Somatropin + Leuprorelin vs Somatropin Alone in Pubertal Children With Idiopathic Short Stature: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Somatropin + Leuprorelin vs Somatropin Alone in Pubertal Children With Idiopathic Short Stature (NCT00355030), a randomized phase 3 study. The primary outcome is Number of Participants With One or More Drug-related Adverse Events.

2. Clinical Question

3. Trial Design

The registry record identifies NCT00355030 as a randomized, parallel-group, phase 3 trial comparing somatropin plus leuprorelin with somatropin alone in pubertal children with idiopathic short stature. Masking is listed as none, so the trial was not masked according to the record. The enrollment field reports 91; the record does not specify the number assigned to, treated in, or analyzed within each arm for the primary outcome.

The study was initially intended to examine combined treatment with growth hormone and a gonadotropin-releasing hormone agonist. The registry summary says treatment stopped in January 2012 at the request of the French drug agency. A protocol amendment divided the study into two periods. Period 1 involved the treatment comparison. Participants from France who took part in Period 1 were asked to join a long-term safety follow-up defined as Period 2. Participants from the Netherlands were offered long-term safety follow-up through GeNeSIS, identified in the record as NCT01088412, independent of this study.

The registry lists the trial status as completed, with a start date of 2006-06 and primary completion of 2015-07. These record-level dates do not by themselves describe the duration of treatment received by each participant or the completeness of follow-up. The primary endpoint timeframe is baseline through end of study (up to 9 years). The record does not report the randomization method, allocation concealment, detailed schedules, or the statistical plan. Those details should not be inferred from the phase, allocation, or masking fields.

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.

Study Period 1 Treatment

Reasons for not completing this period:

Study Period 2 Long Term Follow-Up

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who received at least one dose of study drug in Period 1 and all participants who entered Period 2 (safety population).

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 full analysis set (FAS) includes all data from all randomized patients receiving at least one dose of the study drug according to the treatment to which the patients were assigned and with at least one follow-up visit.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With One or More Drug-related Adverse Events, measured over Baseline through End of Study (up to 9 years).

The primary endpoint is the number of participants with one or more drug-related adverse events. It is a count of participants meeting the event definition, rather than a measure of height or a count of every event occurrence. The timeframe runs from baseline through end of study (up to 9 years), and the stated population includes participants who received at least one dose in Period 1 and all participants who entered Period 2.

The registry definition includes an adverse event that occurred after dosing, or one present before dosing that became more severe after dosing, when considered related to study treatment. This kind of endpoint is used to describe the occurrence of potential treatment-related harms during the specified follow-up. Its interpretation depends on the event definition, observation period, and population included.

The record also lists secondary outcomes concerning height velocity, height SDS, adult height relative to target or baseline measures, normal adult height SDS, and bone age. These outcomes do not replace the named primary safety endpoint. The registry record does not report a single primary-outcome comparison or a numerical estimate with uncertainty, so the relative frequency of participants meeting the endpoint cannot be assessed from the stated primary outcome information alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant-count endpoint represent? The primary outcome is a count of participants with one or more drug-related adverse events. In general, this kind of endpoint records whether a participant met a defined event criterion during a stated observation period. A participant with several qualifying events may still be represented as one participant in an endpoint defined this way. That distinction matters because a count of affected participants and a count of event occurrences answer different questions. The registry record defines relatedness and gives the timeframe, but it does not provide a single comparison of this endpoint between the arms.

What does randomization contribute? In general, random assignment is intended to make treatment groups comparable at the start of a study, on average, with respect to both measured and unmeasured characteristics. It supports a comparative interpretation when allocation, follow-up, outcome measurement, and analysis are adequately reported. The registry identifies this trial as randomized and parallel-group, but does not report the randomization procedure, allocation concealment, or a complete analysis for the primary outcome. Those unreported details should not be filled in by assumption.

How should uncertainty be expressed? In general, a point estimate describes the observed comparison, while a confidence interval describes the range of values reasonably compatible with the data under the model and assumptions used. A wide interval indicates limited precision; a narrow interval indicates greater precision, though it does not remove possible bias or problems with outcome measurement. No primary-endpoint estimate or confidence interval is reported in the registry record, so the magnitude and precision of the primary comparison cannot be evaluated from it.

What does a p-value contribute? In general, a p-value measures how incompatible the observed data are with a specified null model, under the statistical assumptions used. It is not the probability that the null hypothesis is true and does not measure clinical importance. The record does not report a primary-outcome p-value or a corresponding comparison. A p-value should not be inferred from event counts alone, and no unreported test should be reconstructed as if it were the sponsor's analysis.

