A Research Study in Children With a Low Level of Hormone to Grow. Treatment is Somapacitan Once a Week Compared to Norditropin® Once a Day (REAL4): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Research Study in Children With a Low Level of Hormone to Grow. Treatment is Somapacitan Once a Week Compared to Norditropin® Once a Day (REAL4) (NCT03811535), a randomized phase 3 study. The primary outcome is Height Velocity: In-trial Observation Period.

2. Clinical Question

The trial was randomized, open-label, and parallel-group. Treatment assignment was determined by chance, but participants and study doctors knew which treatment was assigned. The comparison is therefore a randomized comparison of two dosing regimens over the main trial period, with height velocity as the primary growth measure. The record describes safety as another study objective and lists several secondary growth and metabolic outcomes.

3. Trial Design

REAL4, registered as NCT03811535, was a randomized phase 3 parallel-group trial in children with growth hormone deficiency. Enrollment was 200. The record lists Novo Nordisk A/S as sponsor and marks the study completed. The study started on 2019-05-20, and primary completion was 2021-11-10.

One group received somapacitan weekly and the other received Norditropin daily for the 52-week main trial period. The trial was not masked: participants and study doctors knew the assigned treatment. This open-label design is relevant when considering outcomes that may involve judgment or participant-reported information. Height measurements are more directly measurable, though the registry record does not describe the measurement procedures in detail.

Participants completing the main period in either arm were to receive weekly somapacitan for a 3-year extension. Thus, the randomized treatment contrast described by the primary endpoint is the comparison during the first 52 weeks; treatment after that period was somapacitan in both extension groups. The brief study description says the study would last for 4 years and describes 19 clinic visits and one phone call with the study doctor.

The primary endpoint was height velocity from baseline (week 0) to visit 7 (week 52), reported in centimeters per year. The primary population is described as the full analysis set, including all randomized participants. The posted endpoint summaries list 68 participants for Norditropin and 132 for somapacitan. The reason for the difference in these group counts, and the handling of missing primary measurements beyond the endpoint description, are not reported in the registry record.

The registry lists 29 outcome measures and 2 analyses. It reports the primary treatment comparison using ANCOVA and labels it as a non-inferiority analysis. The model covariates, non-inferiority margin, and detailed analysis plan are not reported in the registry record. Randomization supports a treatment comparison, while the open-label conduct and incomplete reporting of analysis details limit how fully the results can be evaluated.

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: Participants were randomised (2:1) to receive norditropin or somapacitan until week 52 (main trial period). After week 52 participants received somapacitan until week 208 (Safety extension period). After week 208 (additional extension period), participants who remained on treatment received somapacitan until it becomes available for prescription for children with GHD or September 2025 at the latest.

Main Period (52 Weeks)

Reasons for not completing this period:

Safety Extension Period (Week 52 to 208)

Reasons for not completing this period:

Additional Extensionperiod(afterweek208)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set included all randomized participants.

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: Full analysis set included all randomized participants.

6. Primary Endpoint

The registry lists the primary outcome as Height Velocity: In-trial Observation Period, measured over From baseline (week 0) to visit 7 (week 52).

Height velocity is the rate of change in height over time. For this outcome, the registry defines it using the difference between height at the week 52 visit and height at baseline, divided by the elapsed time in years. The result is expressed in centimeters per year. The endpoint therefore puts growth observed over the trial interval onto a yearly rate scale.

This measure is used to assess growth during the treatment period. A rate can make follow-up intervals more comparable when the elapsed time between measurements is not identical, although the registry does not provide the actual interval for each participant. The primary endpoint is described as an in-trial observation, from first administration through visit 7 or the last trial contact, whichever came first. That definition means the observation window may end before visit 7 for some participants.

The reported group values are means with standard deviations. The mean describes the average observed height velocity within each group; the standard deviation describes variation among participants around that group mean. The endpoint is a continuous measure, so the treatment contrast is expressed as a difference in means. A difference does not by itself establish non-inferiority: that judgment requires a prespecified margin and a decision rule. The margin is not reported in the registry record.

7. Results Posted in the Registry

• Somapacitan: mean 11.20 versus 11.80 on control; difference -0.60 (95% CI -1.41 to 0.21), standardized effect d = -0.23; z-test p = 0.147.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change in Bone Age

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Somapacitan: mean 1.13 versus 1.28 on control; difference -0.15 (95% CI -0.37 to 0.07), standardized effect d = -0.19; z-test p = 0.191.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Somapacitan and the control. The interval gives the range of effects that remain compatible with the data.

Change in Height Standard Deviation Score (HSDS)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Somapacitan: mean 1.21 versus 1.37 on control; difference -0.16 (95% CI -0.35 to 0.03), standardized effect d = -0.27; z-test p = 0.095.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Somapacitan and the control. The interval gives the range of effects that remain compatible with the data.

