Traumatic Optic Neuropathy Treatment Trial (TONTT): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Traumatic Optic Neuropathy Treatment Trial (TONTT) (NCT01783847), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Change/Improvement Visual Acuity From the Beseline.

2. Clinical Question

The trial focused on TON, a condition in which injury can affect the optic nerve and visual function. Its registry description discusses observation, medical treatment, and surgery as approaches used in TON, while noting that the best management approach was not established in the description. The treatments examined in this study were EPO, methylprednisolone, and observation; surgery is not listed as a study group.

The clinical question is therefore about visual acuity outcomes across these treatment groups, not about a randomized treatment effect. Because assignment was non-randomized, differences between groups could reflect differences in the patients who received each approach as well as any treatment-related differences. The registry record does not report how treatment assignment was decided or whether the groups were adjusted to account for baseline differences.

The primary outcome description refers to measurements at several times after treatment and defines improvement using more than one visual acuity summary. The record does not give the corresponding group results, so it cannot establish from the information reported whether visual acuity changed differently across the groups.

3. Trial Design

The Traumatic Optic Neuropathy Treatment Trial (TONTT), registered as NCT01783847, is listed as a phase 1 and phase 2 study. It is described as a parallel, non-randomized trial with single masking. The sponsor was Tehran University of Medical Sciences. The registry lists the study as completed, with enrollment of 117.

The three listed groups received recombinant human EPO, methylprednisolone, or observation. The EPO description specifies intravenous treatment daily for 3 days, with a dose depending on age. The methylprednisolone description specifies intravenous treatment every 6 hours for 3 days. The observation group is described as receiving observation. The record does not explain the process used to assign patients to these groups.

Non-randomized allocation is important for interpreting any group comparison. Random assignment is a design method intended to make treatment groups comparable, on average, with respect to measured and unmeasured characteristics. Without randomization, baseline differences or other factors related to treatment choice may contribute to observed outcome differences. The registry record does not report a method for adjusting comparisons for such differences.

The primary endpoint concerns change or improvement in visual acuity at least 3 months after treatment. The outcome description also lists visual acuity assessments at earlier follow-up times. The registry states that 100 patients (100 eyes) completed the study protocol and that 17 patients with incomplete follow-up or who did not follow the treatment protocol were excluded during the study. The record does not provide group-specific completion counts for the visual outcome.

Although the study is marked completed, visual acuity results, statistical comparisons, and a statistical analysis plan are not reported in the registry record. The record therefore describes the design and intended outcome but does not provide enough outcome information to estimate a comparative treatment effect.

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: Seventeen patients with incomplete follow up and not following the treatment protocol were also excluded during the study. There were 100 patients (100 eyes) who completed the study protocol

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 Number of Participants With Change/Improvement Visual Acuity From the Beseline, measured over Change from baseline at least 3 months after treatment.

The primary endpoint is titled as the number of participants with change or improvement in visual acuity from baseline. Its stated timeframe is change from baseline at least 3 months after treatment. The record describes best-corrected visual acuity (BCVA) assessments at 1, 2, and 3 days, 1 week, 2 weeks, and 1 month, as well as at least 3 months after treatment.

The description uses several approaches to characterize improvement: mean logMAR visual acuity; a change of 0.3 in logMAR, classified as improvement, deterioration, or no change; a mean improvement percentage; and the percentage of patients across ordinal BCVA categories. Those categories range from no light perception through light perception, hand motion, and count fingers, to at least 20/200. These measures summarize vision on different scales and do not represent one interchangeable definition of response.

Visual acuity is a clinically relevant way to describe visual function in a study of TON. Repeated assessments can describe how visual acuity changes over follow-up, while a categorical measure can indicate whether participants move between levels of vision. However, interpreting a count of participants with improvement requires a clear prespecified definition, the number assessed at the relevant time, and results by treatment group. Those results and details about how the different definitions were combined are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation starts with the outcome actually defined and the comparison the design can support. The primary outcome is framed as a count of participants with visual acuity change or improvement. For a binary outcome, each participant is classified into a response category, such as meeting or not meeting a specified improvement definition, and the resulting group counts describe the observed responses. The registry record does not report those visual outcome counts.

What does a confidence interval describe?

In general, a confidence interval expresses the uncertainty around an estimated effect under the statistical model used to construct it. A narrow interval indicates greater precision than a wide interval, while either interval can include values compatible with different effect directions or magnitudes. An interval does not correct problems in study design, such as non-random allocation, or guarantee that the model’s assumptions are appropriate. No visual outcome confidence interval is reported in the registry record.

Why does non-randomized allocation matter?

Randomization is a way to reduce systematic differences between groups at the point of assignment. With non-randomized allocation, treatment groups may differ in prognosis or other characteristics before treatment. Such differences can confound an observed association between treatment and outcome. An adjusted analysis may account for measured characteristics, but its interpretation depends on which factors were measured, how they were modeled, and whether important confounders remain unmeasured. The registry record does not report an adjustment method or the baseline comparisons needed to assess this issue.

