Nicotinamide Riboside in LVAD Recipients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Nicotinamide Riboside in LVAD Recipients (NCT03727646), a non-randomized early/phase 1 study. The primary outcome is Number of Participates Experiencing Treatment-Emergent Adverse Events (Safety and Tolerability).

2. Clinical Question

This pilot addresses feasibility and safety in a narrowly defined clinical setting, rather than a randomized treatment comparison. The background in the registry describes preliminary mouse evidence concerning myocardial NAD+ and notes that direct evidence in human hearts was lacking. The proposed study was intended to gather feasibility information before a larger investigation. The registry record does not establish whether the planned biological changes occurred, and the small treated cohort cannot by itself provide a precise estimate of uncommon harms or a reliable estimate of treatment effects.

3. Trial Design

NCT03727646, titled “Nicotinamide Riboside in LVAD Recipients,” is listed as a completed early-phase 1 pilot study sponsored by the University of Washington. The official title describes preoperative NR supplementation in patients undergoing elective LVAD implantation. The registry reports a start date of 2018-09-26, a primary completion date of 2018-11-26, and enrollment of 5 participants.

The design is non-randomized, single-group, and single-masked. The registry does not identify who was masked or describe the masking procedures, so the practical meaning of single masking is not reported in the registry record. The treated participants received open-label NR. The brief summary describes dose escalation over 3 days to a final dose of 1000 mg twice daily. Treatment continued from the first day of study drug until the day before LVAD surgery, described as between Day 6-Day 14.

Although the study description refers to baseline controls, these were patients previously receiving LVADs whose blood and myocardial tissue assays had been performed. The registry states that no baseline control subjects were enrolled. They therefore do not constitute a concurrent randomized or otherwise enrolled comparison group. Differences between historical and treated participants could reflect factors other than NR, and the registry does not provide details sufficient to assess comparability.

The stated purpose was to obtain feasibility data for a planned larger study and to assess safety and tolerability in this patient population. Secondary outcomes concern whole blood NAD+ levels and mitochondrial respiration in isolated peripheral blood mononuclear cells, including between-group comparisons with baseline controls. The registry identifies 5 outcome measures, but the available record does not report numerical results for the biological outcomes. Protocol details beyond the information described in the registry record, including a sample-size justification and a fuller statistical analysis plan, 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: We did not enroll any baseline control subjects.

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: We did not have the funding to enroll baseline controls.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participates Experiencing Treatment-Emergent Adverse Events (Safety and Tolerability), measured over from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14).

The primary endpoint counts participants who experienced treatment-emergent adverse events while taking NR. Its stated purpose is to describe safety and tolerability during the period from the first day of study drug through the day before LVAD surgery. That period varied with the timing of surgery and is described as between Day 6-Day 14. The endpoint is a participant count, not a rate of events per unit of time, a measure of event severity, or a comparison of clinical benefit.

Counting participants with at least one event can offer a direct summary of how many people were affected during the specified exposure period. It does not, on its own, capture how many total events each participant experienced, when events occurred, or how long participants were observed. The registry does not report a more detailed event-level analysis for the primary endpoint.

The endpoint is appropriate to the stated safety and feasibility aim of an early pilot, but five treated participants provide limited information about event frequency and precision. A count from such a small group should be read as a description of those participants, not as a stable estimate for a broader population. The registry includes adverse-event summary figures, but a separate numerical result for the named primary endpoint is not reported in the registry record. The definitions used to classify events as treatment-emergent, and the approach to assessing their relationship to NR, are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a single-group pilot, a participant count is a descriptive endpoint: it records how many people had at least one event during the stated observation period. It does not require a treatment-versus-control test to be reported, and the registry gives no inferential analysis for the primary endpoint. In general, descriptive counts are useful for characterizing what was observed in a small cohort, while formal estimates of uncertainty require a stated method and assumptions. Such an interval is not reported in the registry record.

What does a participant count represent?

A count of participants with an event is different from a count of all events. If one participant experiences multiple events, a participant-level endpoint ordinarily counts that person once, while an event-level summary may count each event. The registry names the primary endpoint as the number of participants experiencing treatment-emergent adverse events, but it does not give detailed event-level results or definitions that clarify how repeated events were handled. The distinction matters because participant counts describe how many people were affected, not the total burden or recurrence of events.

Exposure time is relevant to safety interpretation. The reported period begins on Day 1 and ends the day before surgery, described as between Day 6-Day 14. Because the endpoint is a count rather than a time-to-event measure, the registry summary does not adjust for differences in how long participants took NR or were observed. In general, unequal observation periods can make simple counts difficult to compare, especially when event opportunities differ with time. Individual exposure durations and event timing are not reported in the registry record.

Why does the design affect statistical interpretation?

Random allocation, when used, helps make treatment groups comparable on average and supports causal comparisons under appropriate conditions. This study is listed as non-randomized and single-group. Its baseline controls were patients previously receiving LVADs, and no control participants were enrolled in the pilot. A comparison with historical measurements can be affected by differences in participant characteristics, timing, specimen handling, or other aspects of care. The registry does not report enough detail to evaluate those issues. The historical assays may provide context for planned biological comparisons, but they do not create a concurrent control group for the treated participants.

