Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene (NCT01852071), a na 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

The study aimed to assess safety and efficacy after transfer of human ADA cDNA into participants’ own bone marrow stem/progenitor cells. The stated endpoints also include gene transfer in blood cells and measures of immune function. This makes the primary survival outcome one part of a wider assessment: it addresses survival at a specified follow-up point, while the secondary outcomes cover cell-level and immune-related measures.

The registry lists an enrollment of 46, but does not report how many participants contributed to the primary outcome analysis. Because the design has no separate comparison arm, the primary question is descriptive rather than a randomized comparison of treatment strategies. The registry record does not report the survival estimate, its confidence interval, or details of the analysis population.

3. Trial Design

This was a completed Phase 1/Phase 2, single-group clinical study sponsored by the University of California, Los Angeles. The registry lists an enrollment of 46 participants and ADA-SCID as the condition. The study started on 2013-08-02, had a primary completion date of 2018-08-27, and is marked completed.

The investigational approach used autologous CD34+ cells from bone marrow. The cells were transduced ex vivo with the EFS-ADA lentiviral vector encoding the human ADA gene and then infused. The listed interventions also include busulfan and PEG-ADA enzyme replacement therapy. The registry record does not specify their schedules, whether every participant received each intervention, or how their use related to treatment and follow-up.

The design is recorded as single-group, with allocation listed as NA and masking listed as none. No concurrent control group is described. Accordingly, outcomes from this study can describe what was observed among participants treated in the study, but the design does not itself provide a randomized, like-for-like estimate against an alternative treatment. The registry explicitly cautions against interpreting arms as a like-for-like control comparison.

The primary outcome is overall survival at 12 months. Listed secondary outcomes include event-free survival at 2 years, vector copy number in peripheral blood granulocytes and mononuclear cells, erythrocyte ADA activity, reduction in erythrocyte dAXP, change from baseline in CD3+ T-cell counts at 2 years, and the number of single integration sites representing >30% of total integration sites at 2 years. There are 11 outcome measures and 12 analyses listed. Further details about analysis populations, outcome-specific denominators, follow-up completeness, and the statistical analysis plan are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

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

6. Primary Endpoint

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

The primary endpoint is overall survival, expressed as the percentage of participants alive at 12 months. The registry defines it as the percentage alive 12 months after treatment with OTL-101 or HSCT, and identifies a 95% confidence interval as the measure of dispersion. The registry record does not report the observed percentage or its confidence interval, so the primary result cannot be interpreted quantitatively from this record.

Survival is a direct outcome: it records whether participants are alive at a specified follow-up time, rather than using a laboratory measure as a proxy. In general, a fixed-time survival percentage answers a time-specific question, not how long participants survive beyond that point. Its interpretation depends on knowing who was included, how many had outcome data, and how missing follow-up was handled. Those details are not reported in the registry record.

The endpoint is used alongside outcomes concerning gene transfer and immune function. These address different aspects of the study’s aims and should not be treated as substitutes for survival. The primary endpoint description includes both OTL-101 and HSCT in its wording, but the registry record does not explain the relationship between those terms for endpoint ascertainment or analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design and outcome definitions determine what statistical conclusions can reasonably be drawn. This study is recorded as single-group, with allocation listed as NA and masking as none. There is no separate randomized comparator in the record. The primary analysis therefore concerns a percentage of participants at a specified follow-up time, not a contrast between randomized groups.

What does a percentage endpoint represent?

The primary outcome is defined as the percentage alive at 12 months. In general, a percentage describes the fraction of an analysis population meeting a stated condition. For survival at a fixed time, the condition is being alive at that time. To interpret such a result, readers need the numerator, denominator, follow-up status, and the method used to handle participants whose status is not known at the time point. These details and the numerical result are not reported in the registry record.

The registry identifies the endpoint unit as percentage of participants and the dispersion measure as a 95% confidence interval. In general, a confidence interval presents a range of values compatible with an estimate under the assumptions of the statistical method. It communicates uncertainty; it does not guarantee that the true value lies in the interval. Since the observed percentage and interval are not reported, no trial-specific precision assessment is possible.

Why does the study design matter?

A single-group study describes outcomes in the treated group. In general, a comparison intended to estimate a treatment effect requires a credible reference for what would have occurred without the intervention or under an alternative. Random allocation can make groups more comparable on average, but this record does not describe randomized allocation or a like-for-like control. Thus, any outcomes should be read as observations in the enrolled study population, not as a controlled estimate of benefit or harm relative to another strategy.

Masking is listed as none. In general, masking can reduce the influence of knowledge of treatment assignment on some measurements or judgments. Its relevance varies by outcome: survival status is more objective than some clinical assessments, while other endpoints may involve laboratory measurement or interpretation. The registry record does not give enough detail about outcome assessment procedures to evaluate their potential influence.

