Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 (NCT02122952), a non-randomized phase 1 study. The primary outcome is Number of Participants That Experienced One Grade III or Higher Unanticipated, Treatment-related Toxicity That Presents With Clinical Symptoms and Requires Medical Treatment.

2. Clinical Question

The trial’s stated purpose was to evaluate the safety and efficacy of intravenous AVXS-101 for spinal muscular atrophy type 1. The registry also lists secondary outcomes concerning permanent ventilation or death, change from baseline in mean CHOP-INTEND score, and assessed improvement in motor function. Those outcomes address different aspects of clinical course and function, but their results are not included in the available record. Consequently, the evidence is limited to the design information and adverse-event counts that are reported, rather than a complete account of the stated efficacy and safety questions.

3. Trial Design

This was a phase I, nonrandomized, single-group trial with no masking. The registry lists Novartis Gene Therapies as the sponsor and records enrollment as 15. The trial began on 2014-05-05, had a primary completion date of 2017-12-15, and is listed as completed. The planned intervention was AVXS-101 delivered once by the intravenous route.

Participants were placed in two dose cohorts. Cohort 1 received 6.7 X 10^13 vg/kg, and Cohort 2 received 2.0 X 10^14 vg/kg. The arm descriptions list n=3 for Cohort 1 and n=12 for Cohort 2. These are cohort descriptions, not randomized treatment groups. Since there was no control arm, the study does not directly compare AVXS-101 with an untreated group or another intervention.

Nonrandomized cohort assignment can leave groups different in ways that affect outcomes, whether or not those differences are measured. A comparison between these cohorts therefore cannot isolate the effect of dose from differences in participant characteristics, clinical course, or other influences. The registry does not report the allocation process, baseline characteristics, or an adjusted comparison between cohorts.

The primary endpoint was a count of participants experiencing a specified serious, unanticipated, treatment-related toxicity during a 2-year timeframe. Secondary outcomes included ventilation or death, CHOP-INTEND score change, and motor-function improvement. The registry lists 4 outcome measures and 1 analysis. It does not report a detailed statistical analysis plan, the analysis populations, or the handling of missing observations. These omissions limit how fully the design and reported results can be reconstructed.

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: 30 day screening period prior to enrollment and dosing.

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 Number of Participants That Experienced One Grade III or Higher Unanticipated, Treatment-related Toxicity That Presents With Clinical Symptoms and Requires Medical Treatment, measured over 2 years.

The primary endpoint was the number of participants who experienced one unanticipated, treatment-related toxicity of Grade III or higher that presented with clinical symptoms and required medical treatment. The stated observation timeframe was 2 years. This is a participant-count endpoint: it asks how many participants met a defined safety criterion, rather than measuring the number of separate episodes or the duration of an event.

As a general statistical concept, a prespecified safety endpoint can make the safety question more focused by defining which events count, how severe they must be, and over what timeframe they are assessed. Requiring clinical symptoms and medical treatment distinguishes the endpoint from a count of every recorded symptom or laboratory finding. At the same time, interpretation depends on consistent event classification and complete observation over the specified timeframe.

The primary endpoint result itself is not reported in the registry record. The adverse-event counts listed elsewhere in the record do not establish how many participants met this specific endpoint: the reported serious adverse events are not identified as necessarily unanticipated, treatment-related, Grade III or higher, symptomatic, and requiring medical treatment. Without the endpoint-specific result and its analysis details, the primary safety question cannot be answered from this record alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design determines what comparisons the data can support. This trial was nonrandomized and single-group, with two dose cohorts and no control group. In a randomized comparison, allocation by chance is intended to balance measured and unmeasured characteristics on average. That protection does not apply to these cohort assignments. As a general statistical matter, an observed difference between nonrandomized cohorts can reflect treatment, differences in who entered each cohort, other clinical factors, or random variation. The registry does not report enough detail to assess those possibilities or to reconstruct an adjusted analysis.

What does a participant count describe?

The primary endpoint is defined as a count of participants meeting a particular safety criterion within the stated timeframe. A count is a direct description of the number meeting the definition, but its interpretation depends on the population observed, the completeness of follow-up, and the consistency of endpoint classification. A count alone does not express uncertainty about the underlying event frequency. In this record, the primary endpoint result and its uncertainty are not reported.

The serious adverse-event figures are also participant counts, but they describe a broader category than the primary endpoint. The record reports participants affected by serious adverse events in each cohort. It does not establish that every such event met all the primary endpoint requirements. Accordingly, the broad safety counts should not be treated as a substitute for the endpoint-specific count.

How should event percentages be read?

Percentages can describe the share of a stated denominator associated with an event term, but their interpretation depends on how the denominator is defined and whether participants can contribute more than one event. The registry lists percentages for serious adverse-event terms but does not state their denominator or calculation details in the information available. Those percentages should be retained as reported and not converted into counts or compared as if their denominators were confirmed.

