Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-318 in Subjects With MPS I: 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-318 in Subjects With MPS I (NCT02702115), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events.

2. Clinical Question

3. Trial Design

This was a Phase I / 2, multicenter, open-label, single-dose, dose-ranging study of SB-318 in subjects with MPS I. The registry classifies it as non-randomized and sequential. Its stated purpose was to evaluate the safety and tolerability of ascending doses. Three dose levels were specified, with one single intravenous administration of the three SB-318 components in each cohort.

The planned dose cohorts were 1.00E+13 vg/kg, 5.00E+13 vg/kg, and 1.20E+14 vg/kg. The record reports an overall enrollment of 3 and states that no subjects were enrolled in Cohort 3. The posted adverse-event summary lists 1 participant at risk in Cohort 1 and 2 in Cohort 2, consistent with the reported enrollment. These small groups permit description of the posted counts, but they do not support a stable comparison of dose-specific event rates.

Because the study was open-label, participants and study personnel were not masked according to the registry classification. Because allocation was non-randomized, differences between cohorts cannot be separated from differences in who entered each cohort or from other factors that may vary over time. The registry record does not report the dose-escalation rules, the rationale for the cohort sizes, or whether any formal criteria governed movement between doses.

The study began on 2017-05-24, and its primary completion date is recorded as 2021-11-03. Its status is TERMINATED. The reason for termination is not reported in the registry record. A termination status alone does not establish why the study ended or what happened to follow-up for each participant.

The registry lists secondary outcomes concerning IDUA activity, urine glycosaminoglycan levels, and AAV2/6 clearance in plasma, saliva, urine, stool, and semen. Numerical results for those outcomes are not reported in the registry record. The primary endpoint is an adverse-event count, so the posted results should be read as safety descriptions rather than as a test of efficacy.

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: No subjects were enrolled in Cohort 3

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: The original protocol anticipated 9-12 subjects in 3 cohorts at ascending doses. However, enrollment ended after 3 subjects were enrolled in 2 cohorts. (No subjects were enrolled in cohort 3). After interim data analysis, the sponsor decided to stop enrollment in this study at 3 subjects enrolled, all adults, in 2 cohorts. (No subjects were enrolled in cohort 3) The sponsor continues to monitor the subjects in a 10-year,follow-up study ST-IVPRP-LT01 (NCT04628871).

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-Emergent Adverse Events, measured over Up to 36 months after the SB-318 infusion.

The primary endpoint is the number of participants with treatment-emergent adverse events, assessed up to 36 months after the SB-318 infusion. A participant count indicates how many people experienced at least one qualifying event; it is not the total number of separate events. The registry describes the endpoint as a count of participants, rather than as a severity score, an event rate over time, or a measure of disease response.

Safety outcomes are used in early-phase dose-ranging studies to describe adverse events after an intervention and to support structured monitoring. Counting participants can make the result easier to interpret than a raw total of events when one person may experience multiple events. However, participant counts do not by themselves describe the timing, duration, recurrence, or clinical consequences of each event. Those details are not reported in the primary endpoint description available in the registry record.

The stated observation window is up to 36 months after infusion. The registry record does not report how many participants completed the full window, how follow-up time varied, or how events after withdrawal or loss to follow-up were handled. The posted cohort summaries provide serious and other adverse-event counts, but do not present a separate numerical result for the primary endpoint as worded. The interpretation should therefore distinguish the endpoint definition from the adverse-event figures that are actually posted.

This endpoint addresses safety and tolerability, not whether SB-318 changes MPS I symptoms or disease progression. Although the registry lists IDUA activity and urine glycosaminoglycans as secondary outcomes, their numerical results are not reported in the registry record. The primary endpoint alone cannot answer those biological or clinical questions.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in the registry record is mainly descriptive. Enrollment is reported as 3, and adverse-event summaries are presented by dose cohort as numbers at risk and numbers affected. The record reports 0 analyses. It does not report an inferential model, a hypothesis test, confidence intervals, an adjustment strategy, or a statistical analysis plan. The interpretation therefore rests on the posted counts and on general principles for reading small, non-randomized studies.

What does a participant count represent?

A count of participants with an event is different from a count of events. If a participant has more than one event, a participant-level endpoint may still count that person once, while an event-level total could count several occurrences. The primary endpoint is defined as the number of participants with treatment-emergent adverse events. The registry's adverse-event summaries distinguish serious events from other events and report participants at risk and affected. The record does not provide enough detail to reconstruct event-level totals or the handling of repeated events from these summaries.

For a binary outcome, each participant is classified according to whether the event occurred under the relevant definition and observation window. The resulting count is easy to describe, but it contains little information about variation among participants when the cohort is very small. A count also does not show when an event occurred, how long it lasted, or whether multiple events occurred in the same participant. Those details require more complete event-level reporting.

Why does the design affect interpretation?

Random allocation is a method for making treatment groups comparable, on average, with respect to measured and unmeasured factors. This study was non-randomized and sequential, and it had no like-for-like control comparison. The cohorts received different planned dose levels, but cohort membership was not randomized. Consequently, cohort differences in adverse-event counts cannot isolate a dose effect. They may reflect chance, differences in participants, or other changes associated with sequential enrollment. The registry record does not report methods to adjust for these possibilities.

