Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency (NCT01380990), a non-randomized phase 1, phase 2 study. The primary outcome is Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year).

2. Clinical Question

In statistical terms, this is a question about survival proportions at a specified follow-up time, not a comparison of time-to-event curves as described by the primary endpoint. The trial also lists secondary outcomes comparing overall survival and event-free survival at 3 years and an infection rate. Those secondary outcomes do not replace the primary endpoint, and their presence does not establish that a treatment difference was found.

The design can describe outcomes among people who received gene therapy and set those observations beside historical transplant data. Because treatment allocation was non-randomized, differences between the groups may reflect differences in patient characteristics, clinical care, follow-up, or other factors as well as treatment. The registry record does not report a randomized comparison that would separate those explanations.

3. Trial Design

This is a Phase I/II, open-label, non-randomized, single-centre trial with a historical control. The registry lists a parallel model, but the comparison is not a concurrent randomized allocation: gene therapy participants received autologous modified cells, while the control information came from patients treated with allogeneic HSCT. The record explicitly cautions that the arms are not a like-for-like control comparison.

The gene therapy approach uses autologous CD34+ hematopoietic stem/progenitor cells modified with a lentiviral vector carrying human ADA complementary DNA under the EFS promoter. The trial description states that cells were infused after marrow cytoreduction with busulfan. The registered intervention list also includes HSCT and Peg-Ada. It does not report enough information to reconstruct how each listed intervention was used for every participant.

The registry reports enrollment of 36 and a completed status. The listed dates are a start of 2012-11-15 and primary completion of 2019-12-23. These record-level details describe the trial, but they do not tell us how many participants contributed data to each endpoint or whether all enrolled participants completed follow-up. Those details are not reported in the registry record.

Historical control designs can be useful when a concurrent randomized comparison is not used, particularly for describing outcomes relative to existing clinical experience. Their interpretation depends on how comparable the groups are and whether outcome definitions and follow-up are aligned. Here, the registry identifies the comparator as historical allogeneic HSCT data but does not report the methods used to select, match, or adjust the historical patients.

The open-label and non-randomized features are relevant to interpretation. There is no masking listed, and allocation is non-randomized. The registry record does not report an allocation procedure, masking of outcome assessment, or a statistical plan that would explain how potential differences between groups were addressed.

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

Reasons for not completing this period:

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: All participants were included in the Baseline Analysis Population

6. Primary Endpoint

The registry lists the primary outcome as Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year), measured over 12 months.

The primary endpoint is overall survival of participants treated with the investigational medicinal product at 1 year. The registry defines it as the percentage of subjects alive at 12 months after treatment with OTL-101 or HSCT. In this context, the measure is a proportion at a particular follow-up point: it records whether participants are alive at that time, rather than quantifying a change in a laboratory measure or a symptom score.

In general, a fixed-time survival proportion is easy to interpret because it answers a direct question about the share of a group alive at a prespecified time. A confidence interval, when reported, conveys the precision of that estimated proportion: wider intervals indicate less precision, while narrower intervals indicate greater precision. The registry specifies a 95% confidence interval as the dispersion measure for the primary outcome, but it does not post the estimate or interval.

The endpoint is clinically interpretable as a survival status measure, but it is not enough on its own to establish a causal treatment effect. A comparison with historical HSCT outcomes must account for the fact that the groups were not randomized and may differ in ways that affect survival. The record does not report a primary endpoint estimate, a between-group effect estimate, or its uncertainty. Therefore, the registered endpoint can be described, but its observed result cannot be assessed from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a binary percentage outcome: overall survival at 12 months. For this type of endpoint, each participant’s status at the specified time contributes to a group proportion. The endpoint description defines the outcome as the percentage alive after treatment with OTL-101 or HSCT. The registry specifies a 95% confidence interval, but does not post the calculated proportion or interval.

What does a confidence interval communicate?

In general, a confidence interval describes uncertainty around an estimated quantity. It is not a guarantee that the true value lies within a particular interval, and it does not by itself show whether a difference is clinically important. For a survival proportion, the interval helps readers understand how precisely the observed group proportion has been estimated. The width depends on the data and the estimation method. Since the registry record does not report the primary estimate or its interval, readers cannot assess that precision.

What does the historical comparison allow?

The trial is non-randomized and historically controlled. A comparison of its gene therapy participants with historical HSCT patients is therefore not equivalent to a randomized treatment contrast. In general, randomization helps prevent systematic differences in prognostic factors from driving the comparison. Historical controls may differ from current trial participants because of eligibility, baseline health, treatment setting, care practices, or the way outcomes are recorded. The registry identifies the historical group but does not report whether the groups were matched, adjusted, or otherwise made more comparable.

Because of this, a numerical difference between groups, if reported elsewhere, would need to be interpreted in light of possible confounding. An unadjusted comparison describes the observed groups; it does not automatically isolate the effect of treatment. No adjusted effect estimate or procedure for controlling confounding is reported in the registry record.

