Treatment of Children and Adolescents With Growth Failure Associated With Primary IGF-1 Deficiency: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of Children and Adolescents With Growth Failure Associated With Primary IGF-1 Deficiency (NCT00330668), a na phase 3 study. The primary outcome is Height Velocity During BID Dosing Period.

2. Clinical Question

The study addressed continued treatment with recombinant human insulin-like growth factor-1 (rhIGF-1), also called mecasermin, in children and adolescents with growth failure associated with primary IGF-1 deficiency. It was an extension study to Tercica study MS301 (NCT00125164), intended to collect long-term safety and efficacy data. The secondary objective was to explore the relationship between IGF-1 exposure, normal growth and pubertal development.

3. Trial Design

This was a Phase 3, single-group, open-label extension study. The official title identifies it as a multi-center study. The registry lists allocation as NA and masking as NONE; it does not describe a randomized allocation or a masked treatment comparison. The study was intended to continue rhIGF-1 treatment after MS301 and to collect long-term safety and efficacy information.

The registry reports enrollment of 114. The study start is listed as 2005-11, and primary completion as 2010-02. Its status is TERMINATED. The reason for termination, the timing of the termination decision and its relationship to completion of follow-up are not reported in the registry record. The record does not establish whether all enrolled participants completed the planned observation period.

All subjects entering MS306 began rhIGF-1 BID treatment. The starting dose was based on the dose at completion of MS301. The arm description begins to identify subcutaneous doses of 40, 80, or 120 micrograms, but its text is cut off; the complete dosing description and any subsequent dose changes are not reported in the registry record. The primary endpoint description says that subjects completing each year of BID treatment were used for the corresponding annual height-velocity period.

The record describes a modified Intent-To-Treat (MITT) population that included participants from the ITT population randomised to 120 μg/kg rhIGF-1 BID in MS301 or MS306. It also says that subjects in the 80 μg/kg group were not analysed for efficacy because of variations in dose regimen and duration, but the explanation is incomplete. A full protocol, detailed statistical analysis plan and sample-size justification are not reported in the registry record. The study is an extension, not a controlled trial of continued rhIGF-1 against an untreated or alternative-treatment group.

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: As subjects entered MS306 whilst MS301 was continuing, dosages were adjusted in MS306 after MS301 data became available. Baseline study data for MS306 were taken from the data collected for Visit 9 (Month 12) of study MS301.

BID Dosing Period

Reasons for not completing this period:

QD Dosing Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The modified Intent-To-Treat (MITT) population included subjects from the ITT population who were randomised to 120 μg/kg rhIGF-1 BID (either in MS301 or MS306). The subjects in the 80 μg/kg group were not analysed for efficacy due to the variations in their dose regimen and the duration of the regimen.

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 Height Velocity During BID Dosing Period, measured over At Years 1, 2 and 3 in BID dosing period..

Height velocity is the rate of change in standing height, expressed in centimetres per year (cm/year). The registry says height was measured without shoes as the average of 3 measurements by the same observer using an identical technique and a Harpenden or other wall-mounted stadiometer. It defines annualized height velocity as the difference in height between two dates divided by the difference in age between those dates.

The endpoint was assessed during the BID dosing period at Years 1, 2 and 3. The record describes Year 1 as 0-1 years, Year 2 as 1-2 years and Year 3 as 2-3 years, and says height velocity is presented for subjects completing each year of BID treatment. The numerical means, standard deviations, confidence intervals and analysis counts for these periods are not reported in the registry record.

As a general statistical matter, height velocity expresses growth over time in a common rate unit, which can make measurements from intervals of different lengths easier to interpret. An annualized rate is not itself a direct measure of final adult height, and a rate recorded during an interval does not establish what happens after that interval. The registry also lists changes in height SD score, BMI SD score, bone age and predicted adult height as secondary outcomes. Their numerical results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a continuous primary outcome summarized as a mean, with standard deviation as the stated measure of dispersion. It does not report the numerical mean, standard deviation, confidence interval or analysis count for the primary endpoint. The following explanations are general statistical context, not descriptions of an analysis that the registry confirms was conducted.

What does a mean describe?

For a continuous measure such as height velocity, the mean is an average of the observations included in an analysis. It gives a central summary, but it does not show how widely individual values vary or whether the observations are concentrated near the mean. The mean depends on which participants contribute data and which time period is summarized. Because the registry describes annual values for participants completing each year, the number and characteristics of participants contributing at each period would be relevant to interpretation. Those analysis counts and participant-level distributions are not reported in the registry record.

What does the standard deviation describe?

In general, a standard deviation describes the spread of individual observations around their mean. It is different from the standard error, which concerns the precision of an estimated mean. A standard deviation is useful for understanding variability among participants, but it does not, by itself, show how precisely a treatment effect has been estimated. The record names standard deviation as the primary outcome’s dispersion measure but does not report its value.

How is height velocity calculated?