Why can event categories complicate analysis? In general, several categories, time points, or outcome definitions can create multiple possible comparisons. Selecting one result after examining many can increase the chance of a seemingly notable finding arising by chance. Statistical methods for handling multiplicity may include prespecified testing sequences or adjustment procedures, but the registry record does not report such a plan. The primary outcome is explicitly not reduced to one comparison because it has several categories or time points. Therefore, a single inferential conclusion cannot be recovered from the record's primary outcome description.

How do the safety counts differ from the primary endpoint? The separate adverse-event figures list serious events and other events, whereas the primary endpoint counts participants with one or more events considered related to study treatment. The description says the summary of other nonserious events and all serious adverse events, regardless of causality, is in the reported adverse events section. In general, relatedness, seriousness, and event type are distinct classifications. They should not be treated as equivalent or combined without knowing their definitions, overlap, and analysis populations.

How should planning illustrations be read? In general, a sample-size calculation asks how many participants would be needed under specified assumptions to detect a chosen effect with a stated power and significance level. The registry record describes planning illustrations based on fractions of an observed effect, equal allocation, a two-sided significance level of 0.05, and a normal approximation. Such illustrations are hypothetical planning scenarios, not observed power and not evidence that the completed trial had a particular probability of detecting an effect. Their assumptions do not constitute the trial's original design justification, which is not reported in the registry record.

For non-time-to-event outcomes, the record's stated planning convention is participants per arm; time-to-event illustrations use a total number of events. These are conventions for interpreting the planning displays, not observed trial outcomes. The record does not report an interim-analysis plan, a sample-size justification, or a full statistical analysis plan. General concepts explain how such methods work, but they do not supply missing trial-specific analyses.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome has several categories or time points and is not reduced to one comparison in the registry record. That limits interpretation: without a prespecified primary contrast, the reader cannot identify one reported estimate as the decisive statistical result. In general, multiple comparisons can inflate the chance of a false-positive finding if results are selected or tested without an appropriate plan. The registry record does not report whether multiplicity was controlled, which outcomes were grouped into the categories, or how any adjustment was performed.

The record lists nine outcome measures and zero analyses. It does not report a complete primary-outcome estimate, confidence interval, or p-value. This does not establish that no analyses were conducted; it means the registry record does not present analyses in a form available for interpretation. The statistical analysis plan, any interim analyses, and the sample-size justification are not reported in the registry record.

The safety population is defined as participants who received at least one dose in Period 1 and all participants who entered Period 2. The record does not give outcome-specific denominators for the primary endpoint, details of missing observations, or methods for handling missing data. Period 2 follow-up pathways also differed in the summary: participants from France were asked to participate in Period 2, while participants from the Netherlands were offered follow-up through GeNeSIS, independent of this study. The registry record does not explain how this affected inclusion in each analysis.

In general, missing data can affect estimates when the probability of having an observed outcome is related to treatment or participant characteristics. Without reasons for missingness, analysis populations, and sensitivity analyses, the direction and extent of any effect cannot be assessed. No conclusion about the completeness or bias of the trial's analyses should be drawn beyond what the registry record reports.

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: appendicitis (4.4%), congenital genital malformation (2.2%), gastroenteritis (2.2%), viral infection (2.2%), agitation (2.2%).

The registry lists serious-event figures separately for the two treatment groups. For somatropin and leuprorelin, 12 participants were affected among 46 at risk; for somatropin, 7 participants were affected among 45 at risk. It also lists other-event figures: 41 among 46 at risk in the combination group and 36 among 45 at risk in the somatropin group. These are descriptive counts, not a single adjusted or inferential comparison.

The record lists serious-event terms including appendicitis (4.4%), congenital genital malformation (2.2%), gastroenteritis (2.2%), viral infection (2.2%), agitation (2.2%), and intentional self-injury (2.2%). The record does not identify in this summary which treatment group each listed term belongs to. The percentages should therefore be read as entries in the registry's serious-event listing, not as a basis for comparing arms.

The primary endpoint concerns participants with one or more drug-related adverse events, while the record says all serious adverse events are summarized regardless of causality. Seriousness and treatment relatedness are different classifications. The listed safety counts do not establish the primary-endpoint result, and the record does not state whether event categories overlap. They should not be summed or interpreted as mutually exclusive groups. No causal conclusion about treatment follows from these descriptive entries alone.

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

The registry record establishes that a randomized, parallel-group trial compared somatropin plus leuprorelin with somatropin alone in pubertal children with idiopathic short stature. It also describes a primary safety endpoint based on participants with one or more drug-related adverse events over a long follow-up timeframe, and lists separate serious and other adverse-event counts. These details help define the research question and the type of safety information recorded.