Open-label describes the absence of masking. In general, knowledge of treatment assignment can influence reporting, assessment, or follow-up, particularly for outcomes involving clinical judgment. This does not show that any such influence occurred in this study. The record does not report blinded event adjudication or other procedures for addressing assessment bias.

What does statistical uncertainty mean?

In general, a confidence interval describes a range of values compatible with the data under a specified statistical method. It communicates precision, not certainty that the true value lies in a particular interval. The registry record does not report confidence intervals for these counts or corresponding event frequencies. With only 1 participant in Cohort 1 and 2 in Cohort 2, even a simple event frequency would be highly sensitive to the experience of an individual participant. No new frequency or interval is calculated.

In general, hypothesis tests assess how compatible data are with a specified null hypothesis under a statistical model. A p-value does not measure the size or clinical importance of an effect, and it does not correct weaknesses in design or data collection. No p-values or hypothesis tests are reported for the posted adverse-event summaries. There is therefore no inferential result to interpret as evidence for or against a dose difference.

How should the planning illustrations be read?

The sample-size illustrations are planning exercises, not observed trial results and not observed power. The stated assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. The record also specifies that non-time-to-event illustrations express participants per arm, while time-to-event illustrations express a total number of events. These are hypothetical design assumptions and do not describe the actual non-randomized, sequential dose cohorts.

In general, a planning calculation estimates the amount of information that might be needed to detect a prespecified effect under stated assumptions. It depends on the outcome, statistical model, allocation, and target effect. When an effect is taken from a small observed sample, it may be unstable; planning around it does not establish that the effect is real or that a future study will have the stated performance. The registry record does not report that these illustrations were the trial's original sample-size justification, and they should not be read as such.

What is not available for reanalysis?

The registry record does not report participant-level data, event dates, follow-up completion, missing-data handling, analysis populations, or an analysis plan. Without those details, independent reconstruction of time-to-event summaries, adjusted models, or a sensitivity analysis is not possible from the posted counts alone. The reported value of 0 analyses is consistent with the absence of inferential analyses in this record. Any further statistical conclusion would require information not reported in 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("Cohort 1: SB-318: Starting Dose_1.00E+13 vg/kg", "Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 v")
n      <- c(1, 2)
events <- c(1, 2)
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: SB-318: Starting Dose_1.00E+13 vg/kg  1  1  100.0  2.5  100.0  20.7  100.0  15.8  98.7
ARM  Cohort 2: SB-318 at Next Ascending Dose_5.00E+13 v  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary safety outcome and several secondary outcomes, including IDUA activity, urine glycosaminoglycan levels, and AAV2/6 clearance across multiple sample types. When a study examines several outcomes or multiple measurements, multiplicity can arise: the more questions examined, the greater the chance that a nominally notable result occurs by chance. In general, analysis plans may address this by prioritizing outcomes, controlling error rates, or clearly labeling secondary and exploratory results. The registry record does not report a multiplicity strategy.

There are 0 analyses reported. Numerical results for the listed secondary outcomes are not reported in the registry record. It is therefore not possible to determine whether all planned measurements were collected, whether any analyses were conducted outside the posted record, or how any multiple comparisons were handled. No adjustment for multiplicity should be assumed.

The record also does not report missing-data methods or analysis populations. In general, missing outcome data can affect interpretation if participants with unavailable follow-up differ from those whose outcomes are recorded. The study's primary endpoint timeframe extends up to 36 months after infusion, but the record does not report participant-level follow-up duration, completion of that window, withdrawal details, or how missing observations were treated.

These gaps matter for interpreting both the adverse-event counts and the absence of numerical secondary results. The enrollment and cohort summaries describe the participants represented in the posted safety data, but the registry record does not establish whether the summaries include all participants for all outcomes or how incomplete follow-up was handled.

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 flutter (50.0%), adenovirus infection (50.0%), upper respiratory tract infection (50.0%), haemoglobin decreased (50.0%).

The serious-adverse-event summary lists 1 participant at risk and 0 affected in Cohort 1, 2 at risk and 2 affected in Cohort 2, and 0 at risk and 0 affected in Cohort 3. The other-adverse-event summary lists 1 participant at risk and 1 affected in Cohort 1, 2 at risk and 2 affected in Cohort 2, and 0 at risk and 0 affected in Cohort 3. The death count is 0 in every cohort.

The registry lists atrial flutter, adenovirus infection, upper respiratory tract infection, and haemoglobin decreased as top serious-event terms, each at 50.0%. These entries do not by themselves show the number of distinct event episodes, their timing, or whether they occurred in the same participant. The record does not report enough detail to infer causality from these listings.

These figures are descriptive, not a comparison between randomized groups. Cohort 3 had no participants, so its zero counts indicate no observed participants in that cohort, not evidence that events did not occur at that dose. The small numbers in the other cohorts also make the summaries imprecise. The counts should not be interpreted as population-level rates or as proof of a treatment effect.