More generally, event data can be organized by participants with at least one event or by the number of events. These answer different questions: a participant-level summary records whether a person was affected, while an event-level summary counts episodes. The registry’s serious adverse-event group summaries are participant counts. The top-term percentages do not, by themselves, clarify whether the reporting is participant-based or event-based.

What can uncertainty measures add?

As a general explanation, a confidence interval gives a range of values compatible with the data under a chosen statistical method and conveys precision as well as the point estimate. Narrower intervals usually indicate greater precision than wider intervals, but an interval does not remove bias caused by nonrandomized assignment, incomplete follow-up, or inconsistent measurement. The registry record does not report confidence intervals for the primary endpoint or the serious adverse-event counts.

A hypothesis test evaluates data against a specified statistical model and null hypothesis. A p-value is not the probability that a treatment works, nor does it measure the size or importance of an effect. The available record does not report a primary-endpoint hypothesis test or p-value. Without a defined comparison and inferential result, the event counts should be interpreted descriptively.

What is the role of the planning illustration?

The stated sample-size assumptions describe a planning illustration based on a fraction of an observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation. The assumptions distinguish participant counts per arm from total event counts for time-to-event calculations. These are planning concepts, not evidence that the completed trial had a particular power or that an effect was detected. No planning estimate values or observed effect estimate are reported in the registry record. The illustration is not the trial’s own design justification, and it should not be described as observed power.

In general, a planning calculation depends on the effect size targeted, the variability or event rate assumed, the significance level, the allocation scheme, and the statistical method. Results can change when those assumptions change. A sample-size illustration does not correct for confounding, missing outcomes, or differences between the planned and actual analysis. The record does not report a sample-size justification for this trial.

What analysis details remain unclear?

The registry lists 4 outcome measures and 1 analysis, but does not report the statistical methods for that analysis. It also does not report the analysis population, missing-data procedures, multiplicity approach, interim-analysis plan, or model specifications. Those details matter because they can affect which observations contribute to an estimate and how uncertainty or multiple outcomes are handled. In their absence, interpretation should stay close to the descriptive information that is explicitly reported.

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("Cohort 1", "Cohort 2")
n      <- c(3, 12)
events <- c(1, 3)
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  Cohort 1  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6
ARM  Cohort 2  12  3  25.0  5.5  57.2  8.9  53.2  9.1  53.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures and 1 analysis, but does not describe how multiplicity was handled. Multiplicity arises when several outcomes, comparisons, or repeated tests are considered: the chance of at least one apparently unusual result can increase when many tests are conducted. As a general statistical concept, analysts may prespecify a primary outcome, adjust testing, or treat secondary analyses as exploratory. The record does not state which approach was used, so no multiplicity procedure should be inferred.

Missing-data handling is not reported in the registry record. This leaves unclear how participants without complete outcome observations were treated, whether follow-up differed across cohorts, and whether any imputation or sensitivity analysis was used. These issues can affect both a participant count and an estimate of change from baseline. The registry does not report the number of missing observations for the listed outcomes.

The analysis populations are also not reported. In general, an analysis population defines which participants contribute to a particular result, and it may differ across outcomes. Without that definition, the reported enrollment and cohort descriptions do not establish the denominator used for every analysis. The event counts are described for the listed cohorts, but the record does not provide a complete account of endpoint-specific populations or analysis rules.

No interim analyses or statistical plan are described in the registry record. Their presence or absence should not be guessed. These reporting gaps limit assessment of prespecification, selective reporting, and the robustness of any inferential conclusions. Since the primary endpoint result is not reported, multiplicity and missing-data procedures cannot be evaluated in relation to that 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (58.3%), parainfluenzae virus infection (33.3%), respiratory syncytial virus bronchiolitis (33.3%), transaminases increased (33.3%), bronchitis (33.3%).

The registry reports serious adverse events in 3 of 3 participants in Cohort 1 and 10 of 12 in Cohort 2. It reports 0 deaths in each cohort. These figures describe what the registry records for the listed safety categories; they are not estimates of treatment effect and do not establish whether an event was caused by AVXS-101.

The listed serious adverse-event terms include pneumonia at 58.3%, as well as parainfluenzae virus infection, respiratory syncytial virus bronchiolitis, transaminases increased, bronchitis, and influenza, each at 33.3%. The registry record does not state the denominator or calculation details for these term percentages in the information available. Nor does it clarify whether participants could contribute to more than one term. They should not be added together or treated as mutually exclusive categories.

The primary endpoint was narrower than the general serious-adverse-event category: it required an unanticipated, treatment-related toxicity of Grade III or higher, with clinical symptoms and a need for medical treatment. The adverse-event summaries do not identify which, if any, events met all these criteria. The primary endpoint result is not reported in the registry record, so it cannot be inferred from the broader safety counts.

