Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II (NCT03041324), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion.

2. Clinical Question

The registry describes a Phase I / 2 study designed to assess safety, tolerability, and the effect of ascending SB-913 doses on leukocyte and plasma IDS enzyme activity. It also lists secondary outcomes involving IDS activity, urine glycosaminoglycan levels, annualized frequency of enzyme replacement therapy administration, and AAV2/6 clearance in several body fluids and specimens.

The central statistical question is descriptive: what adverse events were recorded among the participants treated in each cohort, and how much can those counts establish about safety in this small study? The posted adverse-event data give the number at risk and the number affected in each cohort. They do not give a registry result for the primary endpoint as defined by its TEAE and SAE measures, or numerical results for the listed secondary outcomes. Those absences limit what can be concluded about the study’s stated aims from the posted record.

Because the study was not randomized and had no control arm, it cannot provide a controlled estimate of how outcomes would have differed without SB-913. Dose-cohort counts can be described, but differences across cohorts may reflect the sequential design and the small number of participants as well as dose. The registry record does not report enough detail to separate those possibilities.

3. Trial Design

This was a Phase I / 2, multicenter, open-label, single-dose, dose-ranging study. Its allocation was non-randomized, its masking was none, and its model was sequential. The registry lists an enrollment of 9. The study began on 2017-05-11, had a primary completion date of 2021-05-07, and is listed as terminated.

Participants received SB-913 in one of three ascending-dose cohorts. Cohort 1 received 5.00E+12 vg/kg, Cohort 2 received 1.00E+13 vg/kg, and Cohort 3 received 5.00E+13 vg/kg. Each cohort description specifies a single dose of the three SB-913 components—ZFN1, ZFN2, and hIDUA Donor—administered by intravenous infusion. The record describes the overall intervention as an intravenously delivered ZFN therapeutic intended to insert a correct copy of the IDS gene into the albumin locus in hepatocytes.

Sequential, non-randomized assignment means the cohorts were not formed through random allocation. The registry record does not report a concurrent control group, and the listed arms are all experimental dose cohorts. Consequently, cohort comparisons are descriptive rather than randomized treatment comparisons. The open-label design also means masking was not used, although the registry record does not describe how awareness of treatment may have affected particular assessments.

The primary outcome is defined as the number of participants with TEAEs and SAEs, assessed by CTCAE, among those who received any portion of the infusion, through up to 36 months after infusion. The registry lists five outcome measures and several secondary outcomes, but numerical results for the primary endpoint and most secondary outcomes are not reported in the registry record.

The registry record does not report a sample-size justification, planned statistical analysis, dose-escalation decision rules, interim analyses, or a detailed protocol for cohort assignment. Those features should not be inferred from the sequential dose-ranging description alone.

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

Analysis population for the primary outcome, as defined in the registry: All subjects in this study who received any portion of the SB-913 infusion

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 Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 Months After the SB-913 Infusion, measured over Up to 36 months after the SB-913 infusion.

The primary endpoint concerns the number of treated participants who experienced treatment-emergent adverse events and serious adverse events. Events were to be assessed using the Common Terminology Criteria for Adverse Events (CTCAE), and the stated observation period was up to 36 months after the SB-913 infusion. The endpoint population is defined as all study participants who received any portion of the infusion.

Counting participants with an event is a descriptive way to report how many people were affected, rather than how many separate event episodes occurred. It can help characterize the occurrence of adverse events during follow-up, but a count alone does not describe every feature relevant to interpretation. For example, the registry endpoint statement does not itself provide event timing, duration, recurrence, or a participant-level account of multiple events.

TEAEs and SAEs are distinct safety categories. The endpoint names both categories, while the posted adverse-event information separately gives counts of participants with serious and other adverse events by cohort. The registry record does not report a numerical result for the primary endpoint itself, including a combined result or the stated CTCAE assessment results. The posted cohort safety counts therefore offer some descriptive information, but should not be treated as a complete registry report of the primary endpoint.