How should the other outcomes be understood?

The listed secondary outcomes include overall and event-free survival, vector copy number in peripheral blood cell types, ADA activity and dAXP in erythrocytes, CD3+ T-cell counts, and integration sites. These measures address different biological or clinical dimensions, and their results cannot be combined into a single conclusion without a specified analysis. The registry record lists 11 outcome measures and 12 analyses, but does not report the corresponding numerical results or explain how the analyses relate to one another.

In general, count or laboratory outcomes require attention to their measurement scale, timing, baseline values, and missing observations. A change-from-baseline endpoint also requires a clear baseline definition and a stated analysis population. Those details are not reported in the registry record for the listed measures. It would be inappropriate to infer analytical choices from the outcome titles alone.

What do planning illustrations mean?

The stated sample-size assumptions describe planning illustrations based on an observed effect, not the trial’s own design. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. The record also notes that time-to-event illustrations give total event counts using Schoenfeld, while other illustrations give participants per arm. These are hypothetical planning quantities, not observed power, and they do not turn the single-group study into a randomized two-arm comparison.

The registry record does not report the original sample-size justification, any interim analyses, or a complete statistical analysis plan. The stated enrollment of 46 should not be mistaken for proof that the study had a particular power or that every outcome was analyzed in all enrolled participants. Without endpoint estimates, denominators, and analysis details, interpretation must remain focused on the design and the reported definitions rather than unreported statistical results.

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 Gene Therapy", "HSCT Controls Without MRD", "HSCT Controls With MRD")
n      <- c(20, 14, 12)
events <- c(20, 12, 12)
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 Gene Therapy  20  20  100.0  83.2  100.0  83.9  100.0  83.9  99.9
ARM  HSCT Controls Without MRD  14  12  85.7  57.2  98.2  60.1  96.0  59.5  95.7
ARM  HSCT Controls With MRD  12  12  100.0  73.5  100.0  75.8  100.0  75.3  99.8

11. Multiplicity, Missing Data and Analysis Populations

The record lists 11 outcome measures and 12 analyses. The outcomes span several domains, including survival, cellular measures, enzyme activity, and immune-related measures. When multiple outcomes or analyses are examined, the chance of at least one apparently unusual result can increase; in general, multiplicity methods can address this issue by defining a primary analysis or adjusting how evidence is assessed. The registry record does not report whether any multiplicity strategy was planned or used.

The primary outcome is identified as overall survival at 12 months, but the record does not provide the analysis population, outcome denominator, missing-data method, or numerical result. It also does not report whether an intention-to-treat, per-protocol, or other population was used. These are important distinctions: in general, different analysis populations can yield different estimates when participants lack outcome data or do not complete treatment or follow-up.

The registry lists enrollment as 46, while the adverse-event record separately lists 20 at risk for serious events and 20 at risk for other events. The reason those risk-set counts differ from enrollment is not reported in the registry record. They should not be assumed to represent the denominators for the survival endpoint or for other outcomes.

The record does not report interim analyses, stopping rules, prespecified handling of missing observations, or a full statistical analysis plan. Without these details, readers cannot determine how outcome selection, incomplete follow-up, or multiple analyses may have influenced the posted results. The absence of these details is a reporting limitation, not evidence that a particular method was or was not used.

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: vomiting (15.0%), diarrhoea (15.0%), upper respiratory tract infection (10.0%), immune reconstitution inflammatory syndrome (10.0%), pneumonia (5.0%).

The adverse-event record lists an OTL-101 Gene Therapy group with 20 participants at risk for serious events and 9 affected, and 20 at risk for other events and 20 affected. It also lists deaths as 0. These counts describe the registry entries; the record does not state the observation period for these figures or explain the relationship between the listed risk sets and the enrollment of 46.

The serious-event terms listed most often include Vomiting and Diarrhoea, each at 15.0%; Upper respiratory tract infection and Immune reconstitution inflammatory syndrome, each at 10.0%; and Pneumonia and Bronchiolitis, each at 5.0%. The registry record does not provide the denominators or event counts for these term-specific percentages in the registry record used. A participant may also experience more than one event, so percentages for different terms should not be added or interpreted as mutually exclusive categories.

In general, adverse-event listings describe events observed during a study and do not, by themselves, establish that the intervention caused them. The registry record does not report the attribution method, severity grading details, or a comparison group suitable for estimating relative risk. The figures should therefore be read as descriptive safety reporting, not as a controlled causal comparison.

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

The registry record describes a completed single-group Phase 1/Phase 2 study of autologous CD34+ cells modified with an ADA-encoding lentiviral vector in ADA-SCID. Its primary endpoint is survival at 12 months, and its listed secondary outcomes include event-free survival, measures of vector presence and ADA activity, dAXP, T-cell counts, and integration sites. These definitions show the kinds of outcomes the study was intended to assess.

