Citicoline in Non-Arteritic Ischemic Optic Neuropathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Citicoline in Non-Arteritic Ischemic Optic Neuropathy (NCT03758118), a randomized na study. The primary outcome is Change From Baseline in Visual Acuity at 9 Month.

2. Clinical Question

3. Trial Design

This was a randomized, double-masked, parallel-group study of citicoline in patients with non-arteritic ischemic optic neuropathy. Its phase is listed as NA, and its status is completed. The sponsor is Fondazione G.B. Bietti, IRCCS. The registry gives a start date of 2017-02-20 and a primary completion date of 2017-07-25. The intervention is identified as a dietary supplement, rather than assigned a drug phase.

The planned treatment description was oral citicoline at 500 mg/day for 6 months, followed by a three-month suspension. The comparator description says that the untreated group received no type of treatment during 9 months of observation. The record identifies parallel groups and random allocation, but does not report the sequence-generation method, allocation concealment, masking procedures, or whether any placebo was used. It also does not report the original sample-size justification or the intended allocation ratio.

Enrollment was 40. The primary outcome results list 19 participants in the treated group and 17 in the untreated group. These are the group counts attached to the posted outcome summaries; the record does not explain why they do not account for the full enrolled count. The analysis population, participant flow, withdrawals, and handling of missing observations are not reported in the registry record.

Visual acuity change at 9 months was the primary outcome. The record also lists four secondary outcomes: retinal ganglion cell function, optic nerve function, optic nerve morphology, and visual-field defects. Numerical results are posted for three of these secondary outcomes, while numerical group results for visual-field defects are not reported in the registry record. No sponsor-reported analyses are listed. The study’s stated purpose includes both neuroenhancement and neuroprotection, but the record does not describe a formal statistical plan for testing those concepts.

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 Change From Baseline in Visual Acuity at 9 Month, measured over 9 months vs baseline.

The primary endpoint is change in visual acuity from baseline to 9 months. The record describes visual acuity assessment using Early Treatment Diabetic Retinopathy Study (ETDRS) charts and measurement on the LogMAR scale, which expresses the logarithm of the minimum angle of resolution. The posted outcome is a continuous measure summarized by a mean and standard deviation for each group.

Visual acuity is used because it directly quantifies the visual function named in the trial’s primary question. Measuring change from baseline makes the endpoint about the difference in participants’ recorded acuity over the observation period, rather than just their values at the end. The registry describes the intended outcome as an increase in visual acuity, but does not provide a threshold for deciding whether a measured change is meaningful to patients. Nor does it describe how baseline values were incorporated into the statistical comparison beyond identifying the outcome as change from baseline.

On the LogMAR scale, lower values generally correspond to better visual acuity. The group-level changes therefore need to be interpreted with attention to the scale’s direction and to the way the comparison is defined. The posted comparison is untreated minus treated: a positive difference means the reported mean change is numerically higher in the untreated group. That contrast describes the recorded data; by itself, it does not establish the clinical importance of the difference or its cause.

7. Results Posted in the Registry

• NAION Patients Untreated: mean 0.05 versus -0.06 on control; difference 0.11 (95% CI 0.04 to 0.18), standardized effect d = 1.06; z-test p = 0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change From Baseline in Retinal Ganglion Cells Function at 9 Month

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • NAION Patients Untreated: mean 1.38 versus 1.32 on control; difference 0.06 (95% CI -0.16 to 0.28), standardized effect d = 0.18; z-test p = 0.593.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between NAION Patients Untreated and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in Optic Nerve Function at 9 Months

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • NAION Patients Untreated: mean 126.88 versus 127.05 on control; difference -0.17 (95% CI -5.03 to 4.69), standardized effect d = -0.02; z-test p = 0.945.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between NAION Patients Untreated and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in Optic Nerve Morphology at 9 Months

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • NAION Patients Untreated: mean 63.99 versus 57.71 on control; difference 6.28 (95% CI 0.44 to 12.12), standardized effect d = 0.70; z-test p = 0.035.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for NAION Patients Untreated than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes span retinal ganglion cell function, optic nerve function, optic nerve morphology, and visual-field defects. Together, they were intended to address functional and structural features related to the trial’s broader neuroenhancement and neuroprotection aims. Their different measurement scales mean that the numerical effects are not directly interchangeable, and a consistent direction across outcomes should not be assumed.

