An Open-label Phase 4 Study to Explore Immunogenicity of the Liquid Formulation of Saizen® in Subjects With Adult Growth Hormone Deficiency (AGHD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Open-label Phase 4 Study to Explore Immunogenicity of the Liquid Formulation of Saizen® in Subjects With Adult Growth Hormone Deficiency (AGHD) (NCT01806298), a na phase 4 study. The primary outcome is Percentage of Subjects Developing Binding Antibodies (BAbs) to Saizen®.

2. Clinical Question

3. Trial Design

This was an open-label, single-arm, multicenter, Phase 4 trial of the liquid formulation of Saizen® in subjects with adult growth hormone deficiency. The registry lists Merck KGaA, Darmstadt, Germany, as sponsor, enrollment of 78, a start date of 2013-06, primary completion in 2016-03, and status as completed. The trial record describes the intervention as Saizen® solution for injection.

Because the design has a single group, participants were not allocated between competing treatments. Allocation is listed as not applicable, and masking is recorded as none. The trial therefore addresses the occurrence of binding antibodies among people receiving the study intervention, not whether antibody outcomes differ from those under a control treatment. There is no like-for-like control comparison in this design.

The primary endpoint covered baseline up to Week 39. Its analysis population was not simply every person enrolled: the mITT definition required receipt of at least 1 administration and at least 1 post-baseline BAbs assessment. The registry record does not report how many participants met that definition, how many completed follow-up, or how many contributed to the primary endpoint denominator.

Other listed outcomes include the percentage of subjects with BAbs who became positive for neutralizing antibodies (NAbs), IGF-I levels, IGFBP-3 levels, IGF-I standard deviation score, and treatment adherence documented using EasypodTM Connect. Their result estimates and analysis details are not reported in the registry record. The record also does not describe the visit schedule beyond the primary endpoint timeframe, the planned handling of treatment interruptions, or the methods used to collect antibody assessments.

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: The modified Intent-To-Treat (mITT) analysis set included all treated subjects who had received at least 1 administration of Saizen® and had at least 1 post-baseline BAbs assessment.

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 safety analysis set included all treated subjects who had received at least 1 administration of Saizen®.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects Developing Binding Antibodies (BAbs) to Saizen®, measured over Baseline up to Week 39.

The primary endpoint is the percentage of subjects developing binding antibodies (BAbs) to Saizen® from baseline up to Week 39. It measures the proportion of participants in the defined analysis population who had a positive BAbs assessment during the stated period. The registry definition expresses that percentage as the number of BAb-positive subjects divided by the total number of subjects, multiplied by 100.

Immunogenicity studies assess whether an immune response to a therapeutic product is detected. A binding-antibody assessment records antibodies that bind to the product; the endpoint is not itself a measure of clinical benefit or harm. The registry separately lists the percentage of subjects with BAbs who became positive for neutralizing antibodies, which is a distinct secondary outcome. These endpoints should not be treated as interchangeable.

A percentage is useful for describing how commonly an event was observed in the study population. Its interpretation depends on the denominator, the follow-up period, and the antibody assessment process. Here, the stated analysis population includes treated subjects with at least 1 post-baseline BAbs assessment, and the timeframe extends from baseline up to Week 39. The registry record does not report the number of BAb-positive subjects, the endpoint percentage, or the 95% confidence interval. Consequently, the endpoint definition is available, but the magnitude and precision of the observed result cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary percentage represent?

The endpoint is a binary outcome summarized as a percentage. Each subject in the specified population is classified according to whether a positive BAbs assessment occurred during the stated timeframe. The percentage describes the share of the analysis population with that outcome; it does not measure antibody concentration or the strength of an antibody response. This is a general explanation of a percentage endpoint. The registry record defines the numerator and denominator but does not report their values.

The denominator matters because the mITT analysis set is defined by treatment and assessment requirements. A subject had to receive at least 1 administration of Saizen® and have at least 1 post-baseline BAbs assessment. The enrollment of 78 should therefore not automatically be read as the endpoint denominator. The actual mITT size and the number included in the primary analysis are not reported in the registry record.

How should a 95% confidence interval be read?

A confidence interval conveys uncertainty in an estimated quantity. For a percentage, it indicates a range of values compatible with the data and the method used to calculate the interval. It is not a guarantee that the true value lies within the interval, and it does not replace the estimate itself. This is general statistical interpretation. The primary endpoint specifies a 95% confidence interval, but neither its limits nor the corresponding percentage are reported in the registry record.

The width of an interval is affected by the amount of information available and by the variability in the observations. A small analysis population can lead to imprecise estimates, particularly when the outcome is uncommon. That general principle makes the unreported analysis denominator important. No conclusion about the actual precision of this study’s antibody estimate is possible without the denominator and interval.

What does the single-group structure allow?

