Nicotinamide Riboside in SARS-CoV-2 (COVID-19) Patients for Renal Protection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Nicotinamide Riboside in SARS-CoV-2 (COVID-19) Patients for Renal Protection (NCT04818216), a randomized phase 2 study. The primary outcome is Change in Whole Blood NAD+ Level.

2. Clinical Question

3. Trial Design

NIRVANA was a phase 2, randomized, double-masked, parallel-group clinical trial sponsored by The University of Texas Health Science Center at San Antonio. It addressed nicotinamide riboside in hospitalized patients with COVID-19 and acute kidney injury, with whole-blood NAD+ change and safety as central concerns. The registry lists the study as completed, with a start date of 2021-06-11 and primary completion on 2021-12-09. Enrollment was 28.

Participants were assigned to placebo or nicotinamide riboside. The placebo group received 2 capsules twice daily for 10 days. The nicotinamide riboside group received 250mg capsules, 2 capsules twice daily for 10 days. The registry identifies the study as double-masked, but does not report which people were masked or how masking was maintained. It also does not report the randomization procedure or allocation-concealment method.

The primary outcome was change in whole-blood NAD+ level from baseline to 10 days. The recorded analysis population was a modified intention-to-treat set, defined as participants who received at least 1 dose of study drug. The registry lists secondary outcomes concerning area under the curve, major adverse kidney events, estimated glomerular filtration rate, and proteinuria. Although the record lists 7 outcome measures, secondary-outcome results are not reported in the registry record.

The registry record does not report the trial's original sample-size justification, planned statistical analysis methods, missing-data procedures, interim analyses, or multiplicity strategy. Those omissions limit how fully the design and inferential framework can be assessed from the record alone.

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

Analysis population for the primary outcome, as defined in the registry: Analysis set is a modified intention to treat with participants receiving at least 1 dose of study drug.

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 Change in Whole Blood NAD+ Level, measured over Baseline to 10 days.

The primary endpoint was change in whole-blood NAD+ level from treatment beginning to end, with the timeframe specified as baseline to 10 days. NAD+ is the measured biological quantity named in the trial record; the result is expressed in μg/mL. The endpoint is continuous, and the registry reports its mean and standard deviation in each group.

The stated purpose of measuring NAD+ was to determine the effect of nicotinamide riboside on whole-blood NAD+ levels. In general, a continuous endpoint preserves information about the magnitude of measurements rather than reducing results to a binary event such as present or absent. A change measure also focuses the comparison on movement over the specified interval. The record does not report further details about how baseline and end-of-treatment measurements were combined, or how observations from participants with missing measurements were handled.

The registry reports mean change of -0.02 μg/mL in the placebo group and 0.06 μg/mL in the nicotinamide riboside group, with standard deviations of 0.02 and 0.07, respectively. It reports a mean difference of 0.08 μg/mL for the group comparison. These are results for the NAD+ endpoint; they should not be interpreted as direct results for kidney function or clinical kidney events. The record lists several kidney-related secondary outcomes, but their results are not reported in the registry record.

7. Results Posted in the Registry

• Nicotinamide Riboside Group: mean 0.06 versus -0.02 on control; difference 0.08 (95% CI 0.04 to 0.12), standardized effect d = 1.51; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, double-masked, parallel-group phase 2 trial. Randomization is intended, in general, to make assigned groups comparable on average with respect to both measured and unmeasured characteristics. Masking can, in general, reduce the possibility that expectations affect care, measurement, or reporting. These design labels do not establish how the procedures were carried out: the registry record does not report the randomization method, allocation concealment, or which people were masked.

What does a mean difference describe?

The endpoint is continuous, and the reported group summaries are means. A mean is a measure of the center of a set of values. The comparison reports the difference between the group means: 0.08 μg/mL, with the group means reported as -0.02 μg/mL for placebo and 0.06 μg/mL for nicotinamide riboside. A mean difference retains the endpoint's measurement units, so its magnitude can be read on the NAD+ scale. It is a group-level contrast and does not show the range of individual responses or how many participants experienced a particular change.

The record reports standard deviations of 0.02 and 0.07. In general, standard deviation describes the spread of observations around a mean. A standard deviation is not a confidence interval and does not directly state how precisely the difference between two means has been estimated. The reported spreads differ between the groups, and the record does not describe whether the analysis allowed for unequal variability.

What does the p-value tell the reader?

