Treatment of the Cholesterol Defect in Smith-Lemli-Opitz Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of the Cholesterol Defect in Smith-Lemli-Opitz Syndrome (NCT00272844), a na phase 1, phase 2 study. The primary outcome is Number of Responders.

2. Clinical Question

3. Trial Design

The registry identifies this as a phase 1 and phase 2 study with a single-group model. Enrollment was 23. Allocation is recorded as not applicable, and masking as none. These entries describe a study without a randomized, masked comparison between treatment groups; the record does not list a control arm. The named intervention is crystalline cholesterol oil-based suspension, and the arm is described as cholesterol supplementation.

The study status is completed. The recorded start is 1998-01, and primary completion is 2011-06. Boston Children's Hospital is listed as sponsor. The primary endpoint was the number of responders, expressed as a count of participants, and the stated assessment schedule was every 3-6 months for an approximate median of 5 years. That timeframe does not specify that every participant had the same duration of observation.

The record lists two secondary outcomes: number of growth responders and number of participants with improved neuropsychological development. It lists three outcome measures in total, but no analyses. The registry record does not report participant flow, the number assessed at each visit, or the number included in each outcome analysis. It also does not describe the treatment regimen in enough detail to reconstruct how supplementation was administered.

Because the design is single-group, changes during observation can be described within the treated group, but the design does not directly compare those changes with what would have occurred under a separate control condition. The registry record does not report a detailed statistical plan, randomization procedure, or masking procedure beyond the recorded design entries.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

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

Population: All patients had elevation of 7-DHC diagnostic of SLOS

6. Primary Endpoint

The registry lists the primary outcome as Number of Responders, measured over Every 3-6 months for an approximate median of 5 years.

The primary endpoint is the number of participants classified as responders. The registry defines response as an increase in total serum cholesterol together with decreases in 7-DHC (7-Dehydrocholesterol) and 8-DHC (8-Dehydrocholesterol). The description says these measures were obtained on all participants. The outcome is a count, so its intended summary is how many participants met the combined biochemical definition, rather than the average change in any one laboratory measure.

This endpoint was chosen to address the study's stated biochemical question: whether cholesterol supplementation would correct abnormalities in cholesterol and its precursors. Requiring the stated pattern across the measures makes the responder definition a joint criterion. A participant would need to meet the increase criterion for total serum cholesterol and the decrease criteria for both named precursors to be classified as a responder according to the registry description.

The assessment timeframe is every 3-6 months for an approximate median of 5 years. Repeated measurement can describe biochemical status over time, but the registry record does not explain which visit or rule determined the final responder classification, how missing measurements were handled, or whether response had to be sustained. Most importantly, the observed responder count is not reported in the registry record. The endpoint definition is available, but its study result cannot be assessed from that record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation starts with the study design and the type of endpoint. This study is recorded as single-group, and the primary endpoint is a count of participants who meet a binary responder definition. A binary outcome classifies each participant into one of two categories for the endpoint: responder or not responder. The count is the number in the responder category. The registry record does not report that count, so no observed response rate or uncertainty estimate can be discussed.

What does a confidence interval describe?

General explanation: a confidence interval expresses the statistical uncertainty around an estimate, under the assumptions of the method used. For a binary outcome, an interval around a response proportion can show how much uncertainty remains about the underlying response frequency. It is not a guarantee that the true value falls within a particular interval. No primary-outcome confidence interval is reported in the registry record, and no interval can be interpreted without a reported estimate and its analysis details.

Why does the single-group design matter?

The study has no listed control group. A before-and-after pattern within one group can describe changes during follow-up, but does not directly estimate a contrast between supplementation and a separate comparator. General explanation: causal comparisons rely on a credible estimate of what would have happened to comparable participants under the alternative condition. Randomized control groups are one way to support that comparison, but this record identifies allocation as not applicable and the model as single-group. The registry record does not report an alternative comparative analysis.

How should repeated measurements be understood?

The endpoint description states that measures were taken every 3-6 months for an approximate median of 5 years. General explanation: repeated measurements can characterize a trajectory, but the analysis must specify how multiple visits contribute to a participant's final outcome. For example, a prespecified rule might use a particular time point, a sustained pattern, or another summary. The registry record does not report which rule was used for classifying responders, whether response had to persist, or how measurements at different visits were combined. It would therefore be inappropriate to infer a longitudinal analysis method from the assessment schedule alone.

What information is available about the statistical plan?

