Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD) (NCT00418561), a non-randomized phase 1 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events (TEAEs).

2. Clinical Question

The registry describes a single-center, open-label, multiple-dose, dose-escalation study in people with late infantile MLD. Its primary focus was safety as recorded through TEAEs. An adverse event was defined broadly as an untoward, undesired, unplanned clinical event, including signs, symptoms, disease, or laboratory or physiological observations, regardless of whether it was considered related to study drug. A TEAE was an event that began after treatment or worsened relative to the pretreatment state.

The study also listed secondary outcomes involving nerve conduction velocity, nerve biopsy findings, MRI-Loes scores, and Paediatric Evaluation of Disability Inventory (PEDI) scores at Week 26. These outcomes address different kinds of observations, but the registry record does not give their results. The question supported by the posted safety listings is therefore descriptive: what event counts were recorded across the dose cohorts? The design does not establish a randomized treatment contrast or isolate the effect of dose from other cohort differences.

3. Trial Design

This was a Phase 1, single-center, open-label, non-randomized, uncontrolled, multiple-dose, dose-escalation study. The registry lists 13 participants enrolled. The methodology description says that 12 patients would be enrolled, so the planned number in that description differs from the enrollment figure recorded for the study. The record does not explain that difference or give a participant flow account.

Three dose cohorts are described. Cohort 1 received Metazym at 25 U/kg as a single dose, followed thereafter by 50 U/kg. Cohort 2 received 100 U/kg, and Cohort 3 received 200 U/kg. The intervention list labels these as dose levels. No randomized allocation is described, and there was no untreated or active control group. Participants and investigators were not masked.

The methodology description states that an infusion would be given every other week for half a year, followed by continued every-other-week treatment until safety data were available. It also refers to a total of thirteen intravenous infusions. The registry record does not clarify whether that total describes each participant, the study as a whole, or a particular treatment period, so it should not be used to infer individual treatment exposure. The record says safety events were monitored at every visit.

The primary TEAE timeframe ran from study drug administration up to Week 28. The description says evaluation was completed when the last cohort had its 26-week evaluation and data management was performed within 4 weeks. The study is recorded as completed, with a start date of 2007-01-22 and primary completion on 2008-03-27. The record identifies a factorial model, but does not explain how that label relates to the described dose-escalation cohorts or specify a model-based analysis. Detailed methods for dose assignment, stopping decisions, or statistical analysis are not reported in the registry record.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT) population included all participants who received at least 1 dose of study drug.

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: Intent-to-treat (ITT) population included all participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events (TEAEs), measured over From study drug administration up to Week 28.

The primary endpoint was the number of participants with treatment-emergent adverse events from study drug administration up to Week 28. It counts participants who experienced an event, rather than measuring the number of events per person or the duration of events. The registry defines an adverse event broadly and includes events regardless of causal relationship to study drug. It defines treatment-emergent events as those absent before treatment or worsened relative to the pretreatment state after study drug administration.

A participant count is a direct descriptive way to report how many people in the defined population experienced at least one qualifying event during the stated observation period. For a safety-focused early-phase study, this kind of outcome can describe the observed event burden while treatment is being given and participants are followed. It does not, by itself, establish whether treatment caused an event. Causal attribution requires more than timing, particularly when there is no control group.

The endpoint is specified for the intent-to-treat population, defined in the registry as all participants who received at least 1 dose of study drug. However, the primary TEAE count and its cohort-specific results are not reported in the registry record. The separate safety listings give counts for serious and other adverse events, but they do not substitute for an explicitly reported result for the primary endpoint. The record also does not report an uncertainty interval, a test of a prespecified hypothesis, or a detailed method for handling participants with incomplete follow-up.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation starts with identifying what the study design can support. This was an open-label, non-randomized, uncontrolled dose-escalation study. A randomized controlled comparison uses allocation to create groups intended to be comparable on average. That protection is absent. Each cohort received study drug at a described dose level, and the registry does not report a concurrent control group. Cohort-level differences are therefore descriptive and may reflect differences between the groups as well as differences in dose.