The record does not report a single numerical comparison for the primary endpoint. As a result, readers cannot determine from this record how the arms compared on that endpoint, how precise an estimated difference might be, or whether a statistical test indicated evidence of a difference. The serious-event counts are not a replacement for the primary endpoint because the endpoint definitions differ, including the role of treatment relatedness.

The trial's completed status is not equivalent to a complete registry presentation of every analysis. Nor does the presence of counts establish that all relevant outcomes were observed for all participants. The record does not report outcome-specific analysis populations, missing-data methods, a detailed statistical plan, or a multiplicity approach. These gaps prevent a fuller assessment of the evidence and its uncertainty.

In general, a randomized comparison can be informative when outcomes and analysis methods are reported clearly, but a study design alone does not establish an outcome. The available entries describe what was planned and some recorded safety information; they do not justify a claim that one treatment works better, is equivalent, or has no effect. They also do not support medical advice. Interpretation should remain confined to the registry information and its reporting limitations.

13. Why This Trial Matters Statistically

This trial is statistically notable because its central question concerns a safety endpoint with follow-up extending from baseline through end of study (up to 9 years), while the study course was altered. The registry summary says treatment stopped in January 2012 at the request of the French drug agency and that a protocol amendment divided the study into two periods. Participants in France were asked to take part in the long-term follow-up, while participants in the Netherlands were offered follow-up through a separate study. Such changes make it especially important to know which participants contributed data to each outcome and how follow-up was analyzed.

The record also illustrates the difference between a defined endpoint and a reported treatment-effect estimate. Naming the number of participants with one or more drug-related adverse events gives the endpoint's general meaning, but does not provide the arm-to-arm comparison needed to assess magnitude or precision. Separate serious and other event counts cannot answer the same question automatically, especially where relatedness and seriousness are distinct classifications.

For clinical researchers and biostatisticians, this is a reminder that interpretation depends not only on trial design but also on transparent reporting of populations, missing data, outcome definitions, multiplicity, and uncertainty. The record reports randomization and a parallel model, yet does not provide a single primary-outcome analysis. Planning illustrations, if consulted, should be treated as assumption-based scenarios rather than evidence of the trial's achieved power. The available information therefore supports careful description of the trial and its reporting, not an efficacy conclusion.

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 registry record does not report a single comparison for the primary endpoint, which is described as having several categories or time points. It lists zero analyses, and does not give a primary-outcome estimate, confidence interval, or p-value. This is the central limitation for interpreting the trial statistically: the named primary endpoint cannot be evaluated as a comparative result from the record.

The record gives an enrollment value of 91 but does not report arm-specific enrollment or outcome-specific denominators for the primary endpoint. It defines a safety population involving Period 1 dosing and Period 2 entry, but does not report how many participants contributed to each period or outcome. It also does not describe missing observations, reasons for missingness, or methods used to address them.

The treatment interruption and protocol amendment are relevant to interpretation. The summary says treatment stopped in January 2012 at the request of the French drug agency and describes different follow-up pathways for participants from France and the Netherlands. The registry record does not explain how these changes affected exposure, follow-up completeness, or analyses. The randomization procedure, allocation concealment, detailed treatment schedule, multiplicity strategy, interim analyses, and statistical analysis plan are also not reported.

Finally, serious and other adverse-event counts are descriptive entries and do not substitute for the primary drug-related endpoint. The record does not clarify overlap among event categories or assign each listed serious-event term to an arm in the summary. These limitations restrict conclusions to what is explicitly recorded and prevent a fuller assessment of treatment effects or precision.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Somatropin + Leuprorelin vs Somatropin Alone in Pubertal Children With Idiopathic Short Stature — NCT00355030.
• Registry record last updated 2019-09-30; status last verified 2019-09.
• Results first posted 2016-10-18.
• 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

NCT00355030 is listed as a completed, randomized, parallel-group phase 3 trial with no masking. It compared somatropin plus leuprorelin with somatropin alone in pubertal children with idiopathic short stature. The registry reports enrollment of 91, a start date of 2006-06, and primary completion of 2015-07.

The primary outcome is the number of participants with one or more drug-related adverse events over baseline through end of study (up to 9 years). Treatment stopped in January 2012 at the request of the French drug agency, and a protocol amendment divided the study into two periods. The registry lists serious and other adverse-event counts, but does not provide a single primary-outcome comparison. It also does not report a complete statistical analysis, analysis populations by outcome, or missing-data methods. The record therefore supports a description of the design and reported safety entries, but not a comparative conclusion about the primary endpoint.