Across the secondary results with numerical comparisons, the pattern is mixed: two confidence intervals include zero, while one excludes it. This is not a uniform signal across the measured domains. The primary visual-acuity estimate is more clearly separated from zero in its posted interval, but secondary findings do not establish that all aspects of visual function or optic nerve structure changed in the same way. Numerical group results for visual-field defects are not reported in the registry record.

All listed secondary p-values are unadjusted. When multiple outcomes are tested, the chance of obtaining at least one apparently notable result can increase, even if the tests are individually evaluated at a conventional threshold. The registry does not report whether a hierarchy, multiplicity correction, or prespecified interpretation strategy was used. The secondary evidence should therefore be read as exploratory context rather than as a collection of independent confirmatory claims.

The secondary outcomes can help readers see whether the primary pattern is accompanied by related measurements, but they cannot substitute for a prespecified primary analysis or fill gaps in reporting. The record gives no numerical result for one of the four listed secondary outcomes, and it does not report sponsor analyses. Accordingly, the secondary evidence is incomplete for judging the full set of stated aims.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change From Baseline in Retinal Ganglion Cells Function at 9 Month
• Change From Baseline in Optic Nerve Function at 9 Months
• Change From Baseline in Optic Nerve Morphology at 9 Months
• Change From Baseline in Visual Field Defects at 9 Months

9. Statistical Interpretation

10. Statistical Methods Explained

The registry reports continuous outcomes as group means and standard deviations. A mean describes the average recorded value in a group, while a standard deviation describes how dispersed individual values are around that average. A mean difference contrasts the group averages on the outcome’s original scale. For the primary outcome, the comparison is defined as untreated minus treated, so its sign depends on that ordering. The same ordering applies when interpreting the secondary group contrasts.

What does a confidence interval describe?

In general, a confidence interval conveys uncertainty around an estimated quantity. A narrower interval indicates greater precision under the method used; a wider interval indicates less precision. For a difference, an interval that includes zero is compatible with no group difference at the confidence level used, while an interval wholly on one side of zero is incompatible with zero under that interval procedure. The confidence level for the posted intervals is not reported in the registry record, so it should not be assumed from the interval values alone.

A confidence interval is not a range containing a fixed proportion of individual participants’ outcomes, and it does not give the probability that the true effect lies inside the particular interval. It communicates uncertainty about the estimated group contrast. Its interpretation depends on the sampling and analysis assumptions, as well as on how the outcome and contrast were defined. The posted group standard deviations describe spread among observations; they are not substitutes for intervals around the mean difference.

How should the p-value be read?

In general, a p-value measures how unusual data at least as incompatible with a specified null model would be if that model and the calculation’s assumptions held. It is not the probability that the treatment has no effect, nor does it measure the size or clinical importance of an observed difference. The primary p-value is 0.001 and is identified as unadjusted. The secondary p-values are also unadjusted. Since the registry does not report a complete analysis plan, the exact test and its assumptions are not reported in the registry record.

The difference between statistical evidence and practical importance matters in this trial. A result can be estimated with enough precision to distinguish it from zero under a particular analysis, while the clinical value of that difference remains uncertain. The registry does not provide a minimum clinically important difference or another threshold for evaluating whether a change matters to patients. The scale’s direction also matters: LogMAR values are interpreted differently from measures where larger values indicate better function.

What does randomization contribute?

In general, random allocation is intended to make treatment groups comparable, on average, with respect to factors measured and unmeasured before allocation. That design can support a causal comparison when allocation is implemented appropriately, follow-up is adequate, and the analysis preserves the intended group comparison. The registry labels the study randomized, but details of sequence generation, concealment, adherence, crossover, and participant flow are not reported in the registry record. Thus, the label alone does not establish how those protections worked in practice.