A single-group study can estimate the frequency of an observed outcome within the participants who were assessed. It cannot provide a randomized estimate of the difference between Saizen® and a comparator, because no comparator group is listed. A before-and-after structure, if measurements are taken at multiple times, would still not by itself separate treatment-related changes from time trends, measurement variation, or other influences. This is a general design point, not a reported result of the trial.

The study is described as open-label, with masking recorded as none. In general, knowledge of treatment assignment can influence some aspects of study conduct or assessment. The extent to which that could affect this endpoint depends on the antibody testing and assessment procedures, which are not described in the registry record. No details about blinded laboratory analysis or assay validation are reported there.

What do planning calculations mean?

Any sample-size illustrations associated with these results are planning examples rather than evidence that the study had a particular power. The stated assumptions for those illustrations 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. The record characterizes the illustrations as based on the observed effect, not as the trial’s own design. They must not be interpreted as an observed power calculation or as evidence that the single-arm study was designed for a two-arm comparison.

The stated two-arm assumptions do not match this trial’s single-group structure. Consequently, such hypothetical calculations do not describe the trial’s actual allocation or provide a basis for judging its design adequacy. The registry record does not report its own sample-size justification or a planned detectable effect. It also does not give numerical results for these illustrations in the registry record described in the record summary, so no planning counts can be stated.

Why do multiple outcomes and event rates need context?

The registry lists several secondary outcomes in addition to the primary antibody endpoint. When several outcomes are assessed, the chance of at least one apparently notable result can increase if each is tested separately. Statistical approaches for addressing multiple testing may include prespecified hierarchies or adjustments; this is general methodology. The registry record does not report a multiplicity strategy, a testing hierarchy, or inferential analyses for the outcomes.

For safety outcomes, a count or percentage describes the number or share of participants with a recorded event under the stated category. It does not by itself establish that the intervention caused the event. Interpretation also depends on event definitions, follow-up, exposure, and the completeness of reporting. The registry lists serious and other adverse-event counts, but does not report comparative safety analyses or detailed event-level narratives. The listed counts should therefore be read as descriptive observations in this study group.

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("Saizen®")
n      <- c(77)
events <- c(0)
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  Saizen®  77  0  0.0  0.0  4.7  0.0  4.8  0.0  4.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary BAbs endpoint and several secondary outcomes: the percentage of subjects with BAbs who became positive for NAbs, IGF-I levels, IGFBP-3 levels, IGF-I standard deviation score, and treatment adherence documented using EasypodTM Connect. Assessing multiple outcomes can raise questions about multiplicity: when many hypotheses are examined, some results may appear notable by chance. This is a general statistical concern. The registry record does not report a multiplicity adjustment, an outcome-testing hierarchy, or the statistical tests used for the secondary outcomes.

The primary population is defined as treated subjects who received at least 1 administration of Saizen® and had at least 1 post-baseline BAbs assessment. This definition clarifies eligibility for the mITT analysis set, but the record does not give its size. It also does not report the number of missing antibody assessments, the reasons for missingness, or whether the analysis used imputation, complete-case methods, or another approach. Missing-data handling is not reported in the registry record.

It is therefore not possible to determine from the record whether participants with incomplete follow-up differed from those with evaluable assessments, or how missing observations might affect the estimated BAbs percentage. The full enrolled group, the treated group, and the primary analysis set are conceptually distinct; their counts are not all reported. No sensitivity analyses for the primary endpoint are reported in the registry record.

The record also does not report interim analyses, stopping rules, or a detailed statistical analysis plan. Their absence from the registry record should not be taken to establish whether such procedures existed elsewhere; their details are not reported in the registry record.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: infection (1.3%), pneumonia (1.3%), iron deficiency anaemia (1.3%), oesophagitis (1.3%), non-cardiac chest pain (1.3%).

The registry safety figures list 78 subjects at risk for serious adverse events and 4 subjects affected. For other adverse events, the figures list 78 at risk and 65 affected. These counts describe events recorded in the study group; they are not a comparison between Saizen® and a control treatment. The categories should be read according to the registry’s serious and other adverse-event groupings, not as evidence of causation.

The listed serious adverse-event terms are Infection, Pneumonia, Iron deficiency anaemia, Oesophagitis, and Non-cardiac chest pain. Each is reported at 1.3%. These term-level percentages should be interpreted as registry descriptions, not as comparative risks. The record does not provide a control group, a detailed account of event timing, or event narratives sufficient to assess causal relationships.

Deaths are not reported in the registry record. This means the available record does not give a death count; it should not be interpreted as evidence that no deaths occurred. The registry record also does not provide additional breakdowns by severity, duration, treatment discontinuation, or participant characteristics. The figures are therefore a limited descriptive account of reported safety events.

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

The study asks a focused descriptive question: what proportion of subjects receiving the liquid formulation of Saizen® developed BAbs during the period from baseline up to Week 39? Its single-arm, open-label design is suited to recording outcomes in the treated group, but it does not support a randomized comparison with a control treatment. The registry record specifies the endpoint and analysis population but does not report the endpoint percentage or its 95% confidence interval.

