A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD) (NCT03852498), a na phase 3 study. The primary outcome is Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24.

2. Clinical Question

3. Trial Design

This completed phase 3 study evaluated Lenti-D Drug Product in participants with CALD after myeloablative conditioning with busulfan and fludarabine. The record lists 35 participants enrolled and describes a single-group model. Allocation is recorded as not applicable, and masking as none. With no concurrent control group, the design can describe outcomes among treated participants but cannot directly estimate a treatment contrast against a randomized comparator.

The intervention involved collecting participants’ blood stem cells, modifying them with the Lenti-D lentiviral vector, and transplanting the modified cells back after conditioning. The registry identifies the product as Lenti-D, also known as eli-cel or elivaldogene autotemcel. Its arm description says participants received a single intravenous infusion. The study’s enrollment and treatment are described as completed; follow-up remains ongoing in a separate long-term follow-up study.

The study began on 2019-01-24, and primary completion is recorded as 2023-07-24. Its status is completed. The record names 29 outcome measures, including outcomes concerning gadolinium enhancement on MRI, neurologic function, MFD-free survival, overall survival, vector copy number, neutrophil engraftment, and platelet engraftment. These additional outcomes address different aspects of disease status, survival, and treatment course; they do not replace the stated primary endpoint.

The registry record does not report the protocol’s sample-size justification, a detailed statistical analysis plan, or the reasons for choosing this design. It also does not give a concurrent control result. Any interpretation should therefore distinguish the stated study design and endpoint definitions from evidence about comparative treatment effects, which this single-group design does not directly provide.

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.

Before assignment: A total of 35 male participants were enrolled. All underwent mobilization and were treated with Lenti-D Drug Product also referred to as eli-cel (elivaldogene autotemcel) in this study. For study ALD-104 the Transplant Population (TP), Neutrophil Engraftment Population (NEP), and Intent-to-Treat Population (ITT) are identical.

Overall Study

Analysis population for the primary outcome, as defined in the registry: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants are defined as participants who have been followed for 24 months (i.e. Rel Day of last contact \>=730) or have completed the Month 24 Visit, or discontinued from the study but would have been followed for 24 months if still on the study (i.e. Rel Day of data cut \>=730), at the time of the data cut.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Transplant Population (TP) consisted of participants who received Lenti-D Drug Product infusion.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24, measured over At Month 24.

The primary endpoint is the percentage of participants who were alive at month 24 and had none of the six major functional disabilities (MFDs): loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, and complete loss of voluntary movement. The endpoint definition also requires that participants have not received rescue cell administration or allo-hematopoietic stem cell transplantation by month 24, and have not withdrawn from the study or been lost to follow-up by that time.

This is a composite endpoint: meeting its criteria depends on several distinct conditions, rather than on one clinical event alone. It combines survival with the absence of specified functional disabilities and with study-follow-up and treatment-related criteria. A participant who fails any part of the definition does not meet the full endpoint as written. This makes the endpoint a measure of being alive and free of the specified disability outcomes under the registry’s stated rules; it is not simply a measure of survival or of change in a single neurologic score.

A percentage expresses how common endpoint attainment was in the defined analysis population. A confidence interval would communicate uncertainty around that estimate, but the registry record does not report the primary percentage or its 95% confidence interval. The record’s description of evaluable participants is incomplete, so the exact denominator and handling of participants who did not complete follow-up are not fully established by the available wording.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a percentage endpoint and specifies a 95% confidence interval as its measure of dispersion. A percentage is a binary-outcome summary: each participant is classified according to whether the endpoint criteria were met, and the reported proportion describes the share meeting them in the analysis population. For this study, the criteria combine survival, disability status, rescue treatment or transplant status, and follow-up status at month 24. A confidence interval expresses uncertainty around an estimated proportion. Its width depends on the observed estimate and the amount of information available, among other features of the analysis. The registry record does not report the actual percentage, interval limits, or method used to construct the interval, so none can be assessed directly.

What does a binary percentage capture?

