Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD) (NCT01510028), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity.

2. Clinical Question

3. Trial Design

This was a multicenter Phase I/II, open-label, non-randomized, parallel-group dose-escalation study in children with metachromatic leukodystrophy. The study title names HGT-1110; the intervention is described as recombinant human arylsulfatase A. The registry lists Shire as the sponsor and the study status as completed.

The registry lists enrollment of 24 and four cohorts, each described as including 6 patients. Cohort 1 received 10 mg, Cohort 2 received 30 mg, and Cohorts 3 and 4 each received 100 mg. The first three cohorts are labelled Process A; the fourth is labelled Process B. Each arm description specifies intrathecal administration EOW. The registry summary describes 38 weeks of treatment with 20 injections.

Because allocation was non-randomized and masking was absent, the cohorts should not be read as randomized treatment groups. Dose, cohort, and process labels differ, and no control arm is described. The record does not report how participants were assigned to cohorts, whether cohort entry depended on earlier safety review, or whether any other design features governed dose escalation.

The primary safety outcome covered the period from the start of study treatment up to Week 42. The listed secondary outcomes include motor function measured by GMFM-88 at Week 40, and several Week 40 swallowing and nerve-conduction assessments. The registry lists 28 outcome measures overall. Details of the analysis plan and the rationale for the enrollment target 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.

Before assignment: A total of 34 participants were screened and 24 participants were enrolled in the study. Out of which 23 participants completed the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery.

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: Safety set consisted of participants who received at least 1 dose of investigational product or underwent device implant surgery.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity, measured over From start of study treatment up to Week 42.

The primary endpoint was the number of participants with treatment-emergent adverse events (TEAEs), classified by type and severity, from the start of study treatment up to Week 42. An adverse event was defined as an untoward medical occurrence in a participant who received study drug, without regard to whether it was considered causally related to treatment. TEAEs were events occurring at or after the first dose, or device implant surgery if earlier, through the last follow-up date. Drug-related and device-related TEAEs were analyzed and reported.

Severity was assessed by the investigator using the NCI CTCAE Version 4.0 grading scale: grade 1 was mild, grade 2 moderate, grade 3 severe, grade 4 life-threatening, and grade 5 fatal. This endpoint is used to describe the observed safety experience during treatment and follow-up, including event severity rather than only event occurrence. It does not, by itself, establish whether an event was caused by the study drug. The record defines the safety population as participants who received at least one dose of investigational product or underwent device implant surgery.

Detailed overall TEAE counts by type and severity are not reported in the registry record in the registry record for this analysis. The separately listed serious-event figures should therefore be distinguished from a complete account of the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The principal outcome is a count of participants with adverse events. This is a binary-outcome structure at the participant level: for a particular event definition, a participant either meets the definition or does not. A count is useful for describing how many participants experienced an event, but it does not convey all information about timing, recurrence, duration, or clinical context. Those details are not reported in the registry record.

What does a participant count tell the reader?

A count should be interpreted alongside its group size and the outcome definition. The registry lists 6 participants in each cohort, and the serious-event results include both affected and at-risk counts. For example, the serious-event figure for the 10 mg Process A cohort is 5 affected among 6 at risk. This is a description of observed participants, not a model-based estimate. The count does not measure how many separate events occurred, because one participant may experience more than one event. Whether the reported event-term percentages count participants, event occurrences, or both is not explained in the record.

Why does the study design affect interpretation?

Random allocation helps balance measured and unmeasured participant characteristics across groups on average. This study is explicitly non-randomized, so cohort differences can be associated with factors beyond dose. The record does not report the assignment process or cohort-specific baseline characteristics. The parallel-cohort structure allows each cohort's observed safety experience to be described, but it does not provide the protections of a randomized comparison. Open-label conduct also means treatment was not masked; the record does not report whether outcome assessment was independently masked.

These points matter even when an outcome is counted objectively. How adverse events are detected, classified, and attributed can depend on study procedures and clinical judgment. The registry says investigators graded severity using NCI CTCAE Version 4.0 and that events were recorded without regard to a possible causal relationship. This definition supports systematic description, but it does not make every recorded event treatment-caused.

What does a confidence interval represent?

In general, a confidence interval expresses the statistical uncertainty around an estimated quantity under a specified method. A narrow interval indicates greater precision than a wide interval, while both are conditional on the assumptions and data used. No confidence intervals for these adverse-event results are reported in the registry record. With cohort sizes listed as 6, the raw counts are especially important to keep visible; unsupported precision should not be inferred from them.