How should the secondary outcomes be approached?

The record lists overall survival and event-free survival comparisons at 3 years and an infection rate among the secondary outcomes. These are distinct questions. Event-free survival depends on a definition of which events count and how timing is handled; that definition is not reported. The registry record also does not report the statistical methods used for these outcomes, nor their numerical results. The number of listed outcome measures and analyses does not reveal whether they were prespecified in the same way or how they were prioritized.

What can sample-size illustrations tell us?

In general, a sample-size calculation is a planning exercise based on assumptions about the effect to detect, variability, significance level, power, and allocation. It is not evidence that an observed result has a particular probability of being correct. The planning illustrations associated with this page use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They take a stated fraction of the observed effect as the effect to detect. For time-to-event calculations, the displayed quantity is a total number of events; for other calculations, it is participants per arm. These are planning illustrations, not the trial’s own design justification, and the registry record does not report its sample-size justification.

Where a planning illustration is based on an observed effect, it should not be confused with observed power or a retrospective test of whether the trial succeeded. The illustrations depend on the assumptions and do not establish that the trial actually enrolled the numbers implied by a calculation. No specific numerical illustration is described.

What statistical plan is documented?

The registry record does not report the analysis model, handling of censoring, missing-data approach, interim analyses, prespecified covariates, or the statistical plan for comparing the historical group with gene therapy participants. It also does not report whether any recalculated analyses were performed. Without these details and the primary outcome results, a statistical assessment is necessarily limited to explaining the endpoint and design rather than evaluating the analysis itself.

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("OTL-101* On-Study Subjects", "OTL-101* On-Study and CUP Subjects", "HSCT Controls Without MRD", "HSCT Controls With MRD")
n      <- c(10, 20, 5, 11)
events <- c(10, 20, 5, 11)
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  OTL-101* On-Study Subjects  10  10  100.0  69.2  100.0  72.2  100.0  71.5  99.8
ARM  OTL-101* On-Study and CUP Subjects  20  20  100.0  83.2  100.0  83.9  100.0  83.9  99.9
ARM  HSCT Controls Without MRD  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6
ARM  HSCT Controls With MRD  11  11  100.0  71.5  100.0  74.1  100.0  73.5  99.8

11. Multiplicity, Missing Data and Analysis Populations

The record lists 14 outcome measures and 32 analyses, with a primary endpoint and several secondary outcomes. Multiple outcomes or analyses can raise a multiplicity question: when many statistical tests are conducted, the chance of at least one apparently notable result may increase. In general, analysis plans may address this by defining a hierarchy of outcomes or adjusting the interpretation of multiple tests. The registry record does not report whether any multiplicity strategy was used, how the primary endpoint was prioritized among analyses, or which analyses were prespecified.

Missing data also affect interpretation, especially for an endpoint assessed at 12 months. Readers would need to know how many participants had survival status available at that point and how any unavailable status was handled. The registry record does not report missing-data counts, reasons for missingness, censoring rules, or a method for handling incomplete follow-up. Enrollment of 36 does not establish that all participants contributed to every outcome analysis.

The analysis populations are not described in the record. It does not specify whether results were based on all enrolled participants, all participants who received treatment, or another population. Nor does it describe exclusions from analyses or how the historical control population was assembled. These omissions make it difficult to judge whether the populations underlying any comparison were comparable and how broadly the results would apply.

The non-randomized historical comparison adds a further interpretive concern: statistical adjustment, if used, would depend on measured covariates and model assumptions. The record does not report whether adjustment was undertaken. No particular missing-data method, multiplicity correction, or analysis population should be assumed.

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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pyrexia (50.0%), device related infection (30.0%), immune reconstitution inflammatory syndrome (20.0%), device related sepsis (10.0%), gastroenteritis norovirus (10.0%).

The registry safety figures are grouped under “OTL-101* On-Study and CUP Subjects” and “OTL-101* On-Study Subjects.” In the first group, 20 participants are listed as at risk for serious adverse events and 11 as affected; 20 are listed as at risk for other adverse events and 20 as affected. The record lists 0 deaths in this group. In the on-study group, 10 are listed as at risk for serious adverse events and 7 as affected; 10 are listed as at risk for other adverse events and 10 as affected. The record lists 0 deaths in this group as well.

The selected serious adverse-event terms include Pyrexia, Device related infection, Immune reconstitution inflammatory syndrome, Device related sepsis, Gastroenteritis norovirus, and Influenza. Their listed percentages are 50.0%, 30.0%, 20.0%, 10.0%, 10.0%, and 10.0%, respectively. These entries are event-term summaries, not a complete description of each participant’s course. The record does not explain whether one participant could contribute more than one event or how the term-specific percentages were calculated.

In general, adverse-event counts describe events recorded in the defined safety groups; they do not establish that the treatment caused each event. The listed group denominators also differ, so the groups should not be treated as interchangeable. Comparable historical-control safety data and further event details are not reported in the registry record.