The registry record lists no analyses. It does not report the statistical model, hypothesis tests, confidence-interval method, covariate adjustment, handling of repeated measures, or a prespecified analysis population. The study's phase labels and outcome definitions do not establish which methods were used. General explanation: an analysis plan clarifies which outcomes and time points are primary, how data are summarized, and how uncertainty is quantified. Without those details and the outcome results, readers cannot reproduce or evaluate the statistical analysis from the registry record.

What do the planning assumptions represent?

The planning illustrations are described as calculations based on an observed effect, not as the trial's own design. Their stated assumptions are 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. For non-time-to-event outcomes, the described output is participants per arm for 80% or 90% power; time-to-event calculations are described in terms of total events. These assumptions are general features of a planning exercise, not evidence that the actual study used two arms or was designed with those targets. The actual trial is recorded as single-group. The observed primary effect is not reported in the registry record, and no numerical planning result is available in the registry record to interpret.

General explanation: statistical power is a design-stage probability of detecting a specified effect under specified assumptions if that effect is present. It is not a measure of whether a completed study's result is reliable, and a planning calculation based on an observed effect should not be described as observed power. Sample-size planning values, when available, are illustrations of assumptions rather than observed participant outcomes. Here, the registry record does not report an observed primary effect or the study's own sample-size justification, so no trial-specific power conclusion is supported.

Why do event counts require context?

For a binary endpoint, a count alone is more informative when accompanied by the relevant denominator and a clear definition of who was assessed. Enrollment was 23, but the record does not state the primary-outcome denominator or report missing outcome data. General explanation: if some enrolled participants lack endpoint data, the count among assessed participants may not represent the full enrolled group. The analysis population and missing-data procedures therefore matter when interpreting a response count. Neither is described for the primary endpoint 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("Cholesterol Supplementation")
n      <- c(18)
events <- c(18)
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  Cholesterol Supplementation  18  18  100.0  81.5  100.0  82.4  100.0  82.4  99.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists three outcome measures: the primary count of responders, number of growth responders, and number of participants with improved neuropsychological development. It does not report an analysis for any of them. The record also does not describe a strategy for handling multiple outcomes or multiple comparisons. General explanation: examining several outcomes can increase the chance of finding an apparently notable result by chance, so an analysis plan may specify which outcome is primary and whether adjustment or other safeguards will be used. No such strategy is reported in the registry record, and the absence of results prevents assessment of how multiplicity affected interpretation.

Missing-data handling is not reported. The record does not give the number with evaluable data for the primary or secondary outcomes, describe withdrawals or missed visits, or state whether missing measurements were imputed, excluded, or otherwise handled. The assessment schedule was every 3-6 months for an approximate median of 5 years, but that schedule alone does not establish how complete follow-up was or how measurements were used.

The analysis population is also not reported. Enrollment was 23, but the registry record does not say whether outcomes were analyzed for all enrolled participants, only those with follow-up measurements, or another defined group. It does not describe exclusions or provide participant flow. These gaps prevent checking whether the outcome denominator matches enrollment and whether missing observations could influence the reported results. Since no outcome analyses are listed, the record supports no conclusion about how multiplicity, missing data, or population definitions were addressed.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 1% reporting threshold.

The safety record lists 23 participants at risk for serious adverse events and 0 affected. It also lists 23 at risk for other adverse events and 0 affected. These are counts within the registry's safety reporting, not estimates of the probability of an event under every possible duration or circumstance. The record does not specify the safety observation window or give detailed event definitions, so those aspects cannot be assessed.

The death value is not reported in the registry record; it should not be read as a reported count of zero. No serious-event terms are listed. A zero count means that no events are recorded in that category for the stated at-risk group, but a zero does not establish that the underlying risk is absent. General explanation: when event counts are low or zero, uncertainty about the true event frequency can remain, particularly when the group is limited in size. No confidence interval or further safety analysis is reported.

These safety figures should be kept separate from the primary biochemical endpoint. They do not indicate whether participants met the responder definition, and the registry record does not provide the clinical detail needed to relate safety events to particular participants, doses, or follow-up periods.

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

The record establishes that a completed single-group study enrolled 23 participants with Smith-Lemli-Opitz Syndrome and evaluated cholesterol supplementation. It also defines a biochemical responder as someone with an increase in total serum cholesterol and decreases in 7-DHC and 8-DHC. These registry entries describe the study question and planned endpoint, but they do not reveal the observed outcome.