How should dose patterns be assessed?

A dose-escalation study can describe what occurred at each dose level, but an apparent pattern in counts is not, by itself, evidence of a dose-response relationship. Such an interpretation would need to account for the non-randomized allocation, cohort composition, exposure, follow-up, and event definitions. The record gives four cohort labels, including two different process labels at 100 mg, but does not report the methods used to compare them or establish a trend. No statistical test or adjusted dose comparison is reported.

What are planning illustrations?

In general, sample-size planning uses assumptions about the effect to detect, variability, allocation, and a chosen significance level. The planning illustrations associated with this analysis use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. They are planning illustrations, not observed power and not proof that the study had adequate power. Because the study has no randomized comparison and the posted analysis details do not include a numerical effect estimate or the resulting planning values, no specific planning conclusion can be drawn from these assumptions.

For event-count outcomes, over-dispersion is a general concern when participant or event counts vary more than a simple statistical model expects. It can make uncertainty larger than a model that assumes a single common rate would suggest. The registry record does not report an over-dispersion assessment, a fitted count model, or a model-based treatment estimate. The descriptive participant counts should not be mistaken for results from such a model.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 28 outcome measures, including the primary safety outcome and multiple secondary measures at Week 40. When a study evaluates many outcomes or categories, the chance of at least one apparently notable result can increase if each is tested separately. Statistical approaches can address this issue, but the registry record does not report a multiplicity strategy, a hierarchy of secondary outcomes, or which outcomes were considered confirmatory.

The registry lists zero analyses. No statistical analysis plan, hypothesis tests, adjustment procedures, or outcome-level confidence intervals are reported in the registry record. Consequently, the posted descriptive counts should not be read as evidence that a prespecified statistical comparison was performed.

Missing-data methods are not reported in the registry record. The available information does not state how participants without a Week 40 assessment, participants who stopped treatment, or incomplete event records were handled for each outcome. It also does not report whether outcome-specific denominators differed from the cohort listings. These omissions limit interpretation of the Week 40 secondary outcomes and any comparison of outcomes across cohorts.

The primary safety population is defined as participants who received at least one dose of investigational product or underwent device implant surgery. The record does not describe additional analysis populations or how the safety set related to each outcome's denominator. Without those details, the results are most appropriately read as the descriptive counts specifically reported, rather than as a complete account of missingness or analysis-population handling.

11. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: device failure (33.3%), nasopharyngitis (33.3%), viral upper respiratory tract infection (33.3%), vomiting (16.7%), device dislocation (16.7%).

The serious-event figures report affected participants and participants at risk for each cohort. The 10 mg Process A cohort lists 5 affected among 6 at risk; the 30 mg Process A cohort lists 4 among 6; the 100 mg Process A cohort lists 3 among 6; and the 100 mg Process B cohort lists 2 among 6. These are cohort-level counts. They do not establish that dose caused any difference, because the study was non-randomized and had no like-for-like control comparison.

The other adverse-event figures list 6 affected among 6 at risk in each cohort. No deaths are listed for the four cohorts. The serious-event terms reported most often are Device failure, Nasopharyngitis, and Viral upper respiratory tract infection, each at 33.3%; Vomiting, Device dislocation, and Device malfunction are each at 16.7%. The record does not explain whether these terms overlap or whether percentages refer to participants or event occurrences, so they should be read as separate reported terms rather than summed.

These results do not give the full severity distribution for all TEAEs. The primary outcome includes TEAEs classified by type and severity through Week 42, while the available figures are a subset of safety information. The registry definition also makes clear that an adverse event need not be judged treatment-related to be counted.

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

The results describe adverse events recorded in four cohorts during a non-randomized, open-label study of intrathecal HGT-1110 in children with MLD. They show that serious adverse events were reported among participants in each cohort, with the listed affected counts ranging from 2 to 5 among 6 at risk per cohort. The record also lists other adverse events in each cohort and no deaths in the listed groups. These observations are descriptive and specific to the study record.

The counts do not establish that the intervention caused an event or that one dose is safer than another. The study lacks a randomized comparator, and the 100 mg groups have different process labels. Participant characteristics, assignment details, exposure differences, and other possible explanations for cohort variation are not reported. The figures therefore cannot isolate a dose effect or support a like-for-like comparison.

