Open-label Extension Study to Evaluate the Safety of Long-term Twice-monthly Administration of Somavaratan in Adult Growth Hormone Deficiency (AGHD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open-label Extension Study to Evaluate the Safety of Long-term Twice-monthly Administration of Somavaratan in Adult Growth Hormone Deficiency (AGHD) (NCT02719990), a na phase 2 study. The primary outcome is Number of Participants With Adverse Events (AEs).

2. Clinical Question

The trial’s focus was the safety of long-term twice-monthly somavaratan administration in adults with growth hormone deficiency. Its primary outcome was the number of participants with adverse events, including events regardless of whether they were considered related to study drug. The registry definition includes medical occurrences that develop or worsen during the study; an event did not need to have a causal relationship to the drug to count.

The study was open-label and had one treatment group. It therefore describes events among participants who received somavaratan, rather than estimating a difference between somavaratan and another treatment or a control condition. Without a comparator, the counts cannot establish how event occurrence compares with what would have happened under another treatment or without study treatment.

The record also lists secondary outcomes concerning dose levels and adjustments, anti-drug and neutralizing antibodies, and IGF-I and IGFBP-3 measures. Numerical analyses for those outcomes are not reported in the registry record. The trial status is terminated; the reason for termination is not reported in the registry record.

3. Trial Design

This was a phase 2, open-label, long-term extension study of somavaratan in adults with growth hormone deficiency. The study used a single-group model, with no allocation to multiple treatment arms and no masking. Its stated purpose was to evaluate the safety of long-term twice-monthly administration. Somavaratan was administered subcutaneously.

The registry lists enrollment of 36, and the safety population included all participants who received any amount of study drug. The primary outcome timeframe ran from the first dose up to approximately 2 years. The registry dates the study start to 2016-02-11 and primary completion to 2018-01-11. The study status is terminated. The reason for termination is not reported in the registry record, so the status alone does not explain whether or how study conduct or follow-up changed.

Because the study was open-label, participants and study personnel were not masked to treatment. In a single-group extension, the main descriptive evidence is the experience of participants who received the study drug. There is no like-for-like control group in the design, so observed event counts cannot be used as a direct treatment-versus-control contrast.

The listed secondary outcomes include average dose level during titration or maintenance, participants with dose adjustments, participants positive for anti-drug antibodies or neutralizing antibodies, and IGF-I and IGFBP-3 measures during maintenance. Numerical analyses of these outcomes are not reported in the registry record. The registry record does not report a sample-size justification, interim analyses, or a detailed statistical analysis plan.

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: The study was open to participants completing a Versartis adult growth hormone deficiency (GHD) study (15VR7 \[NCT02526420\]) as well as new somavaratan naïve participants (either recombinant human growth hormone \[rhGH\] treatment naïve or receiving daily rhGH therapy).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population included all participants who received any amount of study drug.

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 population included all participants who received any amount of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events (AEs), measured over From first dose of study drug up to approximately 2 years.

The primary outcome is the number of participants with adverse events, measured in participants. Its timeframe is from the first dose of study drug up to approximately 2 years. An adverse event was defined as an untoward medical occurrence that develops or worsens during the study, whether or not it has a causal relationship to study drug. Serious adverse events included events such as death, life-threatening events, inpatient hospitalization or prolonged hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, or another important medical event requiring intervention to prevent one of those outcomes.

Counting participants with events is a way to describe how many people in the safety population experienced an event during the specified observation period. This endpoint is useful for summarizing safety experience, but a count alone does not describe the timing, duration, severity, or recurrence of events. Nor does it by itself establish whether the study drug caused an event. The registry directs readers to its reported adverse-events module for the summary of serious and non-serious events regardless of causality. A treatment comparison would require a suitable comparator and an analysis that accounts for the study design; this trial had a single group.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count describe?

In general, a participant count records how many people met an outcome definition during a specified observation period. It is different from an event count: one participant can have more than one event, while a participant-level outcome ordinarily counts that person once for the relevant definition. The primary outcome is expressed in participants and covers adverse events from the first dose up to approximately 2 years. The record does not provide a numerical analysis beyond the adverse-event counts listed in the registry.

A count is easiest to interpret when its population, outcome definition, and observation period are clear. Here, the safety population included everyone who received any amount of study drug, and the adverse-event definition included medical occurrences that developed or worsened during the study regardless of causal relationship. This makes the counts a description of events recorded in that treated population. The count does not, by itself, indicate why an event occurred.

Why does the single-group design matter?