The primary responder count is not reported in the registry record. Neither are results for the listed secondary outcomes of growth response and improved neuropsychological development. Consequently, the record cannot establish how many participants met the biochemical criteria, whether growth or neuropsychological outcomes changed, or how precisely any such effect was estimated. No confidence intervals or analysis results are listed.

Even if a within-group change were reported, this design would not directly compare outcomes with a control group. General explanation: temporal changes in a single group can be consistent with several possible explanations, and without a comparator the intervention's contribution cannot be isolated in the same way as in a controlled comparison. The design does not, by itself, establish what would have occurred without supplementation.

The safety counts record 0 serious adverse events and 0 other adverse events among 23 at risk in each category, while the death value is not reported. These entries should be interpreted as registry counts, with no further observation-window detail reported. They do not establish that adverse events are impossible.

Accordingly, the defensible interpretation is limited: the registry documents the study design, endpoint definitions, and some safety counts, but not the efficacy outcome results. It does not support a numerical estimate of biochemical response or a comparative conclusion about treatment effects.

14. Why This Trial Matters Statistically

This study is statistically notable for the contrast between a clearly stated biochemical responder definition and the absence of a reported responder count. The endpoint combines an increase in total serum cholesterol with decreases in 7-DHC and 8-DHC. That definition indicates which measurements were intended to represent biochemical response, but a definition alone cannot answer how many participants met it. Reporting the result and the denominator is necessary for readers to judge the frequency and precision of response.

The single-group design also makes the distinction between describing change and estimating a comparative effect especially important. Repeated measurements every 3-6 months for an approximate median of 5 years could describe observations over time, but the registry record does not state how those measurements were combined into a responder classification. Nor does the record list a separate control group for estimating a contrast.

The record also lists developmental and growth outcomes, but no analyses or outcome results. Statistical transparency requires more than outcome names: definitions, analysis populations, missing-data procedures, and uncertainty estimates help readers understand what each result represents. Those details are not reported in the registry record.

Finally, the safety entries illustrate why counts need context. Zero recorded events among 23 at risk is a useful description of the registry entries, but it does not remove uncertainty about less common events or establish a risk of zero. Taken together, the record is informative about study structure and outcome intent, while leaving the central efficacy result and much of the analysis approach unavailable.

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 specific to this record restrict interpretation. First, the primary outcome result is not reported. Although the endpoint definition and assessment schedule are available, there is no responder count, denominator, estimate of uncertainty, or result for the underlying biochemical measures. The two listed secondary outcomes likewise have no reported results.

Second, the single-group design has no listed control arm. It can describe observations in the enrolled group, but does not provide a direct comparison with participants receiving another condition. The registry record also does not report randomization or a masked comparison; allocation is recorded as not applicable and masking as none.

Third, the assessment schedule does not fully define the endpoint analysis. The record does not say which visit determined response, whether the biochemical pattern needed to persist, or how measurements across visits were combined. It does not describe missing-data handling, participant flow, the analysis population, or the number with evaluable outcomes. Enrollment of 23 therefore cannot be assumed to equal the denominator for every outcome.

Fourth, no analyses are listed, and the statistical plan is not reported. There is no information about inferential methods, confidence intervals, multiplicity procedures, or adjustment for other factors. The record also does not provide a dose, supplementation schedule, or treatment duration, which limits reconstruction of the intervention exposure.

Finally, safety information is limited to counts of 0 serious and 0 other adverse events among 23 at risk for each category. The death value and safety observation window are not reported. These limitations mean the record supports description of the design and recorded counts, but not a complete assessment of efficacy, precision, or safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Treatment of the Cholesterol Defect in Smith-Lemli-Opitz Syndrome — NCT00272844.
• Registry record last updated 2017-10-20; status last verified 2017-09.
• Results first posted 2017-10-20.
• 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

The registry record describes a completed phase 1 and phase 2, single-group study sponsored by Boston Children's Hospital. It lists 23 participants with Smith-Lemli-Opitz Syndrome and an intervention of crystalline cholesterol oil-based suspension. The recorded study start is 1998-01, and primary completion is 2011-06.

The primary endpoint was a count of participants whose total serum cholesterol increased while 7-DHC and 8-DHC decreased. Assessments were scheduled every 3-6 months for an approximate median of 5 years. Growth response and improved neuropsychological development were listed as secondary outcomes.

The registry record does not report the primary responder count, secondary outcome results, or analyses. Safety entries list 0 serious and 0 other adverse events among 23 at risk in each category; the death value is not reported. These omissions limit conclusions about outcome frequency, precision, and comparative effects.