What does a participant count tell the reader?

A participant count for an event records how many people experienced at least one event meeting the outcome definition. It is not the same as a count of all event episodes: one participant may have experienced more than one event. The primary endpoint is framed as the number of participants with TEAEs, while the safety listings separately give counts of participants affected by serious and other adverse events. The registry does not report the primary TEAE count, so the serious and other event listings should not be treated as a replacement for that endpoint.

Counts are most interpretable alongside their denominators and a clear account of who was followed and for how long. The safety listings give numbers at risk and affected for each cohort. They do not provide uncertainty intervals for those counts, and the record does not describe how event follow-up differed among participants. With small cohorts, each participant’s experience is an appreciable part of the observed total. A count alone also says nothing about event duration, recurrence, severity beyond the serious classification, or whether the event was considered related to treatment.

Why does the design limit comparisons?

In a controlled randomized trial, random allocation is intended to reduce systematic differences between treatment groups. This study did not use that design. The dose cohorts should not be read as equivalent to treatment and control arms. A higher count in one cohort would not demonstrate that its dose caused more events, and a lower count would not demonstrate that its dose caused fewer events. Those conclusions would require a design and analysis that address group comparability, follow-up, and uncertainty. The registry record does not report such an analysis.

Open-label status means treatment masking was absent. The record does not explain whether outcome assessment was independently masked or how subjective event judgments were reviewed. The broad AE definition includes clinical observations and laboratory or physiological observations, and does not require a causal relationship to study drug. This breadth is useful for safety surveillance, but it also means the event count is a record of observations during the study rather than a direct measure of drug-attributable harm.

How should uncertainty be understood?

A confidence interval, in general, gives a range of values compatible with the observed data under the assumptions of the statistical method. It communicates precision as well as the central estimate. The registry record does not report confidence intervals for the safety counts. Without an interval or another uncertainty measure, the counts should not be interpreted as precise estimates of event frequency beyond these participants. A p-value, in general, evaluates how compatible data are with a specified statistical model or null hypothesis; it does not measure clinical importance or the probability that a hypothesis is true. No p-value or formal hypothesis test for the adverse event counts is reported in the registry record.

For event-count outcomes, statistical models may need to account for variation greater than expected under a simple Poisson model; this is called over-dispersion. In general, ignoring over-dispersion can make uncertainty appear too small. However, the posted endpoint is a participant count, and the registry record does not state that an event-rate model was used or give repeated event counts. Over-dispersion therefore cannot be evaluated from the listed participant counts. No model assumptions or diagnostics are reported.

What do planning illustrations mean?

Sample-size planning illustrations are not observations from the trial. The described illustrations use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect set as a stated fraction of the observed effect. Those assumptions are for planning illustration and are not identified as the trial’s original design assumptions. The record does not report the trial’s sample-size justification or explain a planned two-arm comparison. Any illustrated sample size is therefore not a count of participants observed in this study and is not observed power.

In general, power is a design quantity: it describes the probability that a specified analysis would detect a specified effect under assumptions made before data are observed. It should not be treated as a retrospective measure of whether a study’s result is reliable. The registry record does not report a sample-size justification, target effect, or prospective power calculation for this trial. It also does not report interim analyses, a stopping rule, or the statistical plan used for the posted results. The three analyses listed in the record do not, by themselves, reveal which tests were run or how their results were interpreted.

The registry’s factorial model label is not accompanied by an analysis description. The clinical design is described as non-randomized dose escalation, and no factorial factors, contrasts, or model terms are reported. Statistical interpretation should therefore follow the design description and the posted outcomes rather than assume a factorial analysis was performed.