Double masking can reduce some forms of bias when participants, assessors, or other study personnel are unaware of group assignment. The record does not identify who was masked or explain how masking was maintained, particularly given the untreated comparator description. No placebo is described. The meaning and implementation of the double-masked label therefore cannot be evaluated further from the registry record.

Why do standard deviations and sample size matter?

For continuous outcomes, variability affects how precisely a difference in group means can be estimated. When observations vary widely, the group averages carry more sampling uncertainty; with less variability, a similar group contrast can be estimated more precisely. The number of participants also contributes to precision. These principles are general, and the posted group standard deviations and counts give context for the reported estimates without revealing all details of the analysis.

The planning illustrations use the observed effect and a normal approximation. They are not the trial’s original design justification, which is not reported in the registry record. They show how a hypothetical future study’s required group size changes when the target effect is reduced or the desired power is increased. The illustration assumes equal allocation and a two-sided significance level of 0.05. Its values should be read as planning aids, not as evidence about the probability that the completed trial detected an effect.

There are no sponsor-reported analyses listed. The registry does not state whether the primary comparison was adjusted for baseline values or other covariates, how missing data were handled, whether an intention-to-treat population was used, or whether any interim analyses were performed. Those choices can influence estimates and uncertainty, so they remain important unknowns when interpreting the posted summaries.

11. Confidence Intervals and Precision

The primary mean difference is reported as positive, with a confidence interval whose lower and upper bounds are both above zero. Its unadjusted p-value is 0.001. The interval gives a range of values compatible with the estimate under the interval procedure, and its exclusion of zero indicates that the posted estimate is separated from no difference at that procedure’s confidence level. The confidence level itself is not reported in the registry record.

Precision and clinical importance are distinct. The interval does not establish whether the difference is large enough to matter to patients, because the registry does not report a clinical-importance threshold. Nor does the interval describe the range of responses among individuals. The group standard deviations describe observed dispersion, while the interval concerns uncertainty in the estimated contrast.

Precision varies across the secondary outcomes. The intervals for retinal ganglion cell function and optic nerve function include zero; the optic nerve morphology interval does not. The recorded visual-field outcome has no numerical group results reported in the registry record. These differences in interval position reflect the posted estimates and their uncertainty, but should be considered alongside the fact that these secondary comparisons are unadjusted.

The group counts for the primary outcome are 19 and 17. Precision is consequently tied to the information in these recorded groups, not just to the enrollment figure of 40. The record does not explain the difference between enrollment and the group counts or report the analysis populations and missing-data procedures. It also does not state the confidence level used for the intervals. These omissions limit a fuller assessment of why the intervals have their reported widths and how robust the uncertainty estimates are.

12. 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 for 80% power and participants per arm for 90% power; they are not total event counts. The calculation assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It sets the target effect as the stated fraction of the observed effect. The sample-size assumptions for the trial’s original design are not reported in the registry record.

The 80% power column describes the per-arm sample size that the planning calculation associates with an 80% chance of detecting the specified effect under its assumptions, if that effect and model were correct. The 90% power column gives the corresponding planning size for a higher target chance of detection. These are prospective planning interpretations, not statements about what happened in the completed study.

Rows planning for 100%, 75%, and 50% of the observed effect illustrate how the assumed effect size influences the required sample. A smaller target effect requires more participants, because a smaller separation between group averages is harder to distinguish from random variation. The figures are especially sensitive to the observed effect used as their starting point, so they should not be treated as stable estimates of the size needed for every future study.

This is not observed power. The planning calculation does not tell whether the trial had an adequate design, and it cannot replace the estimates and confidence intervals from the completed study. The original design rationale and target sample size are not reported in the registry record.