The reported unadjusted p-value is p < 0.001. In general, a p-value describes how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the statistical model were correct. It does not state the probability that the null hypothesis is true. It does not measure the size or importance of the observed effect, and it does not establish that a result will replicate. The registry record does not report the statistical test or model used for the p-value, so its assumptions cannot be checked from the record.

The comparison is labeled unadjusted. In general, an unadjusted comparison is not corrected for other variables or for multiple comparisons unless an adjustment is separately specified. The registry record does not report covariate-adjusted results or a strategy for handling multiple outcomes or tests. The p-value should therefore be interpreted in the context of a record that lists several outcomes, without assuming an adjustment that is not described.

What can the confidence interval add?

A confidence interval gives a range of estimates compatible with the observed data under a particular method and its assumptions. Its width conveys precision: a narrower interval indicates less statistical uncertainty under that method, while a wider interval indicates more. The reported interval for the mean difference lies above zero. The record does not name the interval method, so its assumptions and exact coverage properties cannot be assessed from the registry record alone. The interval also does not capture every source of uncertainty, such as potential bias or limitations in outcome measurement.

How should the analysis population be understood?

The primary analysis population is described as modified intention-to-treat, including participants who received at least 1 dose of study drug. In general, intention-to-treat analysis aims to retain participants according to randomized assignment, while modified versions apply a stated restriction. Here, the restriction is receipt of at least 1 dose. The record does not report the number excluded from the analysis set, the reasons for exclusion, or how missing outcome observations were handled. It therefore does not allow a full assessment of whether the analysis set differed from the randomized population.

What does over-dispersion mean in general?

Over-dispersion is a general issue for count or binary outcomes when observed variability exceeds what a statistical model assumes. It can make standard errors too small if not accommodated. The primary endpoint in this trial is a continuous mean change, not a count outcome, and the record does not report an over-dispersion assessment. The concept is relevant to understanding methods generally, but it should not be attributed to this trial's analysis without evidence.

The record reports four secondary outcomes, including kidney-related measures and area under the curve. It does not report their results or the methods used to analyze them. It also does not report interim analyses, the original sample-size rationale, or a prespecified statistical analysis plan. Those missing details limit reconstruction of the planned inferential approach and the interpretation of any unreported outcomes.

10. Confidence Intervals and Precision

The reported mean difference in change in whole-blood NAD+ level is 0.08 μg/mL. Its confidence interval lies above zero, indicating that the interval does not include no difference under the calculation used. The registry record does not describe the method used to calculate the interval. Its exact endpoints should therefore be understood as the posted bounds, not as a guarantee about the true effect or a measure of all uncertainty.

In general, a confidence interval communicates both an estimate and its precision. A narrower interval means that the estimated effect is more tightly constrained under the assumptions of the calculation; a wider interval leaves more uncertainty about its magnitude. An interval excluding zero is consistent with a nonzero difference in the direction of the estimate, but it does not establish clinical importance. Clinical interpretation also depends on what change in NAD+ would matter, and that threshold is not reported in the registry record.

The group standard deviations, 0.02 for placebo and 0.07 for nicotinamide riboside, describe variation in the outcome values rather than precision of the mean difference. The registry reports 13 in the placebo group and 15 in the nicotinamide riboside group for the primary result. The size of the groups, variability, analysis method, and missing outcome handling all bear on precision. Missing-data handling and the exact inferential method are not reported in the registry record.

The unadjusted p-value is p < 0.001. A small p-value and a confidence interval that excludes zero address statistical compatibility with a null value under the methods used; neither alone establishes a clinically meaningful change or resolves possible bias, measurement limitations, or multiplicity. The registry record does not report an adjustment strategy for multiple outcomes.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrations based on the observed mean difference, rather than the trial's original design rationale. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The assumed effect is varied as a stated fraction of the observed effect: planning for 100% of the observed effect, 75% of the observed effect, or 50% of the observed effect.

The 80% power column gives the planned number of participants per arm under those assumptions for an 80% chance of detecting the assumed effect if that effect is the true one and the calculation's assumptions hold. The 90% power column gives the corresponding per-arm planning number for a 90% chance. These are design targets under a model, not guarantees about what a future study will find. This is not observed power.

