Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP) (NCT00744042), a na phase 1, phase 2 study. The primary outcome is Change in Rickets Severity From Baseline to Week 24, Based on Assessment of Skeletal Radiographs Using Radiologic Global Impression of Change (RGI-C).

2. Clinical Question

The study also addressed safety, tolerability and pharmacology. Its listed secondary outcomes concern serum concentration measurements: maximum concentration, time to maximum concentration, and area under the concentration-time curve to the last measurable concentration. Their numerical results are not reported in the registry record. Because there is no control group, the central clinical question is descriptive: what outcomes and adverse events were recorded in this group during the study? The design cannot establish how those observations compare with outcomes in a similar group not receiving the intervention.

3. Trial Design

This was a multicenter, open-label study listed in phases 1 and 2. The registry record describes a single-group design, with no masking and allocation marked not applicable. Asfotase alfa was the listed intervention, and there was no separate comparator arm. The study enrolled 11 participants with hypophosphatasia; its brief summary describes infants and young children with infantile-onset disease. The official title refers to a study in up to 10 patients, while the enrollment field lists 11. The registry record does not explain that difference.

The study start is recorded as 2008-09, and primary completion as 2010-05. Its status is completed. The primary endpoint was change in rickets severity from baseline to week 24, assessed using skeletal radiographs and the RGI-C. The endpoint description specifies that the summary measure was the median and the dispersion measure was the full range. The intention-to-treat population is named for this endpoint.

The design has important implications for interpretation. Without random allocation or a concurrent control group, the record describes observations within a treated group rather than a treatment contrast. An open-label study also means masking was not used; the registry does not report whether any other safeguards were used for assessment beyond the involvement of three pediatric radiologists not affiliated with study conduct in rating the radiographs.

The registry record lists three pharmacology outcomes as secondary measures, alongside the primary radiographic outcome. It does not report detailed methods for follow-up, adherence, missing observations, or the statistical analysis plan. The title’s stated intention to include up to 10 patients and the enrollment count of 11 are both registry-record details; their relationship is not explained.

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: All screened patients met eligibility criteria and were enrolled in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT (intention to treat)

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 Change in Rickets Severity From Baseline to Week 24, Based on Assessment of Skeletal Radiographs Using Radiologic Global Impression of Change (RGI-C), measured over 24 weeks.

The primary endpoint was change in rickets severity from baseline to week 24, assessed from skeletal radiographs using the Radiologic Global Impression of Change (RGI-C). The scale runs from -3, indicating severe worsening of rickets, to +3, indicating complete healing. Its values describe a radiographic assessment of change, rather than a direct measure of every aspect of a participant’s health.

Three pediatric radiologists who were not affiliated with study conduct performed the ratings. Average scores were derived for each patient at each assessment. The registry identifies the endpoint summary as a median, with the full range used to describe dispersion, and names the intention-to-treat population. A median communicates the middle of the observed score distribution; the full range describes its lowest and highest reported values. These summaries can be useful when a small group or a bounded rating scale makes a single average an incomplete description of the observations.

The record defines a responder as a participant with a score of at least +2, corresponding to substantial healing of rickets. That threshold supplies a categorical interpretation of the scale, but the registry record does not report the number or proportion of participants meeting it. Nor does it report the median or full-range result for the primary endpoint. Thus, the endpoint’s definition and assessment process are described, but the observed numerical change cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods information describes an open-label, single-group study with enrollment of 11 participants. There was no separate comparator, and allocation is listed as not applicable. The primary outcome was a change score assessed from baseline to week 24, summarized by a median and full range. The registry record does not report a detailed statistical analysis plan or the numerical outcome result.

Why use a median and full range?

In general, a median describes the middle observation when values are ordered. Unlike a mean, it is not pulled as strongly by unusually high or low values. A full range reports the extremes of the observations. Together, these summaries can make the location and spread of a small set of bounded rating scores easier to describe. However, the range can be strongly influenced by just one observation at either end, and the median and range do not show the complete pattern of individual scores. In this study, the registry specifies these summaries but does not report their numerical values.

The RGI-C is a seven-point rating scale described in the record, with values from -3 for severe worsening to +3 for complete healing. Three pediatric radiologists not affiliated with study conduct performed the ratings, and average scores were derived for each patient at each assessment. In general, having multiple assessors can be relevant to the reliability of subjective ratings, but the registry record does not describe assessor agreement, a blinding procedure, or how the individual ratings were combined beyond stating that average scores were derived for each patient at each assessment. No additional rating procedure should be inferred.

What does the responder threshold add?

The record classifies scores of at least +2 as responders, a threshold it describes as substantial healing of rickets. A threshold can translate a graded scale into a yes-or-no category, which may be easier to interpret clinically. That simplification also discards information: participants just below and far below the threshold are grouped together, as are all participants meeting or exceeding it. The registry record does not report the count of responders, so the classification rule cannot be applied to describe observed response frequency.