Single masking is listed, while the identity of the masked party and operational procedures are not reported in the registry record. The NR group is described as open-label. Without more detail, it is not possible to assess how masking could have affected event ascertainment or laboratory measurements. This is a limitation of what can be interpreted from the record, not evidence that a particular bias occurred.

What do significance tests and confidence intervals add?

In general, a significance test evaluates how compatible observed data are with a specified statistical null model. A p-value is not the probability that a treatment works or that the null model is true. A confidence interval gives a range of values compatible with the data and method at a chosen confidence level; its width communicates precision. Neither a p-value nor a confidence interval for the primary safety endpoint is reported in the registry record. The registry also reports no primary endpoint analysis among the analysis entries. Therefore, the adverse-event counts should be read descriptively rather than as evidence from a reported hypothesis test.

The posted planning illustration is described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It is based on the observed effect, with the effect to detect expressed as a stated fraction of that effect. The registry cautions that these are planning illustrations, not the study’s own design. For time-to-event outcomes, the stated illustration concerns total events; for other outcomes, it concerns participants per arm for 80% power or another listed power level. No numerical illustration values or observed biological effect estimates are reported in the registry record, so they cannot be interpreted quantitatively.

In general, power is the probability that a specified analysis would reject a null hypothesis under a particular assumed effect and model. Planning calculations depend on assumptions about the outcome, variability, allocation, and statistical test. They do not show that a completed study had that probability of detecting an effect, and they are not observed power. A small pilot can inform later planning, but the registry does not report a sample-size justification for this pilot or enough outcome information to assess the assumptions underlying a later study’s calculation.

How can variability affect biological outcomes?

For laboratory measures, general statistical interpretation depends on the outcome distribution and its variability. Over-dispersion means that observed variation exceeds what a chosen model expects; in general, accounting for it can widen uncertainty and change the reliability of standard errors and tests. The registry record does not report variance estimates or analyses for NAD+ levels or mitochondrial respiration, so the presence or relevance of over-dispersion cannot be assessed for these outcomes. The record also does not describe transformations, covariate adjustment, or a model for repeated or paired measurements.

These methods concepts explain what the reported design and analysis details would be needed to support. They do not add results to the registry. The biological outcomes, their numerical estimates, and their uncertainty are not reported in the registry record.

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("Open-label Nicotinamide Riboside")
n      <- c(4)
events <- c(2)
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  Open-label Nicotinamide Riboside  4  2  50.0  6.8  93.2  15.0  85.0  14.7  85.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 5 outcome measures, including a safety endpoint and secondary measures concerning whole blood NAD+ and mitochondrial respiration. It reports 0 analysis entries. A plan for handling multiplicity across outcomes or multiple comparisons is not reported in the registry record. In general, testing multiple outcomes can increase the chance of at least one apparently unusual result under a set of null hypotheses. Statistical plans may address that issue by prioritizing outcomes, adjusting tests, or interpreting secondary results as exploratory, but no such approach is described in the record.

Missing-data procedures are not reported in the registry record. The record does not state how missing blood or tissue measurements would be handled, whether outcome availability differed among participants, or whether any participants discontinued NR or lacked an assessment. This absence of reporting does not establish that missing measurements occurred; it means the approach cannot be evaluated from the record.

Analysis populations are also not specified. The registry reports enrollment of 5 and an at-risk count of 5 for the NR group in the adverse-event summary, but it does not describe a separate intention-to-treat, per-protocol, or safety population definition. No baseline controls were enrolled, so a participant-level analysis population for a concurrent two-group comparison is not described. The record does not report a statistical analysis plan, prespecified handling of protocol deviations, or rules for selecting which participants contribute to each biological outcome.

These gaps limit assessment of how outcome selection, incomplete measurements, and analysis decisions might affect any comparisons. They do not change the basic descriptive reading of the adverse-event figures, but they prevent a fuller evaluation of the planned biological analyses.

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

Serious events with the highest arm-level rate: cardiac arrest (20.0%), death (20.0%).

The registry’s adverse-event summary lists 2 participants with serious adverse events among 5 at risk in the open-label NR group. It lists 0 participants with other adverse events among 5 at risk and 1 death. The serious terms shown are Cardiac Arrest and Death, each reported as 20.0%. These figures describe the registry’s recorded categories; they are not a causal assessment of NR.

The death count should not be added to the serious adverse-event count. The record does not explain whether the death is included among the participants with serious events, and event-level details are not reported. The percentage attached to each serious term should also not be taken to imply separate, independent events or participants. The registry does not provide enough detail to determine whether terms overlap or how they were coded.

The baseline-controls group has 0 participants at risk in the adverse-event summary. It therefore cannot serve as a concurrent group for comparing safety counts. The record does not report a formal comparison, event timing, severity grades beyond the serious classification, or an assessment of event relatedness to study drug. Because the cohort is small and the treatment period varied before surgery, these counts offer limited precision and should be interpreted as descriptive observations in the enrolled group.