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

The posted information establishes the trial’s design, intervention, endpoint definition, and selected adverse-event summaries. It shows that serious adverse events were reported for participants in both dose cohorts and that the registry recorded no deaths in either cohort. It also lists several serious adverse-event terms and their reported percentages. These are descriptive observations, not proof that the intervention caused or prevented any event.

The design limits causal interpretation. The cohorts were nonrandomized, and there was no separate control group. Therefore, the results do not estimate what would have happened to comparable participants without AVXS-101, and any difference between dose cohorts cannot be attributed to dose alone. The available record also lacks the baseline and analysis details needed to assess comparability or adjustment.

The primary safety endpoint is clearly described, but its result is not reported. The broad serious-adverse-event counts do not tell how many participants met the primary definition, which includes treatment relationship, unexpectedness, severity, symptoms, and need for medical treatment. Secondary outcome results concerning ventilation or death, CHOP-INTEND score change, and motor-function improvement are also not reported in the available record. Thus, no conclusion about those efficacy outcomes can be drawn from these registry entries.

Precision cannot be judged for the primary endpoint because an estimate and confidence interval are not reported. The listed counts do not provide a substitute for those missing results, and the absence of a reported statistical test is not evidence of either a positive or negative effect. Overall, the record supports a limited descriptive account of safety reporting and trial structure, rather than a causal or efficacy conclusion.

14. Why This Trial Matters Statistically

This trial illustrates why study design and endpoint wording matter as much as an event count. A safety endpoint defined by treatment relationship, unexpectedness, grade, symptoms, and need for medical treatment is not interchangeable with a broader count of serious adverse events. Careful interpretation must keep the endpoint definition separate from other safety summaries, particularly when the endpoint-specific result is not reported.

The nonrandomized, single-group design also highlights the distinction between observing outcomes after an intervention and estimating outcomes caused by that intervention. Without a control group, the record cannot show how outcomes compare with what would have occurred under another condition. Cohort differences do not resolve this issue because dose assignment was not randomized and the cohorts are not a like-for-like control comparison.

The record also demonstrates how incomplete statistical reporting constrains interpretation. The primary endpoint result, confidence interval, analysis populations, missing-data procedures, and multiplicity approach are not reported. Those details are important for understanding the exact estimate, its precision, and the analysis choices behind it. Their absence is not evidence that an analysis was improperly conducted; it means the registry record does not permit those questions to be assessed.

Finally, safety counts and term percentages communicate different kinds of information. Participant counts identify how many people were recorded as affected, while percentages for event terms require clear denominators and a description of overlap to support comparison. Reporting those details alongside endpoint-specific results would make the statistical meaning more transparent. This study is therefore a useful example of the difference between a stated research question, a design capable of addressing it, and results sufficiently reported to evaluate it.

15. Limitations

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

Several limitations are specific to the information available for this trial. It was nonrandomized and had no separate control group, so the listed outcomes cannot establish a causal treatment effect. The two dose cohorts do not provide a randomized comparison, and the registry does not report baseline characteristics or an adjusted analysis that could help assess differences between them.

The primary endpoint is defined, but its result is not reported in the registry record. The serious adverse-event summaries are broader and cannot be used to reconstruct the number meeting the primary endpoint criteria. The listed secondary outcomes also lack results in the available record, limiting evaluation of the trial’s stated efficacy questions.

The record does not report confidence intervals or other precision estimates for the event counts. It also does not describe the denominator and calculation details behind the serious-event term percentages, or whether participants could appear under multiple terms. This limits interpretation of those percentages and precludes reliable comparisons based on them.

Further details not reported include analysis populations, missing-data methods, multiplicity handling, the statistical plan, and any interim-analysis approach. The record also does not provide information on participant characteristics beyond the condition or on cohort allocation procedures. These gaps do not establish that methods were absent; they limit what can be assessed from the registry record. The sample-size assumptions describe a planning illustration, not the trial’s design justification or observed power, and no numerical illustration results are reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 — NCT02122952.
• Registry record last updated 2022-09-15; status last verified 2022-08.
• Results first posted 2019-05-10.
• 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 identifies NCT02122952 as a completed phase I trial of AVXS-101 for spinal muscular atrophy type 1. It was nonrandomized, single-group, and unmasked, with enrollment listed as 15. Participants were assigned to two one-time intravenous dose cohorts: 6.7 X 10^13 vg/kg in Cohort 1 and 2.0 X 10^14 vg/kg in Cohort 2.

The primary endpoint was the number of participants experiencing a specified unanticipated, treatment-related toxicity of Grade III or higher during 2 years. The registry reports serious adverse events for 3 of 3 participants in Cohort 1 and 10 of 12 in Cohort 2, and no deaths in either cohort. It lists serious adverse-event terms with percentages, but the primary endpoint result and secondary outcome results are not reported in the available record.

The nonrandomized design does not support a like-for-like control comparison. Statistical analysis details, including missing-data handling, analysis populations, and multiplicity procedures, are not reported.