The figures rise as the assumed effect becomes smaller: planning for a smaller effect requires more participants under the same general calculation framework. This relationship is expected because smaller differences are harder to distinguish from random variation. The values are illustrations tied to the observed effect in this trial, which may not be the effect a future study should expect. They do not substitute for a trial-specific design calculation incorporating its intended population, outcome, analysis, and anticipated missingness.

The registry record does not report the assumptions used for the trial's original sample-size design. The planning illustration should not be read as evidence that the trial was designed using these assumptions or that it had a particular probability of detecting the observed result.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.080; pooled standard deviation σ = 0.053.
2. n = 2 × (1.96 + 0.842)² × 0.053² / 0.080² = 6.9, rounded up to 7 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.08                      # observed difference in means
sigma <- 0.0531326351979358                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(4818216)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 7 (80% power), 10 (90% power)
 75% of observed effect: n per arm = 13 (80% power), 17 (90% power)
 50% of observed effect: n per arm = 28 (80% power), 38 (90% power)
power.t.test: 8 
Simulated power at n = 7 per arm: 0.733 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and four secondary outcomes. The secondary outcomes concern change in area under the curve, major adverse kidney events, estimated glomerular filtration rate, and proteinuria. The primary comparison is reported with an unadjusted p-value. The registry record does not report a multiplicity strategy, such as how the chance of false-positive findings across outcomes or analyses was addressed.

In general, testing multiple outcomes or conducting multiple comparisons can increase the chance that at least one result appears statistically notable by chance. Methods such as adjusting significance thresholds or specifying a hierarchy can address that issue, but no such method should be assumed. The unadjusted primary result is best understood as the comparison reported, with no documented multiplicity adjustment in the registry record. Results for the listed secondary outcomes are not reported in the registry record.

The primary analysis set is described as modified intention-to-treat, defined as participants who received at least 1 dose of study drug. The registry does not report how many randomized participants did not enter this analysis set, why any participants were excluded, or whether the analysis retained original group assignments after treatment initiation. It also does not report how missing measurements were handled, whether any imputation was used, or whether sensitivity analyses assessed alternative missing-data assumptions.

In general, missing-data methods matter because an analysis based only on observed outcomes can be biased if the availability of a measurement is related to the outcome or treatment. The registry record does not provide enough information to assess that possibility. It does not report a prespecified statistical analysis plan, covariate adjustment, or interim analyses. Those absent details limit evaluation of outcome selection and analytic flexibility, but do not establish that any particular procedure was or was not performed.

14. 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: death (73.3%), worsening of renal function requiring dialysis (26.7%), respiratory failure (13.3%), hypotension (7.7%), thrombocytopenia (7.7%).

The registry reports serious adverse events affecting 7 in the placebo group and 12 in the nicotinamide riboside group. It reports other adverse events affecting 6 in the placebo group and 10 in the nicotinamide riboside group. The listed numbers at risk are 13 for placebo and 15 for nicotinamide riboside. These are descriptive safety counts; the record does not provide a statistical comparison of the groups or enough detail to interpret causal differences.

Deaths are listed as 6 in the placebo group and 11 in the nicotinamide riboside group. The top serious-event terms include Death, Worsening of renal function requiring dialysis, Respiratory failure, Hypotension, Thrombocytopenia, and Septic shock. Their listed percentages are 73.3%, 26.7%, 13.3%, 7.7%, 7.7%, and 7.7%, respectively. The registry record does not explain the denominator for these term percentages or whether event categories can overlap. They should not be added together or treated as mutually exclusive.

These counts do not establish that treatment caused an event or that groups differed in safety. The registry record does not report event timing, severity detail beyond the serious-event classification, exposure-adjusted rates, or a statistical analysis of safety outcomes. Interpretation should remain descriptive.

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

The posted result describes a difference in mean change in whole-blood NAD+ level between the nicotinamide riboside and placebo groups over baseline to 10 days. The mean change was -0.02 μg/mL in the placebo group and 0.06 μg/mL in the nicotinamide riboside group; the reported mean difference was 0.08 μg/mL, with an unadjusted p < 0.001. The confidence interval lies above zero. These statistics describe the primary laboratory endpoint and its estimated group contrast.

They do not establish that the observed change is clinically important. The registry record does not report a threshold for a meaningful NAD+ change, nor does it report results for the listed kidney-related secondary outcomes. In particular, the primary NAD+ result is not itself evidence of a difference in major adverse kidney events, eGFR, or proteinuria. Results for those outcomes are not reported in the registry record.