The record does not report the numerical primary survival result or its 95% confidence interval. It also does not provide numerical results for the listed secondary outcomes in the registry record used for this analysis. Consequently, the record as described does not support a quantitative conclusion about survival, precision, or the magnitude of changes in the other measures.

The single-group design has no stated randomized comparator. In general, outcomes in a treated group cannot alone distinguish the effect of treatment from other explanations, such as differences in participant characteristics, follow-up, or other care. The design therefore supports descriptive interpretation of the treated cohort, not a controlled estimate against an alternative strategy.

The adverse-event entries report affected participants and term-specific percentages, but the registry record does not give the observation period, attribution approach, or term-specific denominators. These entries are useful as descriptions of recorded events, but they do not establish causation or allow a reliable comparison with another treatment group.

In general, a registry entry is most informative when outcome estimates are accompanied by denominators, analysis methods, and missing-data details. Those elements are not reported in the registry record for the primary outcome. The appropriate conclusion is therefore limited: the study’s design and intended outcomes are described, while the available information does not establish the size or precision of the primary result.

14. Why This Trial Matters Statistically

This trial is statistically notable for the questions it sets alongside a fixed-time survival endpoint. The registry lists outcomes spanning overall and event-free survival, vector copy number in different peripheral blood cell populations, erythrocyte ADA activity and dAXP, CD3+ T-cell counts, and integration-site measures. These outcomes represent different kinds of information: clinical status, gene-transfer measurements, and immune or biochemical measures. Interpreting each requires attention to its own definition and follow-up.

The study also illustrates why design matters. A single-group study can document outcomes in a treated cohort, but without a like-for-like comparator it cannot isolate the intervention’s effect from other influences. That distinction is especially important when readers encounter a reported percentage or a change over time: a descriptive result is not automatically a treatment-effect estimate.

Statistical precision is another central issue. The primary endpoint specifies a 95% confidence interval, but the estimate and interval are not reported in the registry record. Without them, readers cannot assess how uncertain the survival percentage is. The stated enrollment of 46 does not resolve this, because the endpoint-specific analysis population and follow-up completeness are not reported.

Finally, the record includes many outcomes and analyses but does not describe multiplicity handling or a complete analysis plan. This makes it important to distinguish the primary question from the wider set of secondary measurements and to avoid treating any one outcome as a stand-alone proof. The study’s statistical value lies in the clearly stated clinical and biological questions, while interpretation of results is constrained by the missing outcome estimates and methods.

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.

A key limitation is that the registry record does not report the numerical result for the primary endpoint, despite defining overall survival at 12 months and naming a 95% confidence interval. The result’s magnitude and precision therefore cannot be assessed. The record also does not report numerical results for the listed secondary outcomes in the registry record used for this analysis.

The study is single-group and has no stated like-for-like comparator. This restricts interpretation to observed outcomes among participants and does not support a randomized comparative treatment-effect estimate. Allocation is listed as NA and masking as none; details of outcome assessment and any measures to reduce ascertainment bias are not reported in the registry record.

The registry lists 46 enrolled participants, but does not report the analysis population or endpoint-specific denominators. The adverse-event risk-set counts are 20 for serious events and 20 for other events; the reason these differ from enrollment is not reported in the registry record. Follow-up completeness, missing-data handling, and the number contributing to survival analyses are also not reported.

Further limitations include the absence of a reported sample-size justification, interim-analysis details, multiplicity procedures, and a full statistical analysis plan. The record lists multiple outcomes and analyses, but does not explain how they were prioritized or analyzed. Details about the use and timing of busulfan and PEG-ADA ERT are not reported, limiting interpretation of the treatment context. These gaps do not establish that methods were inadequate; they limit what can be concluded from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene — NCT01852071.
• Registry record last updated 2022-08-03; status last verified 2022-08.
• Results first posted 2021-09-20.
• 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

NCT01852071 is a completed Phase 1/Phase 2, single-group study sponsored by the University of California, Los Angeles, of autologous EFS-ADA lentiviral-vector-transduced CD34+ cells for ADA-SCID. Enrollment is listed as 46. The study began on 2013-08-02 and its primary completion date is 2018-08-27.

The primary endpoint is overall survival at 12 months, expressed as a percentage with a 95% confidence interval. Secondary outcomes cover survival, gene-transfer measures, erythrocyte measures, T-cell counts, and integration sites. The registry record does not report the primary estimate or its confidence interval, endpoint-specific analysis populations, missing-data methods, or a full statistical analysis plan. With no stated like-for-like control group, the design is descriptive rather than a randomized comparison.