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

The posted results establish that the registry contains adverse-event summaries for participants in Cohorts 1 and 2, with no participants enrolled in Cohort 3. They report serious and other adverse-event counts, along with a zero death count in each cohort. The registry also lists several serious-event terms and their percentages. These observations describe what was recorded among the enrolled participants; they do not provide a controlled estimate of how SB-318 changes the chance of an adverse event.

The study's non-randomized, sequential design is central to interpretation. It does not include a like-for-like control comparison, and its cohorts are very small. Therefore, the posted counts cannot establish that observed events were caused by SB-318 or that event experience differs because of dose. Nor can a zero count in a cohort with no participants be interpreted as reassurance about that dose.

The primary endpoint concerns treatment-emergent adverse events through up to 36 months after infusion. The record does not report a separate numerical result for the overall primary endpoint in the available results summary, detailed follow-up completion, or an analysis of uncertainty. The registry's secondary outcome list includes biological measurements, but numerical findings for those outcomes are not reported in the registry record. The available results therefore do not establish whether IDUA activity or urine glycosaminoglycan levels changed, or how AAV2/6 clearance behaved.

These limitations do not make the posted counts meaningless. They give a limited account of observed safety events in the enrolled participants and identify the scope of the registry's reporting. But the counts cannot support broad conclusions about event frequency in a larger population, clinical benefit, or the comparative safety of dose levels. The termination status is recorded, while the reason for termination is not reported in the registry record. It should not be used to infer an outcome or explanation that the record does not state.

In general, a result can be clinically important while remaining statistically imprecise, and a descriptive result can be useful without establishing causality. Here, the small cohort sizes and lack of a control group constrain both precision and causal interpretation. No medical conclusion about treatment should be drawn from these counts alone.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines an early-phase, ascending-dose question with a very small, sequential, non-randomized design. Such a design can describe what occurred among enrolled participants and can organize dose cohorts for observation. It cannot provide the same type of comparative evidence as a randomized controlled trial. The posted data therefore need to be read in light of the study's aim and structure rather than as a dose-effect test.

The cohort sizes make the distinction between a count and a stable estimate especially important. The record reports enrollment of 3, with no subjects in Cohort 3. Counts in Cohorts 1 and 2 can summarize those participants' recorded experiences, but they provide little basis for estimating the range of experience in a broader group. Small denominators also mean that an individual observation can materially change the apparent pattern.

The registry illustrates why outcome definitions and results should be kept separate. The primary endpoint is a count of participants with treatment-emergent adverse events over a specified follow-up window, while the posted safety summaries separate serious from other adverse events. The distinction helps readers avoid treating an event count as a measure of disease response. The listed secondary outcomes address biological measures, but their results are not reported in the registry record.

The record also makes the limits of registry-based interpretation visible: it reports no analyses, no numerical findings for the secondary outcomes, and no details on missing data, analysis populations, or the reason for termination. Clear reporting of those elements is important for understanding what was measured, who contributed data, and how uncertainty was handled. Without them, the most defensible statistical account remains descriptive and cautious.

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 chief limitation is the very small enrollment: the record reports 3 participants overall and no participants in Cohort 3. Cohort-specific counts are consequently too limited to characterize uncommon events or to provide precise estimates of event frequency. The registry does not report confidence intervals or another measure of statistical uncertainty for the posted counts.

The study was open-label, non-randomized, and sequential, with no like-for-like control group. As a result, differences between dose cohorts cannot be attributed to dose alone. The registry record does not report adjustment methods, blinded outcome assessment, or the rules for dose escalation. These design details may affect interpretation, but their absence means their use cannot be assumed.

The primary endpoint is described as treatment-emergent adverse events up to 36 months after infusion, while the posted summaries separate serious and other events. The record does not report the full event-level details, participant-level follow-up time, completion of the observation window, or handling of missing outcomes. The reason for termination is also not reported in the registry record.

Although the registry lists IDUA activity, urine glycosaminoglycans, and AAV2/6 clearance as secondary outcomes, numerical results for them are not reported. The record reports 0 analyses and does not provide an analysis plan, multiplicity approach, or defined analysis populations. These limits prevent assessment of the planned inferential approach and restrict interpretation to the reported descriptive safety information.

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-318 in Subjects With MPS I — NCT02702115.
• Registry record last updated 2023-01-26; status last verified 2022-12.
• Results first posted 2023-01-26.
• 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

NCT02702115 is a Phase I / 2, multicenter, open-label, single-dose, dose-ranging study of SB-318 in subjects with MPS I. It is classified as non-randomized and sequential. The study began on 2017-05-24, has a primary completion date of 2021-11-03, and is listed as TERMINATED. The reason for termination is not reported in the registry record.

The registry reports enrollment of 3 and describes three ascending dose cohorts: 1.00E+13 vg/kg, 5.00E+13 vg/kg, and 1.20E+14 vg/kg. No subjects were enrolled in Cohort 3. The primary outcome is the number of participants with treatment-emergent adverse events up to 36 months after infusion. The posted summaries include serious and other adverse-event counts and no deaths. The registry lists secondary outcomes involving IDUA activity, urine glycosaminoglycans, and AAV2/6 clearance, but their numerical results are not reported in the registry record.