The endpoint was observed over baseline to 10 days, and the primary analysis population included participants who received at least 1 dose. The record does not report missing-data handling or a comparison of the analysis population with all randomized participants. The result also comes from a phase 2 trial with enrollment of 28; the registry does not report the original sample-size justification. These design and reporting details matter when considering how stable and broadly applicable an estimate may be.

The safety record includes serious adverse events, other adverse events, and deaths in both groups. The counts are descriptive, and the registry record does not report a comparative safety analysis or details sufficient to attribute events to treatment. Accordingly, the posted information supports a statistical description of the NAD+ comparison and recorded safety counts, but does not by itself establish a clinical benefit, lack of benefit, or causal safety conclusion.

16. Why This Trial Matters Statistically

This trial is statistically instructive because it puts a continuous laboratory outcome at the center of a randomized comparison. The mean difference is expressed in the outcome's own units, μg/mL, and can be considered alongside the group means, standard deviations, and confidence interval. Those summaries answer related but distinct questions: the means describe average change, the standard deviations describe spread, and the interval conveys uncertainty in the estimated comparison under its calculation method.

The record also illustrates why a small p-value is not a complete interpretation. The unadjusted p-value, p < 0.001, describes compatibility with a null comparison under a statistical method, but the registry does not report that method. A p-value does not show whether the magnitude matters to patients or whether the outcome corresponds to a clinical kidney outcome. The distinction is especially important because the trial lists several kidney-related secondary outcomes whose results are not reported in the registry record.

Analysis-population definitions are another important consideration. The primary analysis set included participants who received at least 1 dose, and the registry does not describe missing measurements or exclusions. Without those details, readers cannot fully assess the relationship between the randomized groups and the analyzed observations. The missing account of multiplicity and the original sample-size rationale further limits reconstruction of the inferential plan.

Finally, the sample-size illustration shows how planning requirements depend on the effect size a future study aims to detect. Smaller assumed effects require more participants under the stated calculation assumptions. Such planning figures are distinct from the number enrolled in this trial and from evidence about the original design. Together, these issues demonstrate why effect estimates, uncertainty, analysis choices, and the completeness of registry reporting all matter when interpreting trial results.

17. 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 result concerns change in whole-blood NAD+ level from baseline to 10 days. It is not a direct report of kidney function or kidney events. Although the registry lists major adverse kidney events, eGFR, proteinuria, and area under the curve as secondary outcomes, their results are not reported in the registry record. The clinical importance of the observed NAD+ change is also not specified.

The primary analysis population is described as modified intention-to-treat and includes participants who received at least 1 dose. The registry does not report the number or reasons for any exclusions from that set, how missing outcome measurements were handled, or sensitivity analyses for missingness. This limits assessment of potential selection or missing-data effects.

The comparison is reported as unadjusted, and the registry does not report the statistical test or model, covariate adjustment, multiplicity strategy, or exact confidence-interval method. It also does not report the original sample-size justification, interim analyses, randomization procedure, allocation concealment, or which people were masked. These are reporting gaps; they do not establish that a procedure was not carried out, only that it is not reported in the registry record.

The safety figures are descriptive. The registry does not explain the denominator for the serious-event term percentages or whether categories overlap, and it does not report a comparative safety analysis. Event timing and additional event detail are also not reported in the registry record. As a result, the listed counts cannot by themselves establish causation or a between-group safety difference.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Nicotinamide Riboside in SARS-CoV-2 (COVID-19) Patients for Renal Protection — NCT04818216.
• Registry record last updated 2023-12-26; status last verified 2023-12.
• Results first posted 2023-12-26.
• 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.

21. Record Summary

NIRVANA, a phase 2 randomized, double-masked, parallel-group trial sponsored by The University of Texas Health Science Center at San Antonio, studied nicotinamide riboside in hospitalized patients with COVID-19 and acute kidney injury. The registry lists the study as completed, with enrollment of 28, a start date of 2021-06-11, and primary completion on 2021-12-09.

The primary outcome was mean change in whole-blood NAD+ level from baseline to 10 days. The reported mean difference was 0.08 μg/mL, with an unadjusted p < 0.001 and a confidence interval lying above zero. The primary analysis set included participants who received at least 1 dose of study drug. The record also lists kidney-related secondary outcomes and safety counts, but secondary-outcome results and further analysis details are not reported in the registry record.