Without the result, readers cannot determine the observed frequency of BAbs in the study’s primary analysis set or the precision of that estimate. The enrollment figure alone cannot fill this gap, because the endpoint population requires treatment and a post-baseline antibody assessment, and its size is not reported. The listed secondary outcomes likewise do not have reported numerical results in the registry record.

Even if the primary estimate were available, an observed percentage in a single study group would describe the participants and follow-up assessed. It would not establish how the outcome compares with another formulation or with no treatment, because no comparator group is present. Nor would an antibody finding by itself establish a clinical consequence. The trial’s listed outcomes include laboratory measures and adherence, but their relationship to BAbs is not reported.

The safety counts offer descriptive information about events recorded among study participants, including 4 subjects with serious adverse events and 65 with other adverse events among 78 at risk in each category. The listed serious-event terms are reported at 1.3% each. These figures do not establish that treatment caused or did not cause an event, and no comparative safety estimate is available from this single-group design. Deaths are not reported in the registry record.

Accordingly, the posted information describes the purpose, design, endpoint definition, and selected safety observations. It does not provide the primary result or enough statistical detail to quantify its uncertainty, assess missing data, or draw comparative conclusions.

14. Why This Trial Matters Statistically

This trial matters statistically because it illustrates the difference between defining an endpoint and reporting an estimate. The registry record gives a clear primary question: the percentage of the mITT population developing BAbs from baseline up to Week 39. It also defines who belongs to that population. Yet the numerical endpoint result and its 95% confidence interval are not reported in the registry record. Without them, the principal immunogenicity question cannot be quantitatively assessed from the posted information.

The trial also demonstrates why denominators are central to percentage outcomes. Enrollment is 78, while the primary endpoint population requires treatment exposure and a post-baseline assessment. The mITT count is not reported. A percentage without an identifiable analysis denominator is difficult to evaluate, and an enrollment figure should not be substituted for the endpoint population.

Its single-arm design shapes the scope of inference. The study can describe observations among participants receiving Saizen®, but it cannot estimate a randomized treatment contrast. This distinction is especially important when readers encounter a percentage and are tempted to interpret it as a comparative effect. No comparator group is listed, so the trial cannot provide a like-for-like control comparison.

Finally, the registry lists multiple secondary outcomes and safety categories without reporting their analysis methods in detail. Questions about multiplicity, missing assessments, and analysis populations therefore remain open. The record offers enough design information to identify these issues, but not enough results or methods detail to resolve them. The statistical lesson is that endpoint definitions, denominators, uncertainty intervals, and comparator structure all contribute to interpreting a clinical trial result.

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 principal limitation for statistical interpretation is that the primary BAbs percentage and its 95% confidence interval are not reported in the registry record. The mITT analysis set is defined, but its size and the number of BAb-positive subjects are not reported. Thus neither the observed endpoint frequency nor its precision can be assessed from the posted results.

The single-arm, open-label design has no randomized comparator. It can describe outcomes among participants receiving Saizen®, but cannot establish a comparative effect against another formulation or a control condition. The registry record does not report masking, assay procedures beyond the antibody endpoint description, or details of independent laboratory assessment. It also does not give the number completing follow-up or the completeness of endpoint assessments.

Handling of missing data, sensitivity analyses, multiplicity procedures, interim analyses, and the trial’s own sample-size justification are not reported in the registry record. The secondary outcomes are named, but their estimates and statistical analyses are not reported. These omissions limit the ability to evaluate robustness across outcomes and analysis populations.

Safety reporting is also descriptive: the record lists event counts and selected serious-event terms, but no comparator group or detailed event narratives. Deaths are not reported in the registry record. These limitations constrain what can be inferred from the available safety information and do not establish the absence or presence of unreported events.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Open-label Phase 4 Study to Explore Immunogenicity of the Liquid Formulation of Saizen® in Subjects With Adult Growth Hormone Deficiency (AGHD) — NCT01806298.
• Registry record last updated 2017-12-02; status last verified 2017-10.
• Results first posted 2017-04-04.
• 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 NCT01806298 as a completed, open-label, single-arm, multicenter, Phase 4 study sponsored by Merck KGaA, Darmstadt, Germany. It enrolled 78 subjects with AGHD and assessed the immunogenicity of Saizen® solution for injection. The recorded start was 2013-06, and primary completion was 2016-03.

The primary endpoint was the percentage of subjects developing BAbs from baseline up to Week 39, in a modified Intent-To-Treat population defined by treatment exposure and at least 1 post-baseline BAbs assessment. The endpoint result, confidence interval, and analysis-set size are not reported in the registry record. The record lists several secondary outcomes but does not report their results.

Safety figures list 4 subjects with serious adverse events and 65 with other adverse events among 78 at risk for each category. Five serious-event terms are listed at 1.3% each. Deaths are not reported in the registry record. The single-group design provides no randomized comparator, limiting interpretation to descriptive observations in the study group.