The registry defines annualized height velocity as the change in height divided by the change in age over the interval, with height expressed in centimetres so that the result is in centimetres per year. Height was measured standing and without shoes, using the average of 3 measurements by the same observer and an identical technique. This definition describes how the rate is derived; it does not provide the observed rates. The record says results were intended for participants completing each annual BID-treatment period, which makes completion and availability of measurements important to the interpretation of each time-specific summary.

What does a confidence interval add?

As a general statistical concept, a confidence interval expresses uncertainty around an estimated quantity under the assumptions of the method used to calculate it. It is not a range containing a known proportion of individual participant values, and it does not correct for bias from missing data, lack of a control group or other design limitations. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed from the posted information.

Why does the study design matter?

General statistical interpretation of a single-group study differs from interpretation of a randomized comparison. In a randomized comparison, groups can provide a basis for estimating a between-group contrast, subject to the study’s conduct and analysis. In this single-group extension, the record identifies continued rhIGF-1 treatment but no concurrent control arm. An observed mean or change in this setting would describe the participants measured; it would not, by itself, estimate a causal difference against an alternative. The record does not report a comparator-based effect estimate.

What can be inferred from the analysis-population description?

The primary endpoint description refers to a modified Intent-To-Treat population drawn from the ITT population and identifies participants randomised to 120 μg/kg BID in MS301 or MS306. It states that the 80 μg/kg group was not analysed for efficacy because of variations in dose regimen and duration, but the registry text is incomplete. The full definition, the handling of participants outside the described dose group and the analysis set used for each annual endpoint are not reported in the registry record. These details matter because a population definition determines which observations contribute to a summary.

What do the planning illustrations mean?

General sample-size calculations are planning exercises, not observed trial findings. The registry’s stated illustration assumptions are 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. It says that continuous-outcome illustrations are expressed as participants per arm. Such assumptions do not describe this single-group extension’s enrollment plan and cannot replace a trial-specific justification. The trial’s own sample-size justification is not reported in the registry record. Numerical planning values and the observed effect used for those illustrations are not reported in the record.

For this study, the most important methodological boundary is the distinction between a clearly defined endpoint and a reported result. The record gives a measurement procedure and formula, but without endpoint estimates, dispersion, analysis counts or missing-data methods, readers cannot independently evaluate the numerical outcome or its precision.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists height velocity as the primary outcome and also names changes in height SD score, BMI SD score, bone age and predicted adult height as secondary outcomes. The registry lists 5 outcome measures and zero analysis records. Numerical results for the primary and secondary outcomes are not reported in the registry record.

When a study examines multiple outcomes or multiple time points, general statistical interpretation must account for the possibility that testing many hypotheses can increase the chance of finding an apparently notable result by chance. Methods to address multiplicity can include a prespecified hierarchy or adjustment of statistical testing. Whether any such method was planned or used in this study is not reported in the registry record. The record also does not report p-values or a testing hierarchy for the primary and secondary outcomes.

The primary endpoint description gives annual periods at Years 1, 2 and 3, but it does not report the number analysed at each period or how missing measurements were handled. The reason for missing observations, rules for excluding measurements, imputation methods and sensitivity analyses are not reported in the registry record. These omissions prevent assessment of whether the available annual summaries might be affected by incomplete follow-up or selective availability of measurements.

The registry gives a partial description of the MITT population and says the 80 μg/kg group was not analysed for efficacy owing to dose-regimen and duration variations. The complete population definition and its relation to the primary endpoint analysis are not reported in the registry record. A statistical analysis plan, interim-analysis plan and sample-size justification are also not reported. These items should not be inferred from the endpoint description or the study’s status.

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: appendicitis (0.9%), cholelithiasis (0.9%), forearm fracture (0.9%), hypoglycaemia (0.9%), otitis externa (0.9%).

The registry reports serious adverse events for the group titled All rhIGF-1 Subjects. It lists 114 subjects at risk for serious adverse events and 6 affected. The listed serious-event terms are Appendicitis, Cholelithiasis, Forearm Fracture, Hypoglycaemia, Otitis Externa and Pneumonia, each reported as 0.9%. The record does not give event-specific counts alongside those terms, so they should be read as the reported terms and percentages rather than used to reconstruct counts.

For other adverse events, the record lists 114 subjects at risk and 107 affected. It reports 0 deaths. The broad “other” category should not be treated as a severity grade or as a count of serious events; the registry presents it separately from serious adverse events. The record does not provide further details about event definitions, duration, exposure-adjusted rates, relationship to treatment, severity grading beyond the serious-event classification or how recurrent events were handled.

These figures are descriptive safety counts in a single treated group. They do not establish that treatment caused any particular event, and the absence of reported deaths does not establish the absence of other risks. With no concurrent comparator and no further event-level context reported in the registry record, comparative safety rates cannot be assessed from these figures alone.

