Gene Therapy for X-linked Retinitis Pigmentosa (XLRP) - Retinitis Pigmentosa GTPase Regulator (RPGR): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Gene Therapy for X-linked Retinitis Pigmentosa (XLRP) - Retinitis Pigmentosa GTPase Regulator (RPGR) (NCT03252847), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone..

2. Clinical Question

3. Trial Design

This was an open-label, multicentre Phase I/II trial of subretinal AAV5-hRKp.RPGR for X-linked retinitis pigmentosa associated with RPGR defects. The registry lists randomized allocation and no masking overall, but its description distinguishes two phases with different assignment procedures. Phase 1 was a sequential dose-escalation study: participants entered dose groups according to enrollment timing, and the arm descriptions identify low, intermediate, and high doses. Phase 2 was a cohort expansion with random assignment to immediate or deferred treatment and two dose options.

That distinction matters when interpreting the posted results. Sequential assignment in Phase 1 is not the same as a randomized comparison across its three dose groups. Conversely, Phase 2's immediate-versus-deferred assignment is randomized according to the registry description, but the primary endpoint was analyzed for Phase 1 participants only. The posted primary results therefore do not constitute a randomized treatment-versus-control comparison. The listed primary endpoint arms contain 3 participants in the immediate low-dose group, 4 in the intermediate-dose group, and 3 in the high-dose group; the deferred group has 0 participants for that endpoint.

Overall enrollment was 49, and the study is listed as completed. Its start date is 2017-07-31 and its primary completion date is 2021-11-18. The registry does not report the reasons the endpoint analysis includes only the Phase 1 population, or how participants were selected for each analysis beyond the assignment descriptions. The trial's stated aims differ by phase: assessing safety during dose escalation, then assessing safety and efficacy during cohort expansion. Those aims do not, by themselves, establish that every outcome was analyzed in both phases or that all participants contributed to each result.

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.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The primary endpoint was analyzed for participants in the dose escalation phase (i.e., study Phase 1) only

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 Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone., measured over 9 weeks.

The primary endpoint is a participant count for a composite of specified events in the 9 weeks following administration. A participant met the endpoint if at least one event occurred and was considered at least possibly related to the Advanced Therapy Investigational Medicinal Product, not surgery alone. The events covered a reduction in visual acuity of 15 ETDRS letters or more, severe unresponsive inflammation, infective endophthalmitis, ocular malignancy, or a Grade III or above non-ocular SUSAR.

A composite endpoint can capture several types of safety events in one measure. This can be useful when the question concerns whether any of a prespecified set of serious or clinically important events occurred, rather than the frequency of one particular event. It also means the count does not identify which component occurred unless component-specific results are reported. The registry record does not report component-specific primary endpoint counts.

The posted primary endpoint values are 0.0 in each of the three Phase 1 dose groups, with group sizes of 3, 4, and 3. The deferred group has no participants listed for this endpoint. These are short-window participant counts, not a measure of all safety outcomes across the full study period. They should not be read as evidence that no adverse events of any kind occurred: the registry reports separate adverse-event results, including serious and other adverse events.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted results include a participant-count endpoint, a continuous visual-acuity outcome, and a binary static-perimetry outcome. Each type of outcome calls for a different way of describing the data. General statistical explanation is distinguished below from what the registry record reports about this trial.

What does a participant count show?

For the primary endpoint, the outcome is the number of participants meeting a composite definition, rather than a mean score or a rate over person-time. A value of 0.0 means no participants in that listed group were recorded as meeting the defined composite in the stated window. It does not tell how often individual symptoms or events occurred unless component-level counts are also reported. The registry record gives no primary endpoint confidence interval or test result. Because the endpoint is analyzed in Phase 1 only and the deferred group has no participants listed, a two-arm treatment-versus-control estimate is not available for this outcome.