Safety and tolerability are central questions in an early-phase, dose-ranging study. A participant count can summarize the observed experience in the study, but the small cohort sizes and absence of a control group limit precision and comparative interpretation. The endpoint does not establish what would have occurred in a different group or under a different treatment strategy.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods describe how observations are collected, summarized, and compared. In this study, the registry describes a non-randomized, open-label, sequential dose-ranging design. That description supports a basic reading of the cohorts, but it does not specify the full analysis plan. The statistical analysis plan is not reported in the registry record.

What a participant count means

The primary endpoint is framed as the number of participants with TEAEs and SAEs. A participant count records whether people experienced an event category during the stated observation period. It differs from a total event count: one participant may experience more than one event, while a participant-level count still counts that person once within the relevant category. The posted adverse-event information gives counts of participants affected by serious and other adverse events for each dose cohort. It does not provide a full event-by-event dataset in the registry record.

Counts are easy to interpret as descriptions of the observed sample, but they are uncertain estimates of what might be seen in other participants. This uncertainty is particularly important when groups are small. A count in a small cohort can change substantially if the experience of even one participant differs. Without reported confidence intervals or another uncertainty analysis for these outcomes, the precision of broader estimates cannot be assessed from the registry record.

Why randomization matters

Randomization is a method for assigning participants to study groups by chance. In general, it helps make groups comparable on average, including with respect to characteristics that were not measured. This study is listed as non-randomized and has no control arm. Its cohorts are ordered by ascending dose, so observed differences across them cannot be isolated as dose effects. Differences could also reflect the sequential conduct of the study, participant characteristics, or other factors. The registry record does not report details that would support adjustment for such differences.

Open-label means masking was not used. In general, awareness of treatment can influence reporting, clinical decisions, or assessments, depending on the outcome and how it is measured. The registry record does not describe whether or how those possibilities were addressed. It would be inappropriate to assume a specific impact in either direction.

How to interpret event categories

TEAE refers to an adverse event emerging during the treatment period as defined by the study, while SAE identifies events meeting serious-event criteria. The endpoint says events were assessed using CTCAE, a framework for classifying adverse events. The registry record does not provide the detailed operational definition used for treatment emergence, the event grading results, or the complete criteria and procedures applied in this study. The terms should be read as registry categories, not as proof that the treatment caused an event.

Seriousness and severity are not interchangeable concepts. General statistical and clinical reporting distinguishes whether an event meets seriousness criteria from how intense it is graded. The posted counts do not provide a complete severity distribution. They also do not report event onset, duration, recurrence, resolution, or individual clinical histories. Such details could affect interpretation, but are not reported in the registry record.

Uncertainty and comparisons

A confidence interval is a statistical range intended to express uncertainty around an estimate under a specified method. In general, wider intervals indicate less precision, and intervals from small samples are often wide. No confidence intervals for the posted safety counts are reported in the registry record. Because no inferential analysis is listed, there is no reported statistical test establishing a difference among the cohorts.

General comparisons between groups are most informative when the study design and analysis support them. Here, the cohorts are not randomized and there is no control group, so even a numerical difference would not by itself establish a treatment effect or a dose-response relationship. The posted counts are best used to describe what was recorded among participants in each cohort.

Planning calculations are not observed evidence

Planning illustrations based on an observed effect are not the same as an analysis of the trial’s observed outcomes. The stated planning assumptions refer to a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect expressed as a fraction of the observed effect. Those are generic planning assumptions, not evidence that the study used such a design: this trial is non-randomized and has three sequential dose cohorts. No sample-size justification is reported in the registry record. Any such planning illustration must not be read as observed power or as a retrospective test of whether the study was adequately powered.