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

The record establishes that this was an open-label, single-group extension study of continued rhIGF-1 treatment in children and adolescents with growth failure associated with primary IGF-1 deficiency. It identifies height velocity during BID dosing as the primary endpoint, gives a measurement procedure and specifies annual periods. It also reports the enrollment, study status and descriptive adverse-event figures.

It does not report the numerical primary endpoint results or numerical results for the listed secondary outcomes. Without those estimates and their variability, the magnitude and precision of the measured growth outcomes cannot be assessed from the registry record. The record also does not report the number analysed at each time point or the handling of missing observations, both of which are relevant to interpreting a longitudinal outcome.

The single-group design does not provide a concurrent control comparison. As a general statistical principle, a change observed during follow-up cannot by itself separate a treatment-associated change from other influences that may occur over time. The registry record therefore does not support a randomized comparative estimate of continued rhIGF-1 versus another treatment or no treatment.

The safety information describes affected participants and listed serious-event terms in the treated group. It is not a comparative safety analysis, and the registry does not report enough detail to attribute individual events to treatment. The reported zero deaths is a descriptive entry, not evidence that there were no other safety concerns.

The record’s TERMINATED status should be distinguished from an explanation of why the study ended. The reason for termination and its effect on data collection are not reported. The study’s stated aims and endpoint definitions can be understood, but the registry information does not permit a conclusion about the size, precision or comparative meaning of the primary outcome.

13. Why This Trial Matters Statistically

This study is statistically notable as a long-term extension rather than a conventional concurrent-group comparison. Its stated purpose was to collect information on continued rhIGF-1 use after MS301, with attention to safety, efficacy and the relationship between IGF-1 exposure, growth and pubertal development. Extension studies can address follow-up questions that are difficult to frame as a short-term comparison, but interpretation depends on who remains under observation and how outcomes are analysed.

The primary endpoint is a rate derived from repeated height measurements. The record’s measurement description and annualization formula make clear what the endpoint is intended to represent. That definition is useful for interpreting the measurement, but it is not a substitute for numerical estimates, dispersion, analysis counts or information about incomplete follow-up. Those results are not reported in the registry record.

The design also highlights the difference between documenting outcomes during treatment and estimating a comparative treatment effect. With no concurrent control group, the record does not provide a randomized comparison for continued treatment. The listed safety counts likewise describe one treated group rather than a contrast in risk between groups.

For biostatistical readers, the record is a reminder to examine the analysis population and time-specific availability of data in extension studies. The endpoint description refers to participants completing each annual period and gives a partial MITT definition, while the full analysis details are not reported. The study status is TERMINATED, but the reason and any resulting changes to follow-up are not reported. These gaps limit what can be established statistically from the registry record, independently of the clinical importance of the research question.

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 principal limitation for interpreting outcomes is that numerical results for the primary endpoint are not reported in the registry record. Although the endpoint is described as a mean with standard deviation and is defined for annual periods, the record does not give the estimated values, their uncertainty or the number of participants contributing at each period. Numerical results for the listed secondary outcomes are also not reported.

The study was single-group and open-label, with no concurrent comparator. It therefore cannot supply a randomized between-group contrast within this extension. The record does not describe methods to account for changes over time or other potential influences on observed growth measurements. Any causal interpretation of an observed change would require evidence beyond the design information and outcome definitions recorded.

The primary endpoint description says that results are presented for subjects completing each annual BID-treatment period. It does not explain how participants who did not complete a period were handled, whether measurements after discontinuation were included, or how missing observations were addressed. The reason for missing data, if any, is not reported in the registry record.

The description of the MITT population is incomplete, and the explanation for excluding the 80 μg/kg group from efficacy analysis is cut off. Complete eligibility and analysis-population definitions, a statistical analysis plan, multiplicity procedures, interim-analysis details and a sample-size justification are not reported. The record also gives TERMINATED status without a termination reason or an account of its effect on follow-up. These limitations make it difficult to assess selection, analysis choices and the completeness of the outcome record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Treatment of Children and Adolescents With Growth Failure Associated With Primary IGF-1 Deficiency — NCT00330668.
• Registry record last updated 2020-08-14; status last verified 2020-08.
• Results first posted 2011-06-27.
• 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

NCT00330668 is a Phase 3, open-label, single-group extension study of rhIGF-1 for children and adolescents with growth failure associated with primary IGF-1 deficiency. It is described as an extension to MS301 and was intended to collect long-term safety and efficacy information. The registry reports enrollment of 114, a start date of 2005-11, primary completion in 2010-02 and status TERMINATED.

The primary endpoint was height velocity during BID dosing, assessed at Years 1, 2 and 3. The record describes the measurement procedure and annualized calculation. It lists changes in height SD score, BMI SD score, bone age and predicted adult height as secondary outcomes. Numerical efficacy results, uncertainty estimates, analysis counts and missing-data methods are not reported in the registry record.

Safety entries include 6 subjects affected by serious adverse events, 107 affected by other adverse events and 0 deaths. The record does not provide a concurrent control comparison or explain the reason for termination.