In general, a comparator provides a reference for judging whether outcome experience differs between treatment conditions. This study had a single group and no like-for-like control comparison. Its adverse-event counts therefore describe the somavaratan group; they do not estimate a treatment effect relative to another group. Comparisons with unrelated populations or studies would require careful consideration of differences in participants, follow-up, event definitions, and methods. Such comparisons are not reported in the registry record.

Open-label means the study was not masked. In general, knowledge of treatment assignment can affect reporting, assessment, or recording of outcomes, particularly when judgments are involved. That possibility is a design consideration, not evidence that any particular event was misclassified in this study. The registry record does not report additional methods to assess or adjust for such effects.

What do the serious-event categories tell readers?

Seriousness is a classification based on event consequences or the need for medical intervention, as described in the registry definition. It is not the same as causality: a serious event need not have been caused by the study drug. The adverse-event module reports serious and non-serious events regardless of causality. The listed serious-event counts and terms are descriptive; they do not provide a comparative test or establish a causal relationship.

In general, a confidence interval expresses uncertainty around an estimate under the assumptions of the method used. It is not a guarantee that the true value lies within a particular interval. No confidence intervals are reported for the listed outcomes, and the record reports zero analyses. Thus, the precision of the adverse-event counts cannot be evaluated from a posted interval or model-based estimate. A count alone also does not describe variation in risk across participants or the timing of events.

What is not available about the analysis?

The registry record does not report a detailed statistical analysis plan, interim analyses, or a sample-size justification. Those omissions mean readers cannot determine from the record whether analyses were planned around particular comparisons, how missing observations were to be handled, or what inferential procedures were intended. The record lists seven outcome measures and zero analyses, so numerical results for the listed secondary measures are not available for interpretation.

General planning illustrations can describe how a hypothetical study might be sized under stated assumptions, but they are not observed power and do not replace an analysis of trial results. This trial had no randomized comparator, and the registry record does not report a sample-size justification. Any planning calculation should therefore not be read as a result from this study or as evidence that the study was powered to detect a particular difference.

Over-dispersion is a general issue for count data when variation exceeds what a simple model assumes. In such cases, a model that assumes too little variation can understate uncertainty. This is a general statistical consideration, not a reported feature or analysis of this trial. The primary outcome is a count of participants with events rather than a rate of recurring events, and the registry record does not report a model-based analysis addressing over-dispersion.

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("Somavaratan")
n      <- c(36)
events <- c(30)
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  Somavaratan  36  30  83.3  67.2  93.6  68.1  92.1  68.0  92.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures, including the primary adverse-event outcome and secondary measures concerning dose, antibodies, IGF-I, and IGFBP-3. It reports zero analyses. Numerical results for the secondary outcomes and inferential tests for the listed outcomes are not reported in the registry record.

Multiplicity is a general concern when several outcomes or comparisons are tested: the more tests performed, the greater the chance that at least one result appears noteworthy by chance. Statistical plans may address this through a prespecified hierarchy or adjustment, but a plan of that kind is not reported in the registry record. With no listed analyses, there are no posted multiplicity-adjusted estimates or tests to interpret.

The registry record does not report how missing data were handled, the extent of missing outcome data, or whether participants with incomplete follow-up were included in particular analyses. The safety population is defined as all participants who received any amount of study drug; this definition does not explain how missing observations within that population were treated. The outcome timeframe extends from first dose up to approximately 2 years, but the record does not provide participant-level follow-up durations or a missing-data analysis.

The registry record also does not report a detailed statistical analysis plan or interim analyses. These omissions limit assessment of whether outcome definitions, analysis populations, and methods were specified before results were examined. They do not establish that a particular method was or was not used; the relevant information is not reported in the registry record.

12. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: adrenal insufficiency (2.8%), diarrhoea (2.8%), bronchitis (2.8%), hyponatraemia (2.8%), polydipsia (2.8%).

The adverse-event record lists 5 participants with serious adverse events, 30 participants with other adverse events, and 0 deaths among the 36 participants in the safety population. It also lists adrenal insufficiency, diarrhoea, bronchitis, hyponatraemia, and polydipsia as serious-event terms, each at 2.8%. These are descriptive registry figures, and the events are reported regardless of causality.

Seriousness is based on the registry’s criteria, including outcomes such as death, life-threatening events, hospitalization, significant disability, congenital anomaly or birth defect, or an important medical event requiring intervention. Seriousness does not mean that an event was caused by study drug. The listed participant counts also do not indicate the number of separate events or whether an individual experienced multiple events. The record does not establish that the serious and other-event participant groups are mutually exclusive, so their counts should not be combined to infer a total number of affected participants.

There was no control group, and no inferential analysis is reported. The counts therefore describe the recorded safety experience in this study; they do not estimate a comparative risk or establish causation. Further event details beyond those listed are not reported in the registry record.