The numbers also do not predict an individual participant's experience or the frequency of events in a broader population. Cohorts are small, and no uncertainty intervals or adjusted comparisons are reported. Term-level percentages should not be combined because the record does not explain possible overlap or the precise basis of each percentage.

The primary endpoint concerns TEAEs by type and severity, but the detailed grade-specific results and complete TEAE counts are not reported in the registry record. The serious-event figures alone cannot answer every question about the primary endpoint. The listed secondary outcomes include motor function, swallowing, and nerve conduction assessments, but outcome results for these measures are not available in the registry record for this analysis.

Accordingly, the posted data support a limited description of reported safety events in the study cohorts. They do not establish efficacy, comparative safety, or a causal relationship between treatment and any individual event.

13. Why This Trial Matters Statistically

This trial is statistically notable because it combines dose escalation with a non-randomized parallel-cohort design. Such a design can describe safety observations at different dose and process labels, but cohort-to-cohort differences cannot be interpreted as if participants had been randomly allocated. That distinction is essential when reading a sequence of counts that may appear to change across dose groups.

The outcome also illustrates the difference between counting participants and counting events. A participant-level count tells how many people experienced an outcome under its definition, whereas recurrent events and their timing require additional information. The registry's primary outcome is framed as participants with TEAEs by type and severity, but the detailed results concern serious events and selected event terms. Distinguishing these levels prevents a partial safety description from being mistaken for a complete event history.

Another important issue is the combination of a broad safety endpoint and multiple secondary outcomes. The registry lists 28 outcomes, including assessments of motor function, swallowing, and nerve conduction. Without reported multiplicity procedures or a statistical analysis plan, findings across several outcomes would require cautious interpretation. The record lists no analyses, so the available safety counts should be treated as descriptive rather than as evidence from a formal inferential comparison.

Finally, small cohorts make the observed counts sensitive to each participant's outcome. This does not make the counts uninformative: they document what was reported in the study. It does mean they offer limited precision and cannot by themselves support broad generalization. Clear reporting of denominators, event definitions, missing-data handling, and analysis methods is particularly important in this setting.

14. 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 for interpretation is the non-randomized, open-label design. There is no control group, and the registry does not report how participants entered the four cohorts. Differences among cohorts may reflect dose, process, participant characteristics, or other factors that cannot be separated using the posted information.

The two cohorts at 100 mg have different process labels, Process A and Process B. The record does not explain the process distinction or whether the cohorts were otherwise comparable. It also does not report participant characteristics by cohort, treatment exposure by participant, or cohort-specific follow-up completeness. These omissions limit interpretation of differences in adverse-event counts.

The safety results available for this analysis do not include the full primary-endpoint detail. The endpoint is defined as TEAEs by type and severity through Week 42, but detailed grade-specific counts are not reported in the registry record. Serious-event terms are listed with percentages, but the basis of those percentages and whether terms overlap are not explained. No confidence intervals or formal comparison results are reported.

The registry lists 28 outcome measures but provides no analysis count, multiplicity approach, missing-data method, or statistical analysis plan in the available record. The methods for handling participants with incomplete outcome assessments are not reported. These gaps make it difficult to assess the precision and completeness of results across the primary and secondary outcomes.

Finally, the reported cohort sizes are small, so the observed counts offer limited precision and should not be generalized beyond the study without additional evidence. The record does not report the sample-size justification or the basis for selecting the enrollment target.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD) — NCT01510028.
• Registry record last updated 2021-06-14; status last verified 2021-05.
• Results first posted 2018-10-15.
• 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.

18. Record Summary

NCT01510028 was a completed, multicenter, open-label, non-randomized Phase I/II dose-escalation study of intrathecal HGT-1110 in children with metachromatic leukodystrophy. The registry lists Shire as sponsor, enrollment of 24, and four parallel cohorts: 10 mg, 30 mg, 100 mg Process A, and 100 mg Process B. Each cohort description lists 6 patients and EOW administration.

The primary outcome was participants with TEAEs by type and severity through Week 42. The registry also lists secondary motor-function, swallowing, and nerve-conduction outcomes at Week 40. The available safety figures report serious adverse events by cohort, selected serious-event terms, other adverse events, and deaths. The study was not randomized, and no inferential analyses are listed. Further details on the statistical plan, missing data, multiplicity, and complete primary-endpoint results are not reported in the registry record.