General: a count is most informative when read alongside its denominator, population, outcome definition, and follow-up period. Here, the denominator varies across the three listed Phase 1 groups, and the endpoint window is 9 weeks after administration. The same count can convey very different levels of precision in groups of different sizes. Zero observed events is not proof that the event cannot occur.

How should the continuous comparison be read?

Visual acuity is reported as a mean number of ETDRS letters at Baseline and Month 6, with standard deviations. The immediate group has a posted mean of 0.6 and the deferred group -3.2. The unadjusted recalculated mean difference is -3.8, with a 95% confidence interval from -6.607 to -0.993. The interval is for the difference as defined by the calculation, deferred relative to immediate. Since the full interval is below zero, it indicates that the estimated difference in this unadjusted comparison is on the negative side. The unadjusted p-value is 0.008.

General: a mean difference expresses the difference between group averages, not the change experienced by every participant. A confidence interval describes a range of values compatible with the data and the calculation's assumptions; it conveys uncertainty as well as the direction and scale of the estimate. The interval does not account for unreported design features, outcome selection, or multiplicity. A p-value measures how unusual data at least as discrepant as those observed would be under a specified null model and assumptions. It is not the probability that the null hypothesis is true, and it does not show that a result is clinically important.

How should the binary comparison be read?

Static perimetry is reported as a number of participants meeting the outcome: 6 in the immediate group of 23 and 2 in the deferred group of 10. The unadjusted recalculated risk difference is -0.061, with a 95% confidence interval from -0.367 to 0.245. The interval includes zero, so the data are compatible with a range that includes no difference as well as differences in either direction. The unadjusted p-value is 0.708. The registry also gives relative-risk and odds-ratio estimates, each with intervals, but no sponsor-reported analyses are listed.

General: a risk difference compares the proportions experiencing an outcome, whereas a relative risk compares those proportions as a ratio and an odds ratio compares event odds. These measures answer related but nonidentical questions. For small groups, estimates can be imprecise, and their uncertainty should be considered rather than relying on a single point estimate or p-value. The present recalculations are unadjusted and should not be treated as evidence of an analysis plan reported by the sponsor.

What are the planning figures?

The planning illustrations use the observed secondary effect as a starting point and consider detecting stated fractions of that effect. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustrations give participants per arm for 80% and 90% power. They are not the trial's own sample-size justification, and they do not represent observed power. The registry record does not report the trial's sample-size justification or whether these assumptions were used in planning.

General: planning calculations translate an assumed effect and variability into an approximate sample size under stated assumptions. If the true effect differs from the observed estimate, the required size can differ as well. Using an observed effect from a small study can yield unstable planning estimates, so the displayed fractional-effect scenarios are illustrations, not guarantees. They also do not establish that the trial was adequately powered for its primary endpoint.

Why does over-dispersion matter?

General: over-dispersion occurs when the variability in outcome data exceeds what a model assumes. When it is present and ignored, standard errors can be too small and confidence intervals too narrow, making uncertainty appear lower than it is. The primary endpoint is a short-window participant count, and no dispersion estimate or model-based analysis is reported. The continuous visual-acuity result includes a standard deviation, but the registry record does not report a fitted model or a method for adjusting for other factors. No claims about model fit or over-dispersion can therefore be made from the posted 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("Immediate Low Dose AAV5-hRKp.RPGR", "Immediate Intermediate Dose AAV5-hRKp.RPGR", "Immediate High Dose AAV5-hRKp.RPGR")
n      <- c(3, 4, 3)
events <- c(0, 0, 0)
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  Immediate Low Dose AAV5-hRKp.RPGR  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Immediate Intermediate Dose AAV5-hRKp.RPGR  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Immediate High Dose AAV5-hRKp.RPGR  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists seven secondary outcomes, but it does not report a multiplicity adjustment or a hierarchy specifying which secondary outcomes would be treated as confirmatory. It also lists no reported analyses. Consequently, the posted unadjusted secondary p-values cannot be interpreted as results adjusted for examining multiple outcomes. When several outcomes are tested, the chance of at least one apparently unusual result can increase; general statistical practice may address this with prespecified testing strategies or adjustment methods, but no such strategy is reported.