13. 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 = 0.111; pooled standard deviation σ = 0.104.
2. n = 2 × (1.96 + 0.842)² × 0.104² / 0.111² = 13.9, rounded up to 14 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 <- 0.1109                      # observed difference in means
sigma <- 0.104385171924211                     # 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(3758118)
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 = 14 (80% power), 19 (90% power)
 75% of observed effect: n per arm = 25 (80% power), 34 (90% power)
 50% of observed effect: n per arm = 56 (80% power), 75 (90% power)
power.t.test: 14.9 
Simulated power at n = 14 per arm: 0.769 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and four secondary outcomes. Numerical group comparisons are posted for the primary outcome and three secondary outcomes; numerical results for visual-field defects are not reported in the registry record. The record does not report a multiplicity adjustment, a testing hierarchy, or another procedure for controlling the interpretation of several outcomes. The available p-values are unadjusted.

Multiplicity matters because each additional statistical test creates another opportunity for an apparently unusual result. When results are interpreted together, a single small unadjusted p-value among several outcomes may be less persuasive than a result from a single prespecified test. This is a general statistical concern, not proof that any particular result is false. Without a reported analysis plan, it is not possible to tell which secondary outcomes were intended as confirmatory or how the investigators planned to interpret multiple comparisons.

Missing-data details are also absent. The registry does not describe the number of participants with outcome data at each assessment, reasons for missing observations, imputation methods, or sensitivity analyses. It records enrollment of 40 and group counts of 19 and 17 for the primary outcome, but does not explain the difference. This does not establish that missing data occurred in a particular way; it means the flow and analysis population are not described sufficiently to assess the issue.

The registry does not state whether the analysis followed intention-to-treat, per-protocol, or another population definition. It also does not report covariate adjustment, interim analyses, stopping rules, or a detailed statistical analysis plan. Each of these can affect how an estimate should be understood, but none should be inferred from the randomized and double-masked design labels. The listed outcomes and posted summaries can be described, while the unreported analytical choices remain unknown.

15. 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.

The posted safety counts list zero serious adverse events in the citicoline group among 19 participants at risk and zero in the untreated group among 17 participants at risk. The counts for other adverse events are also zero in both groups, and deaths are listed as zero in both groups. These figures describe the adverse-event entries in the registry record for the groups and at-risk counts shown.

A zero count in a group does not establish that an intervention is free of risk. Safety interpretation depends on the duration and completeness of observation, how events were collected and classified, and the amount of information available. The treatment period was described as 6 months followed by three months without treatment, while the untreated group was observed for 9 months. The registry does not provide further detail on event definitions, collection procedures, severity categories beyond the serious-event listing, or follow-up completeness.

No serious adverse-event terms are listed. The record’s zero counts should therefore be read as the reported observations, not as proof that no unrecorded events occurred or that the findings apply to other populations or durations.

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

The primary outcome summaries show different mean changes in visual acuity between the citicoline-treated and untreated groups at 9 months. The estimated contrast is positive when calculated as untreated minus treated, and the reported confidence interval lies above zero. The unadjusted p-value is 0.001. These are statements about the posted group-level data and their statistical uncertainty, not a determination of whether the difference was important to patients.

The endpoint is measured on the LogMAR scale, where lower values generally correspond to better acuity. The numerical direction of a change should be interpreted with that scale in mind. The registry does not report a clinically meaningful threshold, individual participant responses, or enough baseline detail to judge how the changes relate to initial visual acuity. It also does not provide a full account of the analysis population or missing data.

The record identifies a randomized, double-masked design, but does not describe implementation details for randomization or masking. The comparator is described as untreated, and no placebo is specified. These gaps make it difficult to evaluate possible sources of bias beyond the design labels. The result cannot establish the mechanism of any observed difference or show that the same pattern would occur in other settings.

The secondary results are mixed, and numerical results for visual-field defects are not reported. The unadjusted secondary comparisons do not establish a consistent effect across the trial’s functional and structural measurements. The posted safety counts show no adverse events or deaths recorded in either group, but zero reported events do not demonstrate absence of risk.