A binary endpoint reduces a participant’s status at a specified time to whether a definition is met or not met. That makes the summary relatively direct, but it compresses distinct clinical histories into a single classification. For this endpoint, not meeting the definition could reflect one of several specified circumstances. The percentage alone would not show which criterion most often determined endpoint status. Separate outcome reporting would be needed to understand the contributions of the different components.

Denominator choice is important. The registry states that the treated population consisted of participants who received Lenti-D Drug Product infusion. It also begins to define evaluable participants using follow-up duration, completion of the month-24 visit, or discontinuation under a particular follow-up condition, but that definition is cut off. The record does not fully state which denominator was used for the primary percentage, how participants with missing month-24 status were classified, or whether any other analysis population was used. Those details matter because a percentage can change when the population included in its denominator changes.

Why does a confidence interval matter?

A point estimate, if reported, would be the sample-based summary for the participants analyzed. The 95% confidence interval would indicate the statistical uncertainty associated with that estimate under the method’s assumptions. It would not guarantee that the true value lies within the reported limits, and it would not account automatically for every source of bias or uncertainty in the study. In particular, an interval around a single-group estimate does not supply a comparison with an untreated or alternative-treatment group. No interval limits or calculation method are reported in the registry record.

The endpoint is measured at month 24, but the endpoint definition also includes follow-up and intercurrent-event criteria. Rescue cell administration, allo-hematopoietic stem cell transplantation, withdrawal, and loss to follow-up are explicitly part of the definition. These are not interchangeable with the six MFDs: they are additional conditions for being counted as meeting the composite endpoint. A statistical analysis plan would ordinarily clarify the operational handling of each condition and the analysis set. Such details are not reported in the registry record.

What can a single-group design estimate?

A single-group study can estimate observed outcome frequencies among its participants, subject to the specified analysis population and data-collection process. It cannot create a randomized contrast because no concurrent comparator arm is listed. Randomization, when used, helps balance known and unknown differences between groups; without it, a descriptive outcome is not an isolated estimate of what the intervention caused. This general design principle applies regardless of whether an observed percentage is high or low. The registry’s allocation value is not applicable, and its model is single group.

The registry lists a phase 3 study and 35 participants enrolled. Those details describe the study, but the enrollment count alone does not reveal the precision of an endpoint estimate. Precision also depends on the number of participants contributing endpoint data and on the outcome distribution. The evaluable-population wording is incomplete, and the primary result is not reported, so a numerical assessment of precision is unavailable.

How should planning calculations be understood?

The record describes a sample-size planning illustration based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It specifies that the target effect is a stated fraction of the observed effect. For time-to-event outcomes, the illustration concerns the total number of events; for other outcomes, it concerns participants per arm. These are planning assumptions, not a record of the trial’s design: the actual study is single group, not an equal-allocation two-arm trial. The registry record does not report that these assumptions were the study’s own sample-size justification.

Planning illustrations estimate the sample size that would be required under chosen assumptions for a future comparison. They are not observed power, do not establish that the original study was adequately powered, and do not prove that an effect exists. In this instance, no numerical planning results are included in the available record information, and the primary endpoint result needed to describe an observed effect is also not reported. Thus no sample-size value or power conclusion can be drawn in the registry record recorded.

Over-dispersion is a general concern when observed outcome variability exceeds what a statistical model assumes. For a binary percentage, a model’s uncertainty estimate may be too narrow if its assumptions fail or if outcomes are more heterogeneous than expected. The registry record does not report an over-dispersion assessment, nor does it specify a model for the primary endpoint. No claim about whether over-dispersion was present is warranted.

Finally, the registry lists 29 outcome measures and no analyses. Multiple outcomes can create interpretive challenges when many statistical tests are performed, because the chance of finding an apparently notable result can increase across tests. A prespecified multiplicity strategy can address that issue, but the registry record does not report such a strategy or a detailed analysis plan. The number of listed outcomes alone does not establish that any particular adjustment was or was not applied.