Missing-data methods are not reported in the registry record. The posted sample sizes differ across outcomes: the visual-acuity comparison includes 25 immediate and 13 deferred participants, while the static-perimetry comparison includes 23 and 10. The primary endpoint is analyzed in Phase 1 only and lists 3, 4, and 3 participants across the dose groups. The record does not explain these differences or describe whether missing observations were excluded, imputed, or handled by another method. It would be inappropriate to assume that every enrolled participant contributed to every endpoint.

The analysis populations are described only in limited terms. For the primary endpoint, the record specifies Phase 1 participants. The Phase 2 design description says participants were randomized to immediate or deferred treatment, and the adverse-event record presents a deferred group before treatment and groups after treatment. The registry does not report a full analysis-population definition, such as whether analyses followed assignment regardless of treatment received, or how crossovers and incomplete follow-up were handled.

These reporting gaps affect how much can be inferred from the posted comparisons. They do not invalidate the recorded summaries, but they limit assessment of selection, missingness, and the relationship between the outcomes examined. A more complete statistical analysis plan, participant flow by endpoint, missing-data account, and multiplicity strategy are not reported in the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: intraocular pressure increased (14.3%), retinal detachment (9.1%), uveitis (9.1%).

The registry reports serious adverse events and other adverse events separately from the primary composite. For serious adverse events, the immediate low-dose group has 2 affected participants among 11 at risk; the intermediate-dose group has 0 among 17, and the high-dose group has 0 among 4. The deferred group before treatment has 0 among 13. After treatment, the deferred low-dose group has 1 among 7, and the deferred intermediate-dose group has 0 among 6. Deaths are reported as 0 in every listed group.

For other adverse events, the reported affected-participant counts are 11 among 11 in the immediate low-dose group, 17 among 17 in the immediate intermediate-dose group, and 4 among 4 in the immediate high-dose group. The deferred group before treatment has 1 among 13; the after-treatment low-dose group has 7 among 7, and the after-treatment intermediate-dose group has 6 among 6. The listed serious-event terms with the highest percentages are Intraocular pressure increased at 14.3%, Retinal Detachment at 9.1%, and Uveitis at 9.1%.

These are descriptive participant counts by group and period. They do not establish that an event was caused by treatment, and they are not identical to the primary endpoint's attribution rule and 9-week time window. The registry record does not report further detail about event duration, severity beyond the listed classifications, or adjusted comparisons.

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

The primary result means that the registry recorded no participants meeting the defined composite safety endpoint in each of the three listed Phase 1 dose groups during the stated 9-week period. It describes the observations available for those groups; it is not a precise estimate of the frequency of rare events, particularly given the small group sizes. The registry provides no primary endpoint confidence interval or inferential comparison, and there is no deferred-group primary result to contrast with the treated groups.

The result does not mean that no adverse events occurred. Separate safety reporting lists serious adverse events in the immediate low-dose group and in the deferred low-dose group after treatment, along with other adverse events across multiple groups. Those adverse-event counts use their own reporting categories and group periods. They cannot be substituted for the primary composite count, nor do they alone establish causation.

The secondary results describe visual-acuity and static-perimetry comparisons at Baseline and Month 6. Their estimates are unadjusted recalculations from posted summary statistics, with different outcome scales and different numbers of participants. The registry record does not list sponsor-reported analyses, and no multiplicity adjustment is reported. These limits mean the results should not be treated as a definitive test across all outcomes or as confirmation of the primary result.

The study is described as a Phase I/II safety and efficacy investigation, with sequential dose escalation in Phase 1 and randomized immediate-versus-deferred assignment in Phase 2. The primary endpoint analysis is limited to Phase 1, while the secondary numerical comparisons use immediate and deferred groups. This design and analysis distinction matters: evidence from one phase or endpoint does not automatically answer every question posed by the other. The registry record reports observations and comparisons, but it does not report enough methodological detail to establish how missing data, multiplicity, or analysis populations were handled.