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

The record describes a small pilot of preoperative NR in patients scheduled for LVAD implantation, with a stated aim of assessing safety and feasibility and informing a planned larger study. The reported adverse-event figures characterize events in the 5-person treated group during the preoperative study-drug period. The record also identifies biological outcomes involving NAD+ and mitochondrial measures, but numerical results for those outcomes are not reported in the registry record.

These registry entries do not establish whether NR changed myocardial NAD+, whole blood NAD+, or mitochondrial function. They also do not establish whether NR caused the serious adverse events or the death. The study was non-randomized and single-group, and the historical controls were not enrolled in the pilot. The available record therefore does not support a randomized or concurrent comparison of safety or biological outcomes.

A small pilot can have a useful role in testing whether a study process is feasible and in identifying practical issues for a later investigation. However, the registry record does not report detailed feasibility results, recruitment experience beyond enrollment, adherence, or a formal sample-size justification. The adverse-event counts should not be treated as precise population estimates, and absence of a reported biological result should not be interpreted as evidence of no biological change.

The record’s completion status indicates that the study is listed as completed; it does not by itself resolve the unanswered outcome questions. More detailed outcome estimates, uncertainty measures, analysis methods, and information about historical-control comparability would be needed to assess the biological aims or make strong comparisons. No medical conclusion about an individual’s treatment follows from these registry figures.

14. Why This Trial Matters Statistically

This trial matters statistically because it illustrates the difference between a feasibility-oriented pilot and a definitive comparison. The registry describes 5 treated participants and a single-group, non-randomized design. That design can record what happened in the enrolled group, but it cannot separate a treatment effect from other explanations through randomized concurrent comparison. Historical assay controls may offer background context, yet no baseline control subjects were enrolled in the study.

The safety endpoint is a participant count over a preoperative exposure period that could vary from Day 6-Day 14. Counts are straightforward to understand, but they do not account for varying observation time or explain event recurrence. The summary also illustrates why categories and denominators matter: serious events, other events, and death are listed separately, while the record does not explain overlap between the serious-event and death counts.

Statistical interpretation also depends on transparent reporting of analysis methods. The registry lists outcome measures but no analysis entries, and does not report a multiplicity plan, missing-data approach, or analysis populations. Without numerical results for the biological outcomes, readers cannot assess effect size or precision for the study’s stated NAD+ and mitochondrial questions. These are reporting and evidence limitations, not proof that the study failed to collect measurements.

For later research, the pilot’s stated role is to contribute feasibility information for a planned larger study. Planning calculations can help assess the implications of assumed effects and variability, but illustrations based on an observed effect are not observed power and are not a substitute for the original design rationale. A larger, clearly specified analysis would need to define outcomes, comparisons, estimands, and handling of uncertainty in advance. The registry record does not report those details for this pilot.

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 trial-specific limitation is the very small treated cohort: 5 participants were enrolled. With so few observations, the event counts describe only a limited set of participants and cannot precisely characterize less common outcomes. The record provides no confidence intervals or other uncertainty estimates for the safety figures.

The single-group, non-randomized design limits causal interpretation. Historical controls were described for blood and myocardial assays, but no controls were enrolled in the study. The registry does not report their characteristics, the timing of their measurements, or procedures for ensuring that their assays are comparable with those from the treated group. Thus, the intended biological comparisons cannot be independently evaluated from the registry record.

Exposure was preoperative and varied in duration, ending the day before surgery between Day 6-Day 14. The record does not report participant-level exposure, adherence, event dates, follow-up after stopping NR, or detailed descriptions of adverse events. It also does not report an assessment of whether events were considered related to NR. The serious-event terms and death count therefore provide limited clinical and temporal context.

Numerical results for the stated NAD+ and mitochondrial outcomes are not reported in the registry record. Further, the registry does not report a statistical analysis plan, sample-size justification, approach to multiplicity or missing data, or definitions of analysis populations. These omissions prevent a fuller assessment of how the planned biological comparisons were conducted and how precise their estimates might be. They should not be mistaken for evidence that measurements were not collected or that any particular analysis was performed.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Nicotinamide Riboside in LVAD Recipients — NCT03727646.
• Registry record last updated 2024-09-20; status last verified 2024-05.
• Results first posted 2024-09-20.
• 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

NCT03727646 is a completed early-phase 1 pilot sponsored by the University of Washington. It enrolled 5 participants in a non-randomized, single-group study of open-label nicotinamide riboside before elective LVAD implantation. The registry lists single masking but does not identify who was masked. NR was escalated over 3 days to 1000 mg twice daily, with treatment ending the day before surgery, described as between Day 6-Day 14.

The primary endpoint concerns the number of participants experiencing treatment-emergent adverse events during the study-drug period. The adverse-event summary reports 2 participants with serious adverse events among 5 at risk, 0 with other adverse events, and 1 death. The registry lists Cardiac Arrest and Death as serious-event terms, each at 20.0%. No baseline control subjects were enrolled; the described controls were patients previously receiving LVADs. Numerical results for the biological outcomes, inferential analyses, and detailed statistical methods are not reported in the registry record.