More broadly, statistical interpretation depends on a prespecified analysis plan, definitions of analysis populations, treatment of missing observations, and appropriate summaries of uncertainty. The registry record does not report those details for the outcomes. As a result, the counts can be stated directly, but more elaborate claims about adjusted effects, statistical significance, or comparative safety are not supported by the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Experimental: Cohort 1 SB-913 Starting Dose 5.00E+", "Experimental: Cohort 2 SB-913 at Next Ascending Do", "Experimental: Cohort 3 SB-913 at Next Ascending Do")
n      <- c(2, 2, 5)
events <- c(2, 2, 5)
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  Experimental: Cohort 1 SB-913 Starting Dose 5.00E+  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2
ARM  Experimental: Cohort 2 SB-913 at Next Ascending Do  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2
ARM  Experimental: Cohort 3 SB-913 at Next Ascending Do  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates several outcomes, time points, groups, or statistical tests. In general, as the number of tests increases, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for it. The registry lists five outcome measures and several secondary outcomes, including IDS activity, urine GAG levels, enzyme replacement therapy administration frequency, and AAV2/6 clearance. However, the registry record reports 0 analyses. It does not report a multiplicity strategy, a hierarchy of outcomes, or a statistical testing plan. No conclusion about adjustment for multiple testing can therefore be made.

The record does not provide a numerical primary-endpoint result or numerical results for the listed secondary outcomes. It also does not report how missing measurements were handled, whether all scheduled observations were available, or whether any participants discontinued follow-up before the stated observation period. The endpoint timeframe is up to 36 months after infusion, but the actual follow-up available for each participant is not reported in the registry record.

Analysis populations also matter. The primary endpoint defines its population as all participants who received any portion of the SB-913 infusion. The registry record does not give a fuller account of analyzed populations for the primary or secondary outcomes, nor does it report exclusions or outcome-specific denominators beyond the posted adverse-event risk counts. It is therefore not possible to determine from this record whether every enrolled participant contributed to every outcome or how incomplete outcome data affected summaries.

These omissions do not establish that analyses or procedures were absent; they mean that the details are not reported in the registry record. Without the analysis plan and outcome results, interpretation should remain descriptive and limited to the information that is posted.

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: atrial fibrillation (50.0%), bronchitis (50.0%), influenza (50.0%), incarcerated umbilical hernia (20.0%), intestinal obstruction (20.0%).

The serious adverse-event counts are 1 of 2 participants in Cohort 1, 1 of 2 in Cohort 2, and 3 of 5 in Cohort 3. The counts for other adverse events are 2 of 2, 2 of 2, and 5 of 5, respectively. The record lists no deaths in any cohort. These figures describe participants recorded as affected; they do not state how many separate events occurred.

The small cohort sizes matter. Each count represents the observed experience of only a few participants, so the figures do not precisely establish how often events would occur in a larger population. The cohorts also were not randomized and there was no control group. Differences between their counts cannot establish that dose caused a difference in safety outcomes.

The listed serious-event terms include atrial fibrillation, bronchitis, influenza, incarcerated umbilical hernia, intestinal obstruction, and pyrexia, with percentages recorded in the registry. The listing does not provide enough event-level detail to determine timing, recurrence, or causal attribution. The primary endpoint is defined through up to 36 months after infusion, but participant-specific follow-up duration is not reported in the registry record.

These are safety observations, not a complete risk estimate or a causal assessment. The registry record does not report a numerical result for the full primary endpoint as defined.

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

The record documents a small, non-randomized, sequential dose-ranging study and posts participant counts for serious and other adverse events by cohort. It also lists no deaths in the cohorts. These observations describe what was recorded among the participants included in the posted safety data. They do not, on their own, establish how frequently events would occur in a larger or different population.

The study’s stated purpose included evaluation of safety, tolerability, and effects on leukocyte and plasma IDS enzyme activity. The registry record does not report numerical results for the primary endpoint as defined or for the listed enzyme-activity outcomes. It also does not provide numerical results for the other secondary outcomes. Thus, the posted record does not allow a complete assessment of the study’s stated objectives.

The counts do not establish that SB-913 caused any listed event, nor do they establish that an event was unrelated to treatment. The design has no randomized control group, and the participants were assigned to sequential dose cohorts. There is consequently no controlled comparison against which to distinguish treatment-related changes from other explanations. A difference between the cohort counts would not by itself demonstrate a dose effect.