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("Lenti-D Drug Product")
n      <- c(35)
events <- c(30)
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  Lenti-D Drug Product  35  30  85.7  69.7  95.2  70.6  93.7  70.5  93.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 29 outcome measures, including the primary endpoint and secondary outcomes addressing MRI findings, neurologic function, survival, vector copy number, and engraftment. It lists no analyses. This means the available record information does not contain the analysis results or a description of which statistical tests were conducted. The multiplicity strategy, if any, is not reported in the registry record. It is therefore not possible to determine whether tests across outcomes were adjusted, whether a testing sequence was prespecified, or how any such choices affected interpretation.

Multiple outcome measures are not automatically evidence of a statistical problem. They can capture different aspects of a study, but interpreting many tests requires care because selective emphasis or repeated testing can make chance findings appear more compelling. A prespecified analysis plan can define which outcome is primary, how secondary outcomes are treated, and whether any adjustment is used. The registry identifies the primary outcome, but the detailed statistical plan and multiplicity approach are not reported in the registry record.

Missing data are particularly relevant to the primary endpoint because it is assessed at month 24 and its definition excludes participants who withdrew or were lost to follow-up by that time. The record gives a partial evaluability definition based on follow-up and visit completion, but the detailed wording is incomplete. It does not report how missing month-24 status was handled, whether any imputation method was used, or what sensitivity analyses were performed. The effect of missing information on the estimate therefore cannot be evaluated.

The analysis population is also not fully specified in the available wording. The record says the treated population consisted of participants who received an infusion, but does not give the complete evaluable-population definition. These limitations prevent a full account of the denominator and of how participants with incomplete follow-up contributed to the primary result.

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: pyrexia (14.3%), febrile neutropenia (11.4%), neurological decompensation (5.7%), pancytopenia (5.7%), disease progression (5.7%).

In the Lenti-D Drug Product group, 22 participants were recorded as affected by serious adverse events among 35 at risk. Other adverse events were recorded for 35 participants among 35 at risk. The record lists zero deaths in this group. These are descriptive counts from the treated study group; they do not compare event rates with a control group.

The most frequently listed serious adverse-event terms are pyrexia, 14.3%; febrile neutropenia, 11.4%; neurological decompensation, 5.7%; pancytopenia, 5.7%; disease progression, 5.7%; and pseudomonal bacteraemia, 5.7%. These percentages are reported for the listed terms. They should not be added together to infer the percentage of participants with any serious event, since participants may have experienced more than one event. The overall count of participants affected and the term-specific percentages describe different summaries.

An adverse event recorded during a study is not, by that fact alone, established as caused by the intervention. The registry information does not provide comparative safety estimates or establish causality. Nor does the zero-death count in this group mean that no serious events occurred: serious adverse events were recorded among participants. The counts describe the reported study experience and should be interpreted within the limits of the single-group design.

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

The study’s primary question is whether participants met a demanding composite definition at month 24: being alive, having none of six specified MFDs, not having received rescue cell administration or allo-hematopoietic stem cell transplantation, and not having withdrawn or been lost to follow-up by that time. This definition makes the endpoint clinically interpretable as a combined survival, disability, and follow-up outcome. It does not, by itself, show which component drove an individual’s classification.

The registry record does not report the primary endpoint percentage or its 95% confidence interval. Therefore the record cannot establish how many participants met the criteria, how uncertain the estimate was, or how the result compares with a prespecified target. The enrolled count of 35 does not answer those questions because the primary analysis denominator and the observed result are not fully reported.

Even if an observed percentage were available, a single-group study would describe outcomes in the participants treated under the study conditions, not the difference caused by Lenti-D relative to a control. There is no concurrent comparator in the registry design. Conclusions about comparative benefit or harm would require evidence and assumptions beyond a single-group frequency. This is a distinction about what the design can estimate, not a claim about the direction of any result.

The safety record reports serious adverse-event counts and selected terms, along with other adverse events and deaths. These observations describe events recorded among participants but do not establish that the intervention caused them. The study’s follow-up is also described as continuing in a separate long-term follow-up study, so the recorded month-24 endpoint should not be mistaken for a complete summary of later outcomes.