What can the study design estimate?

In general, a single-group study can report outcomes observed in its participants, but it cannot directly estimate a randomized difference between intervention and control groups when no control group exists. A baseline-to-week-24 change is a within-participant or within-group description, not the same thing as a controlled treatment effect. Changes can have multiple possible explanations, and this design does not isolate the intervention’s contribution. Open-label status means masking was not used. The record does not report whether outcome assessors were masked to assessment timing or other information, so that should not be assumed.

Statistical methods for small samples often require careful attention to the form of the outcome and missing observations. In general, a bounded ordinal rating scale is not equivalent to an unrestricted continuous measurement. A median and range avoid some assumptions associated with means and standard deviations, but they do not remove uncertainty or resolve missing-data concerns. The registry record names the intention-to-treat population for the primary outcome, but it does not explain how participants without a week-24 assessment were handled, whether every enrolled participant contributed a score, or whether any imputation was used.

How should planning calculations be read?

Any sample-size figures associated with this study are planning illustrations based on an observed effect, not the study’s original design justification and not observed power. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Those assumptions describe a hypothetical two-arm planning exercise, whereas the actual study is listed as single-group with no comparator. The registry record does not report the original sample-size justification, and the numerical primary outcome needed to understand an observed-effect-based planning calculation is not reported in the registry record.

In general, a planning sample size estimates how many participants might be required under specified assumptions to detect a chosen effect with a chosen level of power. It is not evidence that the completed study had that power, and it is not an estimate of the probability that a finding is true. A calculation framed around two arms is especially distinct from a single-group study’s design. The planning assumptions should therefore not be mistaken for a feature of the study’s actual allocation or analysis.

What is not specified?

The record does not report the statistical model or software, hypothesis-testing details for the primary endpoint, confidence intervals, p-values, handling of repeated assessments, or a multiplicity plan. It lists four outcome measures and one analysis, but those counts alone do not explain which hypotheses were tested or how any tests were conducted. General methods cannot fill in those omissions. The sound interpretation is limited to the outcome definition, the named summaries, the design details, and the results that are actually reported.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists four outcome measures and one analysis. The primary outcome is the change in RGI-C score from baseline to week 24. Three secondary outcomes concern asfotase alfa pharmacology: maximum serum concentration, time at maximum concentration, and area under the serum concentration-time curve to the last measurable concentration. The numerical results for those secondary outcomes are not reported in the registry record.

Multiplicity is a general statistical concern that arises when several outcomes or hypotheses are examined: the chance of obtaining at least one apparently unusual result can increase as the number of tests grows. A prespecified approach can explain how multiple tests are handled. The registry record does not report a multiplicity adjustment or other plan for interpreting multiple outcomes. The count of outcome measures does not establish that each was tested, nor does the count of analyses reveal the testing procedure.

The primary endpoint names the intention-to-treat population. In general, intention-to-treat analysis aims to retain participants in the groups to which they were assigned, but this study is single-group and the registry does not describe the operational rules used for its named population. The record does not explain how missing baseline or week-24 radiographic assessments were handled, whether participants were excluded from the endpoint analysis, or whether imputation or sensitivity analyses were used. It also does not report the amount or pattern of missing data.

These omissions limit assessment of how robust the endpoint summary is to incomplete observations and how multiple outcomes were interpreted. They do not establish that missing data or multiplicity affected the result; the necessary details are not reported in the registry record.

11. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: craniosynostosis (27.3%), pneumonia (18.2%), respiratory distress (18.2%), hypoxia (18.2%), convulsion (18.2%).

The safety record lists 11 participants at risk for both serious and other adverse events. Seven participants were affected by serious adverse events, and 11 were affected by other adverse events. The record lists craniosynostosis at 27.3%, and pneumonia, respiratory distress, hypoxia, and convulsion each at 18.2%; H1N1 influenza is listed at 9.1%. These are the percentages reported for the serious-event terms.

These figures describe events recorded in this study group. They are not a comparison with an untreated or alternative-treatment group, because the study had no separate comparator. The registry record does not state whether each participant had one or multiple events, give event-level timing or duration, or report how the listed term percentages were calculated. It also does not establish from these counts whether an event was caused by asfotase alfa. A serious adverse event is a safety reporting category, not by itself proof of causation or a measure of treatment effect.

The deaths field has no numerical count reported in the registry record. That should not be interpreted as evidence of zero deaths. The safety figures also do not substitute for the missing primary efficacy result or the missing pharmacology results.

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

The registry record establishes that an open-label, single-group study enrolled 11 participants and assessed change in radiographic rickets severity from baseline to week 24. It gives the RGI-C scale, defines a responder threshold, identifies a median and full range as the summary measures, and names the intention-to-treat population. These details explain what the primary endpoint was intended to capture and how it was meant to be summarized.