The registry record’s terminated status indicates the study is listed as terminated; it does not explain the reason or supply missing results. The reason for termination is not reported in the registry record. No conclusion about the unreported outcomes, the reasons the study ended, or the treatment’s effects should be inferred from that status alone.

Overall, the posted information supports a limited descriptive account of adverse-event counts in the enrolled cohorts. It does not support a broad estimate of safety, a causal conclusion, or a conclusion about enzyme activity or other secondary outcomes. Those questions require results and methods that are not reported in the registry record.

14. Why This Trial Matters Statistically

Early-phase dose-ranging studies often focus on describing safety and gathering initial information across dose levels. Statistical interpretation in such studies depends not only on the observed counts, but also on the number of participants, follow-up, outcome definitions, and design. This record makes those issues especially visible: the total enrollment is 9, the cohorts are sequential and non-randomized, and there is no control group.

Reporting the number of participants affected in each cohort is useful because it keeps the observed data in view. It also discourages treating a small study as if it produced a precise population-level estimate. The cohort counts are informative descriptions of the people observed, but the record does not report uncertainty intervals or a comparative analysis that would support stronger statistical claims.

The record also illustrates why an outcome’s stated purpose and its posted results must be distinguished. The primary endpoint concerns TEAEs and SAEs through up to 36 months, while the study’s stated aims include IDS enzyme activity. Numerical results for these outcomes are not reported in the registry record. A design description and a list of outcomes are not substitutes for outcome estimates.

Finally, sequential dose cohorts cannot be interpreted like randomized arms. Even if counts differ, the design cannot separate dose from cohort order or other differences among participants. This is a key statistical limitation when reading dose-ranging data: descriptive patterns may be worth noting, but they are not controlled evidence of a dose-response relationship. The registry record therefore supports cautious description rather than comparative or causal conclusions.

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 main limitation is the very small enrollment: the registry lists 9 participants distributed across three dose cohorts. Counts from groups of this size are imprecise descriptions of broader event frequencies, and individual experiences can strongly shape the observed pattern. No confidence intervals or other uncertainty estimates for the safety counts are reported in the registry record.

The design is non-randomized, sequential, and open-label, with no control arm. Cohort comparisons therefore cannot isolate the effect of dose from cohort order or other participant differences. The registry record does not report participant characteristics or adjustment methods that would allow those differences to be assessed.

The primary endpoint is defined for up to 36 months after infusion, but participant-level follow-up duration and completeness are not reported. The record also does not report the full numerical primary-endpoint result, event-level details, or numerical results for the listed secondary outcomes. Missing-data procedures, the detailed analysis plan, and analysis populations are not reported in the registry record.

The study is listed as terminated, but the reason is not reported in the registry record. Without that information, the termination status should not be used to infer a particular outcome or explanation. Together, these limitations mean that the posted safety counts are descriptive and incomplete evidence for the study’s broader objectives.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II — NCT03041324.
• Registry record last updated 2022-10-25; status last verified 2022-10.
• Results first posted 2022-09-27.
• 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

NCT03041324 is a Phase I / 2, multicenter, open-label, non-randomized, sequential dose-ranging study of a single SB-913 infusion in people with MPS II. The registry lists 9 participants and three ascending-dose cohorts: 5.00E+12 vg/kg, 1.00E+13 vg/kg, and 5.00E+13 vg/kg. The study began on 2017-05-11, had a primary completion date of 2021-05-07, and is listed as terminated.

The primary endpoint concerns the number of treated participants with TEAEs and SAEs through up to 36 months after infusion. Posted adverse-event data give cohort counts, and no deaths are listed. A numerical result for the full primary endpoint and numerical results for the stated secondary outcomes are not reported in the registry record. With no randomized comparator and very small cohorts, the available safety counts are descriptive and do not establish causal or comparative effects.