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

The posted adverse-event information provides a descriptive account of safety events recorded among participants who received somavaratan. The registry lists 5 participants with serious adverse events, 30 with other adverse events, and 0 deaths among the 36-person safety population. It also identifies five serious-event terms, each reported at 2.8%. These figures are relevant to understanding what the registry records for this study, but they are not a complete account of every clinical detail or event trajectory.

The findings do not show whether somavaratan caused any particular event. The registry definition explicitly includes adverse events regardless of causal relationship, and the study did not include a control group. The counts cannot establish whether event occurrence differed from another treatment condition or from what would have occurred without study drug. They also do not describe event duration, recurrence, or severity beyond the serious-event classification.

No statistical analyses are listed for the outcomes. There are consequently no posted confidence intervals or hypothesis tests to indicate the precision of an estimated effect or to support a comparative conclusion. Results for the listed secondary outcomes are not reported in the registry record. The absence of such analyses does not mean that no measurements were collected; it means numerical analyses are not available in the registry record.

The study status is terminated, but the reason is not reported in the registry record. The status alone does not explain the safety counts, the reason for ending the study, or the completeness of follow-up. The appropriate reading is limited to the recorded design and posted outcomes: a single-group safety description, not a controlled assessment of treatment effect.

14. Why This Trial Matters Statistically

This trial illustrates an important distinction in clinical statistics: a safety description and a comparative treatment-effect analysis answer different questions. A single-group study can record adverse events among people who received a study drug, but without a comparator it cannot estimate how those outcomes differ from another treatment condition. The design and the available analyses therefore determine what conclusions the posted data can support.

The record also makes clear why outcome definitions matter. The primary outcome counts participants with adverse events during a stated timeframe, and the definition includes events regardless of causal relationship. Seriousness is separately defined by the consequences or intervention associated with an event. Keeping those concepts distinct prevents a count of serious events from being interpreted as a count of events proven to be drug-related.

For statisticians and clinical researchers, this is also a useful example of how registry completeness affects interpretation. The registry lists outcome measures but reports zero analyses. It does not report a detailed statistical analysis plan, sample-size justification, missing-data methods, or interim analyses. Readers can describe the counts that are posted, but cannot assess inferential precision or the handling of unreported analytic details from the record.

The terminated status is another record feature that calls for restraint: without a reported reason, it cannot be treated as evidence of a particular safety or efficacy conclusion. Overall, the study matters statistically as a case where design, outcome definitions, and reporting boundaries shape interpretation as much as the numerical counts do.

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 single-group, open-label design is the central limitation for interpreting outcomes comparatively. There is no like-for-like control group, so the registry counts cannot estimate a treatment-versus-control difference. Open-label conduct also means masking was absent; the registry record does not describe additional safeguards or analyses addressing possible effects of unmasked assessment.

The primary outcome is a participant count, which does not convey event timing, duration, recurrence, or the number of events per person. The record lists serious and other adverse-event participant counts but does not establish whether those categories are mutually exclusive. The five serious-event terms are reported at 2.8% each, but further details about the events are not reported in the registry record.

The registry reports zero analyses. It does not provide confidence intervals or hypothesis tests for the outcomes, numerical analyses for the listed secondary measures, a detailed statistical analysis plan, interim analyses, a sample-size justification, or methods for handling missing data. The registry record does not describe participant-level follow-up or the completeness of outcome data. The reason for the terminated status is also not reported in the registry record.

These limitations constrain what can be inferred from the posted record. They do not establish that unreported procedures were not used or that the study had a particular follow-up problem. They mean that the relevant details are not reported in the registry record and that interpretation should remain descriptive.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Open-label Extension Study to Evaluate the Safety of Long-term Twice-monthly Administration of Somavaratan in Adult Growth Hormone Deficiency (AGHD) — NCT02719990.
• Registry record last updated 2023-04-13; status last verified 2023-03.
• Results first posted 2023-04-13.
• 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

This phase 2 study evaluated long-term twice-monthly somavaratan in adults with growth hormone deficiency. It was open-label and single-group, with subcutaneous administration and no comparator. The registry lists enrollment of 36 and a safety population of 36 participants who received any amount of study drug. The study started on 2016-02-11, had primary completion on 2018-01-11, and is listed as terminated.

The primary outcome was the number of participants with adverse events from first dose up to approximately 2 years. The adverse-event record lists 5 participants with serious adverse events, 30 with other adverse events, and 0 deaths. Five serious-event terms are listed, each at 2.8%. The registry lists seven outcome measures and zero analyses. Numerical analyses for secondary outcomes, the reason for termination, and several statistical planning and analysis details are not reported in the registry record.