How should repeated and differently scaled outcomes be understood?

The outcome description includes visual acuity assessments at several follow-up times and multiple definitions or summaries of improvement: mean logMAR, a 0.3 logMAR change classified as improvement, deterioration, or no change, an improvement percentage, and ordinal visual acuity categories. Repeated measurements can provide information about the course of an outcome over time, but they are correlated within a participant. A valid analysis should account for that dependence or define a particular assessment time as the primary comparison. The record names a primary timeframe but does not explain how the other assessments were incorporated into the analysis.

Different outcome scales answer related but distinct questions. A mean logMAR change describes average change on a numerical scale; a categorical response count describes how many participants meet a threshold; and ordinal categories retain an ordering of visual function. Analyses can yield different summaries because the scales preserve different information. The record does not report which definition governed the primary statistical test or how results across definitions were reconciled.

What role does over-dispersion play?

In general, over-dispersion arises when observed variability is greater than a statistical model expects. It can make standard errors too small if a model assumes less variability than the data contain. This issue is most relevant to particular count or grouped-data models; a participant-level binary outcome does not, by itself, establish that over-dispersion is present. The registry record does not describe a model for the visual outcome, so it is not possible to assess whether over-dispersion was relevant or how variability was handled.

What can planning calculations say?

Sample-size calculations are planning illustrations, not observed power. The stated assumptions for the planning illustration are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. These assumptions describe a calculation framework rather than the trial’s original design. The registry record does not report a sample-size justification or a statistical plan for the study. A planning calculation cannot establish that the trial had adequate precision, and it does not substitute for reporting the actual outcome estimates and their uncertainty.

Finally, a p-value, when reported, measures how compatible the observed data are with a specified null model under the analysis assumptions. It does not measure the probability that a treatment works, nor does it quantify clinical importance. No visual outcome p-value or inferential test is reported in the registry record. In this study, the lack of reported estimates and uncertainty measures prevents readers from assessing either the direction or the precision of the visual outcome comparison.

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("Recombinant Human Erythropoietin (EPO)", "Methylprednisolone", "Observation")
n      <- c(69, 15, 16)
events <- c(28, 3, 5)
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  Recombinant Human Erythropoietin (EPO)  69  28  40.6  28.9  53.1  29.8  52.4  29.8  52.4
ARM  Methylprednisolone  15  3  20.0  4.3  48.1  7.0  45.2  7.3  45.6
ARM  Observation  16  5  31.2  11.0  58.7  14.2  55.6  14.2  56.0

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when an analysis considers several outcomes, definitions, time points, or comparisons. The more results examined, the greater the chance that at least one may appear notable by chance if each is tested separately. This does not mean multiple measures are inherently inappropriate; it means the analysis should distinguish the primary question from secondary or exploratory questions and state how the testing strategy was handled.

The registry describes a primary visual acuity endpoint with multiple ways of defining or summarizing improvement, repeated assessments at several follow-up times, and a secondary outcome concerning participants with RAPD grade +4. It lists two outcome measures. The registry record does not report which visual acuity definition was used for a primary statistical test, whether any multiplicity adjustment was planned, or how the secondary outcome related to the primary analysis. Multiplicity handling is therefore not reported in the registry record.

Missing data are also important because the record states that 17 patients with incomplete follow-up or who did not follow the treatment protocol were excluded during the study. The record says 100 patients (100 eyes) completed the protocol. It does not report the timing or group distribution of exclusions, whether any visual acuity values were missing among those retained, or whether sensitivity analyses were used. It also does not report an imputation method or explain whether the primary analysis included all enrolled participants or only those who completed the protocol.

These details affect how well a result represents the participants initially considered for the study. When follow-up or protocol adherence is related to outcomes, analyzing only those with complete records can produce a biased estimate. The registry record does not provide enough information to assess that possibility or determine whether the reported analysis population matched the intended population.

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.

The registry lists adverse event counts for the EPO, methylprednisolone, and observation groups. It records zero serious adverse events, zero other adverse events, and zero deaths in each group. The corresponding at-risk counts are 69 for EPO, 15 for methylprednisolone, and 16 for observation. These are reported counts, not estimates of comparative safety.

A zero count means that no event of that category is listed for the group in the registry record. It does not prove that the true risk is zero. Interpretation depends on how events were sought, what was counted, the completeness and duration of follow-up, and whether all events were entered into the record. Those details are not reported in the registry record. No serious adverse event terms are listed.

The at-risk counts should be read as the denominators associated with these safety entries, not assumed to be the number analyzed for the visual acuity outcome. The registry separately reports that 100 patients (100 eyes) completed the study protocol, but does not explain the relationship between the safety denominators and the visual outcome population.