Change in Height Velocity Standard Deviation Score (HV SDS)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Somapacitan: mean 7.97 versus 8.97 on control; difference -1.00 (95% CI -2.19 to 0.19), standardized effect d = -0.27; z-test p = 0.099.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Somapacitan and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary growth outcomes broadly point in the same direction as the primary estimate: the somapacitan group means are lower than the Norditropin means for the listed changes in bone age, height standard deviation score, and height velocity standard deviation score. Their unadjusted confidence intervals include zero. This pattern is compatible with uncertainty about the size and direction of each difference; it does not independently resolve the primary non-inferiority question.

The registry also lists secondary metabolic outcomes, including fasting plasma glucose at several follow-up weeks and HOMA-B at week 52. The existence of these listed outcomes indicates that the study assessed measures beyond growth, but the record does not provide their numerical results in the material summarized for interpretation. Their findings therefore cannot be characterized from the available record.

Secondary outcomes can help describe different dimensions of a trial, but they usually carry less confirmatory weight when many outcomes are examined without a reported multiplicity strategy. Testing multiple outcomes increases the chance that at least one result appears notable by chance. An unadjusted p-value or interval for an individual secondary endpoint does not account for that broader set of comparisons.

The registry lists 29 outcome measures and 2 analyses, while 27 secondary outcomes are posted. It does not report whether a hierarchy, family-wise error procedure, or other multiplicity approach was prespecified. Secondary findings should therefore be treated as supportive or exploratory descriptions rather than as a collection of independent confirmatory tests. They do not replace the primary endpoint or the sponsor's reported analysis.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change in Bone Age
• Change in Height Standard Deviation Score (HSDS)
• Change in Height Velocity Standard Deviation Score (HV SDS)
• Change in Fasting Plasma Glucose (FPG) at Week 52
• Change in FPG at Week 104
• Change in FPG at Week 156
• Change in FPG at Week 208
• Change in Homeostatic Model Assessment Steady State Beta Cell Function (HOMA-B) at Week 52

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: height velocity is measured in centimeters per year, and the registry reports a mean and standard deviation for each treatment group. For a continuous outcome, a difference in group means expresses how far apart the average observed values are. The sign depends on the comparison direction. In the recalculation, somapacitan is compared with Norditropin, so a negative estimate corresponds to a lower posted mean in the somapacitan group.

What does the sponsor's ANCOVA do?

ANCOVA is a regression-based method for comparing groups while accounting for specified covariates. In a randomized trial, adjustment can improve precision when the chosen covariates explain outcome variation, while preserving a comparison based on randomized assignment when the model is appropriately specified. The registry reports ANCOVA for the sponsor's treatment difference, but does not report which covariates were included, how the model was specified, or how missing measurements were handled. Those details therefore cannot be assessed from the registry record.

The posted recalculation is different: it uses the group means and standard deviations to form a simple unadjusted comparison. It does not reproduce the sponsor's model or its adjustments. The recalculated estimate and interval are useful for understanding the summaries, but they should not replace the sponsor's reported ANCOVA result. The record marks discrepancy as false, so there is no flagged disagreement between the reported and recalculated results; the methods still differ.

How should a confidence interval be understood?

A confidence interval gives a range of values compatible with the data and the assumptions of the analysis at a stated confidence level. It communicates uncertainty around an estimate rather than guaranteeing that the true effect lies inside a particular interval. A narrower interval indicates greater precision; a wider one indicates less precision. Interpretation also depends on the question. For superiority, an interval crossing zero may be consistent with no difference. For non-inferiority, the key comparison is against a prespecified margin, not simply against zero.

The sponsor's result is explicitly labeled non-inferiority. The margin and decision rule are not reported in the registry record. Without them, the interval can be described, but the formal non-inferiority criterion cannot be checked. The registry gives a 95% confidence interval for the sponsor's estimate but no sponsor p-value. The recalculated unadjusted comparison has an unadjusted p-value; that value does not substitute for the non-inferiority analysis.

Why does variability matter?

Standard deviations describe how dispersed individual measurements are around the group mean. When variability is large relative to the treatment contrast, the mean difference is estimated less precisely, all else being equal. The posted primary standard deviations are 2.9 centimeters per year for Norditropin and 2.5 centimeters per year for somapacitan. Sample counts also affect precision: more observations can generally reduce uncertainty, but the effect depends on variability, design, and analysis. A standard deviation is not the same as a standard error or a confidence interval.

The pooled standard deviation and standardized effect size used for the planning illustrations are recalculated summaries, not outcomes reported as part of the sponsor's adjusted model. Standardizing a mean difference expresses it relative to outcome variability, which can help illustrate planning scenarios. It does not make a small effect clinically unimportant or a large effect clinically important; clinical interpretation requires context and a meaningful threshold, which is not reported in the registry record.

What does randomization contribute?