Overall, the registry reports an observed difference in mean visual-acuity change and uncertainty estimates that do not include zero. It does not, on its own, establish clinical importance, explain the difference, resolve multiplicity concerns, or provide a complete account of missing observations and analysis choices. Those distinctions are essential when describing what the result does and does not mean.

17. Why This Trial Matters Statistically

This trial is statistically informative because it reports a randomized comparison and continuous outcome summaries for visual acuity, along with group standard deviations and a confidence interval for the mean contrast. Those elements let readers consider both the direction of the observed difference and its precision, rather than relying on a p-value alone. The primary interval lies above zero, while the unadjusted p-value is 0.001.

The record also illustrates why a result’s statistical separation from zero does not answer every research question. Clinical importance requires an interpretive benchmark, and no such threshold is reported. The outcome’s scale direction matters, as do the group definitions and the meaning of change from baseline. A clear statistical contrast is only one part of assessing the evidence.

Its collection of secondary outcomes offers a chance to compare visual function with measures of retinal ganglion cell function, optic nerve function, optic nerve morphology, and visual-field defects. The pattern among posted secondary estimates is not uniform, while the numerical visual-field results are not reported. Since the secondary p-values are unadjusted, they also illustrate why multiple-outcome findings need cautious interpretation.

The record’s omissions are statistically important as well. Details on missing data, analysis populations, masking implementation, original sample-size justification, and multiplicity are not reported. These are not merely administrative details: they influence how readers assess bias, uncertainty, and the scope of the conclusions. The trial therefore offers a concrete example of the value of reporting estimates and uncertainty together with the decisions needed to interpret them.

18. 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.

Several limitations specific to this record constrain interpretation. Although enrollment was 40, primary outcome group counts are 19 and 17, and the record does not explain the difference. It does not give participant flow, outcome-specific completion counts, or reasons for missing observations. The analysis population and missing-data methods are not reported in the registry record.

The registry identifies randomization and double masking but does not describe how allocation was generated or concealed, who was masked, or how masking was maintained. The comparator is described as untreated, with no placebo specified. These omissions prevent a detailed assessment of implementation and possible bias. The record also does not state whether the primary analysis adjusted for baseline values or other factors.

The primary outcome has no reported clinical-importance threshold, and the confidence level for the posted intervals is not specified. The four listed secondary outcomes are not all represented by numerical group results: visual-field defects have no numerical results reported in the registry record. No multiplicity approach is reported, and the secondary p-values are unadjusted. The record lists no sponsor-reported analyses.

The follow-up descriptions cover 9 months, including the treatment period and suspension for the citicoline group. The registry does not provide evidence about longer-term outcomes. It also does not describe the population beyond identifying patients with NAION, limiting assessment of how well the results may apply to other patient groups. These reporting limits should be kept distinct from the observed findings; they do not prove that an unreported procedure was absent, but they mean it cannot be evaluated from the registry record.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Citicoline in Non-Arteritic Ischemic Optic Neuropathy — NCT03758118.
• Registry record last updated 2023-11-24; status last verified 2021-02.
• Results first posted 2023-11-24.
• 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.

22. Record Summary

NCT03758118, titled “Citicoline in Non-Arteritic Ischemic Optic Neuropathy,” is listed as a completed, randomized, double-masked, parallel-group study with phase NA. The sponsor is Fondazione G.B. Bietti, IRCCS. The registry records enrollment of 40 and describes citicoline oral solution at 500 mg/day for 6 months, followed by three months without treatment, against an untreated group observed for 9 months.

The primary outcome was change in visual acuity from baseline to 9 months, measured with ETDRS charts and expressed in LogMAR. Its posted group comparison has an unadjusted p-value of 0.001 and a confidence interval that lies above zero for the untreated-minus-treated contrast. The secondary results show a mixed pattern; numerical results for visual-field defects are not reported in the registry record. Safety entries list zero serious adverse events, other adverse events, and deaths in both groups. The record does not report the original sample-size justification, analysis populations, missing-data methods, or multiplicity approach.