Because allocation was non-randomized and the groups differ in size, simple counts alone do not establish that safety differed between treatments. The registry entries also do not establish that any treatment is safe or unsafe. They describe only the adverse event information recorded for this study.

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

The record establishes that TONTT was completed as a non-randomized, parallel study of EPO, methylprednisolone, and observation, with a primary question about change or improvement in visual acuity. It describes the intended visual acuity measures and lists safety event counts. These design and reporting details help define what the study set out to examine.

The registry record does not report the visual acuity results by group, an estimated difference between treatments, confidence intervals, or statistical tests. It is therefore not possible from the record to say how many participants improved, how the groups compared, or how precise any estimated difference would be. Missing results do not show that there was no effect or that outcomes were equivalent.

Even if comparative visual outcomes were available, non-randomized allocation would require caution. Treatment groups may differ in ways that influence vision, and the record does not report whether those differences were measured or adjusted for. An association between a treatment and an outcome would not, by itself, demonstrate that treatment caused the outcome.

The listed zero adverse event counts also have a limited interpretation. They represent events recorded in the registry, not proof that events could not occur or that the treatments have equivalent safety. The record does not describe the event collection and follow-up procedures needed to judge the completeness of those counts.

Accordingly, this record is informative about the study’s design, outcome definitions, participant exclusions, and recorded safety counts, but it does not provide the efficacy results needed to draw a statistical conclusion about visual recovery. No treatment recommendation follows from these registry entries.

14. Why This Trial Matters Statistically

This trial matters statistically because it illustrates how a clinical question and an outcome definition are not the same as a reported result. The registry gives a specific visual acuity question, describes several ways to characterize change, and lists follow-up assessments. Without group outcome values and uncertainty estimates, readers cannot determine the magnitude, direction, or precision of the observed visual changes.

It also illustrates why allocation methods shape what a comparison can mean. In a non-randomized study, patient characteristics and clinical decisions may be related both to treatment assignment and to outcome. That makes it important to report how groups were formed, what their baseline characteristics were, and how analyses addressed potential confounding. Those details are not reported in the registry record.

The exclusions described in the record are another important statistical feature. Incomplete follow-up and protocol non-adherence can affect the interpretation of an analysis if inclusion in the final outcome set is associated with prognosis or treatment. Reporting group-specific exclusions and how missing outcomes were handled would help readers assess whether the analyzed participants represent the intended study population.

Finally, the record distinguishes neither a single primary visual acuity analysis from its several definitions and time points nor a testing strategy for the secondary outcome. Clear specification of the primary analysis and multiplicity approach helps readers understand which findings are confirmatory and how to interpret multiple comparisons. The lack of reported outcome analyses means that these statistical questions remain unresolved in the registry record.

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.

Several limitations are specific to interpreting this trial record. First, allocation was non-randomized. The record does not describe the allocation process, so it is not possible to evaluate how treatment selection may have related to injury severity, baseline vision, or other prognostic factors. It also does not report baseline characteristics by group or an adjustment strategy for potential confounding.

Second, the primary endpoint description contains multiple ways to define or summarize visual acuity improvement. The registry does not identify which definition determined the primary analysis or how the different scales and follow-up times were handled statistically. This makes the intended outcome question less straightforward to connect to a single reported estimate.

Third, the record reports that 17 patients with incomplete follow-up or who did not follow the treatment protocol were excluded, while 100 patients (100 eyes) completed the protocol. It does not give group-specific exclusion information, outcomes for excluded patients, or details of missing-data methods. The potential effect of these exclusions on the outcome comparison cannot be assessed.

Fourth, the registry marks the study as completed but does not report visual acuity results or statistical tests. It also does not report a statistical analysis plan, sample-size justification, or multiplicity approach. The safety entries list zero events in each group, but event ascertainment and follow-up details are not reported. These omissions limit both assessment of benefit estimates and interpretation of safety counts.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Traumatic Optic Neuropathy Treatment Trial (TONTT) — NCT01783847.
• Registry record last updated 2019-05-07; status last verified 2016-04.
• Results first posted 2018-09-12.
• 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

NCT01783847, the Traumatic Optic Neuropathy Treatment Trial, is listed as a completed phase 1 and phase 2, parallel, single-masked, non-randomized study sponsored by Tehran University of Medical Sciences. The registry lists enrollment of 117 and describes groups receiving intravenous EPO, intravenous methylprednisolone, or observation.

The primary outcome concerns the number of participants with visual acuity change or improvement from baseline at least 3 months after treatment. The record states that 100 patients (100 eyes) completed the study protocol and that 17 patients with incomplete follow-up or who did not follow the protocol were excluded during the study.

The registry records zero serious adverse events, zero other adverse events, and zero deaths in each group. It does not report visual acuity outcome estimates, comparative statistical tests, confidence intervals, or the statistical methods used for the primary analysis. Therefore, the record describes the study question and design but does not provide results that quantify comparative visual outcomes.