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", "Cohort 3")
n      <- c(4, 5, 4)
events <- c(4, 5, 4)
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  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  Cohort 2  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6
ARM  Cohort 3  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 21 outcome measures and 3 analyses. Several secondary outcomes are named, including nerve conduction velocity, nerve biopsy status, MRI-Loes score shifts, and PEDI scores at Week 26. When a study examines multiple outcomes or performs multiple analyses, the chance of at least one apparently notable result can increase. In general, multiplicity methods can control or describe that issue, but the registry record does not report a multiplicity adjustment, a hierarchy of outcomes, or which outcomes were treated as confirmatory.

The primary endpoint is identified as the number of participants with TEAEs through Week 28, but its numerical result is not reported in the registry record. The outcome listing alone does not show whether every planned outcome was measured, analyzed, or reported. The record does not describe a prespecified statistical analysis plan, analysis populations for the secondary outcomes, or how deviations from any planned analyses were handled.

The primary endpoint population is defined as participants who received at least 1 dose of study drug. That definition does not establish how missing event information or incomplete follow-up was handled. The record does not report missing-data counts, reasons for missingness, imputation methods, censoring rules, or sensitivity analyses. It also does not state whether participants who discontinued treatment remained under safety follow-up through the endpoint timeframe.

These omissions matter because the interpretation of participant counts depends on who contributed information and the observation period represented. The available information does not support assumptions about a missing-data procedure or about whether all participants completed the planned follow-up. A registry record can identify the intended endpoint and population, but those definitions do not replace a reported accounting of missing observations or a full analysis plan.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: malnutrition (50.0%), pneumonia aspiration (25.0%), bronchitis acute (25.0%).

The serious adverse event listings report participants at risk and affected by cohort: Cohort 1, 4 at risk and 1 affected; Cohort 2, 5 at risk and 2 affected; and Cohort 3, 4 at risk and 2 affected. For other adverse events, the listings report 4 at risk and 4 affected in Cohort 1, 5 at risk and 5 affected in Cohort 2, and 4 at risk and 4 affected in Cohort 3. These counts describe the listed participants, not event episodes or treatment-caused events.

The serious-event terms with reported percentages are Malnutrition, 50.0%; Pneumonia aspiration, 25.0%; and Bronchitis acute, 25.0%. The registry record does not report the denominator for these percentages or clarify whether a participant could contribute to more than one term. They should not be read as cohort-specific risks or as percentages of all enrolled participants.

Deaths are not reported in the registry record; a blank or unavailable entry should not be interpreted as zero deaths. The record also does not provide event-level timing, duration, outcome, relatedness judgments, or a complete definition of seriousness. Serious and other adverse events are distinct listings, but the registry entries do not establish that the “other” category is a complete count of all non-serious events. These figures are descriptive safety information and do not establish causation.

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

The study provides a record of a small, single-center experience with three Metazym dose cohorts and selected safety counts. It documents that serious and other adverse events were recorded among participants, and it lists serious-event terms with percentages. The primary endpoint was intended to count participants with TEAEs through Week 28, but that result is not reported in the registry record. The listed counts therefore offer only a partial view of the stated safety endpoint.

The study does not establish how event experience would compare with no treatment or with another treatment, because there was no control group. It also does not establish that any event was caused by Metazym. An event occurring after treatment meets the timing component of the TEAE definition, but the registry’s definition explicitly includes events regardless of causal relationship. Interpretation of causal contribution would require information and comparisons not reported in this record.

The dose cohorts do not establish a dose-response relationship. They were non-randomized, and the registry does not provide a statistical comparison that accounts for potential cohort differences. The safety counts should not be ranked as evidence that one dose is safer or less safe than another. Small participant counts also make the descriptive totals sensitive to individual experiences, while no uncertainty intervals are reported.

The registry’s stated study objectives included safety, efficacy, and pharmacokinetics, and secondary outcomes included several functional and imaging measures. Their presence in the outcome list is not evidence of a particular result. The registry entries available for this analysis do not report efficacy or pharmacokinetic findings, nor do they report the results for the named secondary outcomes. No conclusion about benefit can be drawn from the safety listings.