The record does not report the primary endpoint’s median, full range, or responder count. Therefore, the actual degree and direction of radiographic change cannot be stated from the registry information. The result cannot be characterized as improvement, worsening, or no change on the basis of an outcome value that is not reported. Likewise, the three listed pharmacology outcomes have no numerical results reported in the registry record.

The serious adverse-event count and listed terms are descriptive safety observations in this group. They do not establish that the intervention caused the events, and without a comparator they do not show whether event frequency differed from another group. The field for deaths does not contain a reported numerical count, so a conclusion about deaths cannot be drawn from it.

More generally, an uncontrolled before-and-after study can describe observed changes but cannot separate those changes from other possible influences as a randomized comparison can. The open-label design and the absence of reported details about missing observations and analysis procedures further constrain interpretation. These limitations do not prove that the study findings are invalid; they mark what can and cannot be concluded from the registry record.

Any planning sample-size figures should be read as illustrations rather than observed power or evidence about the certainty of the endpoint. The registry’s stated planning assumptions concern a hypothetical equal-allocation, two-arm calculation, while the study itself was single-group. No sample-size illustration can replace a reported endpoint estimate or create a treatment comparison that the design did not include.

In short, the record documents the study question, design, endpoint definition, and some safety counts, but it does not report the numerical primary outcome. A numerical assessment of efficacy, precision, or comparative safety is therefore not supported by the registry information.

13. Why This Trial Matters Statistically

This study is statistically notable because its registry record distinguishes a defined endpoint from a reported result. The primary question is specific: change in rickets severity on skeletal radiographs between baseline and week 24, rated with the RGI-C. The record also describes the scale’s direction, a responder threshold, and the use of median and full range. Yet it does not report the numerical endpoint outcome. For statistical interpretation, that distinction is fundamental: a detailed measurement definition is not a substitute for the observed estimate.

The study also illustrates how design determines the kind of inference available. A single-group study can describe the participants’ recorded outcomes, but it does not provide a randomized contrast. The absence of a comparator is not a technical detail that can be repaired by a more elaborate summary statistic. It constrains claims about differences attributable to the intervention.

Small clinical studies often need concise summaries and careful attention to each participant’s data. A median and range can describe a bounded scale without implying that its values behave like an unrestricted continuous outcome. At the same time, summaries need reported values to be informative, and missing-data handling matters when the enrolled group is small. The registry names the population for the primary endpoint but does not explain missing assessments or the analytical procedures.

The safety record provides participant counts and percentages for listed serious-event terms, but those observations require cautious interpretation in an uncontrolled study. They do not establish causality or comparative risk. Finally, planning illustrations based on a two-arm design should not be confused with the actual single-group study or with observed power. Together, these features make the record a useful example of how design, outcome reporting, and analysis details set the boundaries of statistical conclusions.

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.

Several limitations specific to this study constrain interpretation. It was open-label and single-group, with no separate comparator, so its design does not yield a randomized estimate of a difference between groups. The record lists enrollment of 11 participants. The official title refers to up to 10 patients, while the enrollment field lists 11; the registry record does not explain the discrepancy.

The most important reporting limitation is that the numerical primary outcome is not reported in the registry record. Although the endpoint definition gives the scale, week-24 timeframe, median and full range, and responder threshold, the actual median, range, and responder count are absent. Numerical results for the listed pharmacology outcomes are also not reported.

The registry record does not describe handling of missing assessments, participant-level exclusions, imputation, or sensitivity analyses. It names the intention-to-treat population, but the operational approach to that population is not reported. Nor does the record report a detailed statistical analysis plan, confidence intervals, p-values, or a multiplicity approach. These omissions prevent evaluation of the numerical precision and robustness of the primary result.

The safety information is also limited. Counts and percentages are reported for adverse events, but details such as event timing, recurrence, and the basis for attribution are not reported in the registry record. The deaths field has no numerical count reported. Without a comparator, the safety observations cannot be interpreted as a comparative estimate.

Finally, the stated sample-size illustrations use equal allocation between two arms, whereas the actual study is single-group. Those calculations are planning illustrations rather than evidence about the study’s observed power. The registry does not report the original sample-size justification.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP) — NCT00744042.
• Registry record last updated 2019-04-01; status last verified 2019-03.
• Results first posted 2011-09-30.
• 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

The registry record describes a completed, multicenter, open-label, single-group study of asfotase alfa in severely affected infants and young children with infantile-onset hypophosphatasia. It lists phases 1 and 2, enrollment of 11, a study start of 2008-09, and primary completion of 2010-05. The primary endpoint was change in rickets severity from baseline to week 24, assessed from skeletal radiographs with the RGI-C and summarized by median and full range in the intention-to-treat population.

The numerical primary endpoint result and the results for the three listed pharmacology outcomes are not reported in the registry record. Safety information lists 7 of 11 participants affected by serious adverse events and 11 of 11 affected by other adverse events. The single-group design provides no concurrent control comparison, and the record does not report detailed missing-data, multiplicity, or analysis-plan methods.