14. Why This Trial Matters Statistically

This trial illustrates why design labels need to be read alongside phase-specific procedures. The registry lists randomized allocation, but Phase 1 assignment was sequential by enrollment timing, whereas Phase 2 participants were randomized to immediate or deferred treatment. The primary endpoint analysis is restricted to Phase 1, so its results are not a randomized comparison against a concurrent deferred group. Recognizing that distinction prevents the primary counts from being overinterpreted as comparative evidence.

It also illustrates that a safety endpoint and functional outcomes answer different questions. The primary composite focuses on specified events in a 9-week window, while the posted secondary outcomes address visual acuity and static perimetry at Baseline and Month 6. A finding on one does not settle the other. The primary outcome's zero counts in small groups are descriptive and do not demonstrate that a qualifying event is impossible or that doses are equivalent.

The record also shows the importance of uncertainty and analysis transparency. The secondary estimates are unadjusted recalculations, and no sponsor analyses are listed. The record does not report a multiplicity strategy, missing-data methods, or a sample-size justification. Planning illustrations based on observed effects are not evidence that the trial had a specified probability of detecting its true effect. For researchers and clinicians reading registry results, these distinctions help separate observed counts, unadjusted comparisons, and design assumptions from conclusions the record cannot support.

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 trial-specific features limit interpretation. The primary endpoint is reported only for Phase 1, with 3 participants in the low-dose group, 4 in the intermediate-dose group, and 3 in the high-dose group. The deferred group has no participants listed for this endpoint. The small listed groups mean the zero counts provide limited precision, and the record reports no primary confidence interval, test, or component-level count.

Assignment procedures differed by phase. Phase 1 used sequential assignment based on enrollment timing, while Phase 2 randomized participants to immediate or deferred treatment. The registry reports overall enrollment of 49 but does not explain the endpoint-specific analysis sizes or provide a participant flow account. The open-label design and absence of masking are also relevant when interpreting outcomes that may involve assessment or reporting; the registry does not report additional safeguards or assessment procedures.

Only two secondary outcomes have numerical results in the posted data described by the record, while the registry lists seven secondary outcomes. No sponsor analyses are listed, and multiplicity handling, missing-data methods, and full analysis-population definitions are not reported in the registry record. The secondary comparisons are unadjusted recalculations from summary statistics; their uncertainty and the possibility of chance findings across multiple outcomes should be considered.

Finally, the primary endpoint covers a defined 9-week period and a particular composite, while other adverse events are reported separately. The registry record does not report component-specific primary counts or enough detail to link every adverse event to the composite's attribution and timing criteria. These limitations constrain conclusions to the posted counts and estimates rather than broader claims about outcomes outside the measured groups, definitions, and time windows.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Gene Therapy for X-linked Retinitis Pigmentosa (XLRP) - Retinitis Pigmentosa GTPase Regulator (RPGR) — NCT03252847.
• Registry record last updated 2025-01-08; status last verified 2024-12.
• Results first posted 2025-01-08.
• 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

The registry record describes NCT03252847, a completed open-label, multicentre Phase I/II trial of subretinal AAV5-hRKp.RPGR for X-linked retinitis pigmentosa caused by RPGR defects. Overall enrollment was 49. Phase 1 used sequential assignment to three dose groups; Phase 2 randomized participants to immediate or deferred treatment.

The primary endpoint counted participants meeting a specified composite during the 9 weeks after administration and was analyzed in Phase 1 only. The posted count is 0.0 in each of the three dose groups, with no participants listed in the deferred group for that endpoint. Numerical secondary comparisons are posted for visual acuity and static perimetry. The registry record lists no reported analyses, and does not report multiplicity adjustment, missing-data methods, or a sample-size justification.