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

The record establishes that a Phase I/II trial of autologous lentiviral gene-modified cells for ADA deficiency was registered as completed and that its primary endpoint was overall survival at 12 months. It also describes the historical HSCT comparison and posts selected safety figures for OTL-101 groups. These details are useful for understanding the question the trial set out to address and the general structure of its evidence.

However, the primary survival result is not reported in the registry record. There is no posted percentage alive at 12 months, confidence interval, or comparison estimate. This means readers cannot assess the observed survival proportion, its precision, or the size and direction of a difference from historical HSCT outcomes based on this record. A completed status should not be interpreted as proof of a particular result.

Even with outcome values, the non-randomized historical comparison would require careful interpretation. In general, outcomes observed in two non-randomized groups can differ for reasons besides treatment. Differences in patient features, clinical context, follow-up, or outcome ascertainment could affect a comparison. The registry record does not report whether the groups were made comparable or whether statistical adjustment was used.

The safety counts and event terms are descriptive entries, not a randomized safety comparison. They do not show that every recorded event was caused by the gene therapy, and the record does not include matching historical safety figures. The listed secondary outcomes also cannot be interpreted as findings because their numerical results are not reported.

Accordingly, this page can explain the endpoint, design, and limitations of the registry record, but it cannot judge the treatment’s efficacy or make a clinical recommendation. The posted information is insufficient to establish either a treatment benefit or a lack of benefit. It describes a trial question and limited safety summaries, while leaving key outcome estimates and analysis details unavailable.

14. Why This Trial Matters Statistically

This trial is statistically notable because it pairs a survival endpoint with a non-randomized historical control. The central analytical issue is not simply how to calculate a percentage alive at 12 months, but how to interpret that percentage when the comparison group comes from earlier clinical experience rather than random allocation. This distinction matters because observed group differences may reflect differences in the participants or care context as well as differences between treatments.

The endpoint itself is straightforward to state: the percentage alive at a fixed time after treatment. Yet a useful interpretation needs both an estimate and a measure of uncertainty. The registry specifies a 95% confidence interval, but does not report the result or interval. This makes the example a reminder that an endpoint definition and an analysis plan cannot replace the actual estimate needed to judge precision.

The record also illustrates why trial completion and enrollment figures have limited statistical meaning on their own. The registry lists enrollment of 36, but does not report endpoint-specific analysis populations, missing follow-up, or primary outcome data. Readers therefore cannot infer how much information contributed to the survival estimate or how precise it may be.

Finally, the multiple registered outcomes and analyses make transparent reporting important. The record lists 14 outcome measures and 32 analyses, but does not describe a multiplicity approach or the analysis plan. Without those details and the results, readers should distinguish carefully between what was planned or listed and what was observed. This distinction is broadly important when interpreting registry records for trials with historical controls.

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 direct limitation of the available record is that it does not report the numerical primary endpoint result, despite identifying 12-month overall survival as the primary outcome. There is also no reported 95% confidence interval, so neither the observed proportion nor its precision can be evaluated. The same limitation applies to the secondary outcomes: their topics are listed, but their numerical results are not included.

The comparison is historical and non-randomized. The record does not describe how historical HSCT patients were selected, whether their characteristics were comparable with gene therapy participants, or whether any adjustment was used. Differences in treatment period, clinical practice, eligibility, follow-up, and outcome measurement could affect comparisons. The record does not report methods that would allow these potential sources of bias to be assessed.

Important analytical details are also unavailable. The statistical analysis plan, endpoint-specific participant counts, analysis populations, treatment of missing data, censoring rules, and any multiplicity strategy are not reported in the registry record. The definitions and analysis methods for event-free survival and infection rate are also not stated in the available information.

The safety summaries have their own limits. They show counts for two OTL-101 groups and selected serious-event terms, but do not provide detailed event-level information, a matching historical safety comparison, or an explanation of the term-specific percentages. The registry’s enrollment of 36 should not be taken as the denominator for every analysis; the record does not explain how the different safety-group sizes relate to the full enrollment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency — NCT01380990.
• Registry record last updated 2021-09-16; status last verified 2021-08.
• Results first posted 2021-09-16.
• 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 describes a completed, open-label, non-randomized Phase I/II trial of autologous EFS-ADA lentiviral-modified CD34+ cells in ADA deficiency, with historical allogeneic HSCT data as the comparator. It lists enrollment of 36 and a primary endpoint of overall survival at 12 months, expressed as a percentage with a 95% confidence interval.

The record does not report the numerical primary endpoint result, its confidence interval, or a between-group estimate. It also does not report key analysis details, including missing-data methods, analysis populations, or methods for making the historical groups comparable. Selected safety counts and serious-event terms are listed for OTL-101 groups, but no comparable historical safety summary is reported. The findings therefore cannot be assessed from this registry information alone.