Overall, the record is useful for understanding the study’s design and the kinds of safety observations recorded. It is not a controlled estimate of comparative safety or efficacy, and it does not supply the primary endpoint result or enough analysis detail to assess precision, missingness, or multiplicity. These limits define what can responsibly be inferred from the posted information.

14. Why This Trial Matters Statistically

This trial matters statistically because its design makes the distinction between description and comparison especially important. The study is explicitly non-randomized and uncontrolled, yet it includes multiple dose cohorts. Readers may be tempted to compare the cohorts as if they were treatment arms in a controlled trial. The design does not warrant that interpretation: cohort differences can arise from factors other than dose, and the registry record does not report an adjustment that would resolve this issue.

It also illustrates why endpoint definitions and endpoint results must be considered separately. The primary outcome is clearly named as the number of participants with TEAEs through Week 28, and its population is defined. But the primary numerical result is not reported in the registry record. Separate counts for serious and other adverse events provide relevant safety descriptions, but they do not fill that reporting gap.

Safety interpretation depends on more than whether an event was listed. Counts refer to participants affected, while event terms may represent distinct event types; percentages require a clear denominator. The registry record does not give the denominator for its top serious-event term percentages. It also does not report uncertainty intervals, the full statistical plan, or missing-data handling. Those absences limit how precisely readers can interpret the observed counts.

Finally, the trial shows why sample-size illustrations must be separated from trial design and results. Illustrations based on a stated fraction of an observed effect are planning exercises, not evidence that the original study was designed for that contrast and not observed power. The registry record does not report its sample-size justification. Keeping these distinctions clear prevents descriptive safety data, planning calculations, and causal conclusions from being conflated.

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 reported design is single-center, open-label, non-randomized, and uncontrolled. It offers no concurrent comparison group, so the safety counts cannot provide a controlled estimate of treatment-associated risk. Dose cohorts are not randomized comparison arms, and differences between them cannot be attributed to dose on the basis of these data alone.

The registry records 13 enrolled participants, while its methodology description says 12 patients would be enrolled. The record does not explain this difference, provide participant flow, or state how many participants completed each assessment. Although the primary population is defined as all participants receiving at least 1 dose, the number included in the primary endpoint analysis is not reported in the registry record.

The primary TEAE result is not reported in the registry record. The serious and other adverse event counts are available, but the registry entries do not provide event-level details, seriousness criteria, relatedness assessments, exposure duration by participant, or complete follow-up status. The denominator for the reported serious-event term percentages is also not reported. Deaths are not reported in the registry record and should not be interpreted as absent.

The record lists multiple secondary outcomes but does not report their numerical results. It does not describe multiplicity handling, missing-data methods, statistical models, confidence intervals, interim analyses, stopping rules, or the trial’s sample-size justification. It also does not explain the factorial model label in relation to the dose-escalation design. These limitations restrict assessment of the precision, completeness, and comparative meaning of the posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD) — NCT00418561.
• Registry record last updated 2021-06-25; status last verified 2021-06.
• Results first posted 2015-08-13.
• 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 NCT00418561, a Phase 1 study of Metazym for late infantile MLD. It was a single-center, open-label, non-randomized, uncontrolled dose-escalation study with 13 participants enrolled. Three cohorts received described dose levels of 25 U/kg as a single dose followed thereafter by 50 U/kg, 100 U/kg, or 200 U/kg. The study is recorded as completed, with a start date of 2007-01-22 and primary completion on 2008-03-27.

The primary endpoint was the number of participants with TEAEs from study drug administration up to Week 28, in an intent-to-treat population defined as participants who received at least 1 dose. The primary endpoint count is not reported in the registry record. Serious and other adverse event counts are listed by cohort, alongside serious-event terms and percentages. The record does not report a control comparison, uncertainty intervals, the sample-size justification, missing-data methods, or a detailed statistical analysis plan. The design and posted safety figures support descriptive interpretation only; they do not establish comparative effects or causation.