sensitivity analyses. The available outcome counts are smaller than the enrollment figure, but the record does not provide a participant flow account that explains all differences.

The registry lists change in Si as a secondary outcome, but no results for it are included in the information. Multiplicity handling, the sample-size justification, and the statistical analysis plan are also not reported. The safety results provide affected-participant counts but lack event terms and additional detail about severity, timing, and relatedness. These limitations restrict interpretation to the posted descriptive summaries and recorded safety counts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: NAD+ and Exercise in FA — NCT04192136.
• Registry record last updated 2026-03-11; status last verified 2026-03.
• Results first posted 2026-03-11.
• 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

NCT04192136 is a completed randomized, quadruple-masked factorial trial sponsored by Children's Hospital of Philadelphia. It enrolled 75 participants with Friedreich Ataxia 1 and studied nicotinamide riboside and exercise. The listed primary endpoint was within-participant change in Peak VO2 from baseline to 12 weeks, measured in L/min. The secondary endpoint was change in whole-body insulin sensitivity, Si.

The posted primary outcome results are arm-level medians with lower and upper limits. The registry record does not report the comparative analysis, the interpretation of those limits, the analysis population, or the missing-data strategy. One participant in the placebo group did not attempt week-12 CPET because of an intercurrent foot injury. No serious adverse events or deaths are listed in the four groups; other adverse events affected participants in each group. The available record supports a descriptive account, but does not provide the inferential results needed to evaluate the primary or secondary questions.