Overall, the registry record supports a clear description of the study’s intervention, design, endpoint definition, enrollment, and selected safety observations. It does not support a numerical conclusion about the primary endpoint or a precise estimate of comparative treatment effects. The distinction between defining an outcome and reporting its observed result is essential to a statistically sound reading.

14. Why This Trial Matters Statistically

This study raises several important statistical issues for clinical researchers. First, its primary endpoint is a composite. Combining survival, six types of major functional disability, rescue treatment or transplant, and follow-up status can create a useful overall summary, but the result would need to be interpreted alongside its component outcomes. A composite percentage alone cannot show which parts of the definition were most influential.

Second, the study is single group. That design can describe outcomes among participants who received the intervention, but it cannot provide a randomized between-group contrast. This distinction matters whenever observed outcomes are discussed as evidence about an intervention’s effect. Descriptive outcome frequencies and causal comparisons answer different questions.

Third, endpoint interpretation depends on the analysis population and follow-up. The registry’s evaluability description is incomplete, and it does not report how missing month-24 information was handled. Without those details and the observed estimate, readers cannot assess the denominator, the influence of incomplete follow-up, or the precision of the primary result.

Fourth, the record lists 29 outcome measures but no analyses. Multiple outcomes can give a broader account of disease status and treatment course, while also making prespecification and multiplicity procedures important for interpretation. Those procedures and the detailed statistical plan are not reported in the registry record.

Finally, the sample-size assumptions described for planning illustrations should not be confused with the design or analysis of this study. The illustrations assume equal allocation between two arms, whereas the registered study is single group. Keeping planning exercises separate from observed trial results helps prevent sample-size calculations from being read as evidence of statistical power or treatment effect.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most consequential limitation of the available registry information is that it does not report the primary endpoint result or its 95% confidence interval. The endpoint’s definition is detailed, but a definition cannot substitute for an observed estimate. The record also does not fully specify the primary analysis denominator because the evaluable-population description is incomplete.

The single-group design has no concurrent control arm. It can support descriptive summaries of participants’ outcomes, but cannot directly estimate the difference between Lenti-D and another treatment or a control condition. Any comparative or causal interpretation would require evidence not contained in this record.

Information about missing data is insufficient for assessing the month-24 endpoint. The definition refers to withdrawal and loss to follow-up, and the population description refers to follow-up and visit completion, but the record does not report the handling of missing endpoint status or sensitivity analyses. It is not possible to determine the extent to which missingness may have affected the estimate.

The registry lists 29 outcome measures and no analyses. It does not report the detailed statistical analysis plan, multiplicity procedures, or the method used to calculate the primary confidence interval. The rationale for the study’s sample size is not reported in the registry record; the planning assumptions described are illustrations, not a stated justification for this study.

Safety figures are descriptive and lack a concurrent comparison. The record gives counts and selected serious-event percentages, but those data alone do not establish causality or comparative risk. Finally, the study’s month-24 endpoint does not summarize all later follow-up; the record says follow-up remains ongoing in a separate long-term follow-up study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD) — NCT03852498.
• Registry record last updated 2024-05-24; status last verified 2024-04.
• Results first posted 2024-05-24.
• 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.

19. Record Summary

NCT03852498 is a completed phase 3, single-group study of Lenti-D Drug Product after myeloablative conditioning with busulfan and fludarabine in participants with CALD. The registry lists 35 participants enrolled and describes a primary endpoint based on being alive and free of six major functional disabilities at month 24, subject to additional rescue-treatment, transplant, withdrawal, and follow-up criteria.

The registry record does not report the primary endpoint percentage or its 95% confidence interval. It lists 29 outcome measures and no analyses. The safety record reports 22 participants with serious adverse events among 35 at risk, 35 with other adverse events among 35 at risk, and zero deaths in the group. The study has no concurrent comparator, and follow-up is described as continuing in a separate long-term follow-up study.