Random assignment is intended to make treatment groups comparable on average at the start of the trial, including with respect to measured and unmeasured factors. It supports causal interpretation of a properly conducted between-group comparison. It does not ensure identical group composition in a particular trial, and it does not remove bias from missing outcomes, deviations from assigned treatment, measurement practices, or analysis choices. The registry says the full analysis set included all randomized participants, but does not give detailed information about adherence or missing-data procedures for this endpoint.

The trial was open-label. Knowledge of treatment assignment can influence behavior, follow-up, or decisions about measurement and reporting. Height is a measurable physical outcome, which reduces some forms of subjective outcome assessment, but open-label status remains part of the design context. The registry does not report whether height assessors were masked or describe measurement standardization.

Why can over-dispersion matter in other outcome types?

General statistical explanation: for count outcomes, over-dispersion means that observed variability is greater than a simple model assumes. If ignored, standard errors may be too small and intervals too narrow. The primary endpoint in this trial is continuous rather than a count, so this issue is not the main modeling concern for the reported height-velocity comparison. The registry's listed adverse-event counts are descriptive safety summaries, and no comparative inferential model for them is reported.

Finally, a statistical analysis plan commonly specifies endpoint definitions, analysis populations, covariates, missing-data methods, multiplicity handling, and decision criteria. These details matter because different choices can change estimates or the strength of conclusions. The registry record does not report the trial's full statistical plan, original sample-size justification, interim analyses, or multiplicity strategy. Their absence limits methodological reconstruction; it does not demonstrate that such procedures were or were not used.

11. Confidence Intervals and Precision

The sponsor's ANCOVA estimate for somapacitan compared with Norditropin is -0.5 centimeters per year, with a 95% confidence interval from -1.1 to 0.2. The interval includes zero and covers estimates on either side of no difference. Its upper and lower limits describe the uncertainty around the adjusted treatment estimate under the sponsor's analysis. The registry does not report the adjustment variables or the non-inferiority margin, so the interval cannot be fully interpreted against the trial's decision threshold.

The unadjusted recalculation gives a mean difference of -0.6 centimeters per year, with a 95% confidence interval from -1.411 to 0.210. This interval also includes zero. It is based on the posted group-level means, standard deviations, and sample counts, rather than the sponsor's ANCOVA model. It should be read as a simple summary-based estimate, not as a replacement for the reported analysis.

Confidence intervals are useful because they show a range of estimates consistent with the data and analysis assumptions, not merely whether a p-value crosses a threshold. Here, the intervals indicate uncertainty about the size and direction of the difference. They do not demonstrate equivalence, and the sponsor interval alone cannot verify non-inferiority without the margin. A statistically nonsignificant difference is not proof that treatments have the same effect.

The intervals also do not capture every source of uncertainty. They do not address unreported choices in the model, possible missing-data bias, or limitations associated with the open-label design. Precision should therefore be considered alongside the trial design and the incomplete reporting of analysis details. The registry gives no separate precision estimate for long-term comparative effects after the main treatment comparison ended.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning illustrations translate an observed mean difference into hypothetical sample sizes under stated assumptions. For these continuous outcomes, the values are participants per arm, not total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The original trial's own sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the number of participants per arm that the illustration estimates would be needed for an 80% chance of detecting the specified effect under those assumptions, if that effect were the true effect and the analysis assumptions held. The 90% power column describes the corresponding planning target for a 90% chance. Higher planned power generally requires more participants for the same target effect.

For the primary outcome, planning for 100% of the observed effect gives 305 participants per arm for 80% power and 408 participants per arm for 90% power. Planning for 75% of the observed effect gives 542 participants per arm for 80% power and 725 participants per arm for 90% power. Planning for 50% of the observed effect gives 1,218 participants per arm for 80% power and 1,631 participants per arm for 90% power. The smaller target effects require more participants because a smaller separation between group means is harder to distinguish from variability.

These are planning illustrations based on the observed effect, not a reconstruction of the trial design. They are not observed power and do not indicate the probability that the trial's conclusion is correct. The calculation uses simplified assumptions; actual design needs can depend on analysis methods, missing outcomes, allocation, and other features. The estimates should be read as conditional planning scenarios rather than as evidence about the quality of the completed trial.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.600; pooled standard deviation σ = 2.642.
2. n = 2 × (1.96 + 0.842)² × 2.642² / -0.600² = 304.4, rounded up to 305 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.600000000000001                      # observed difference in means
sigma <- 2.64214100511481                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(3811535)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 305 (80% power), 408 (90% power)
 75% of observed effect: n per arm = 542 (80% power), 725 (90% power)
 50% of observed effect: n per arm = 1,218 (80% power), 1,631 (90% power)
power.t.test: 305.4 
Simulated power at n = 305 per arm: 0.802 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The sponsor's reported primary analysis is an ANCOVA treatment difference of -0.5 centimeters per year, with a 95% confidence interval from -1.1 to 0.2. The registry labels this a non-inferiority analysis. This is the trial's own reported analysis and is distinct from the unadjusted recalculation based on the posted group means and standard deviations.

The recalculation estimates a mean difference of -0.6 centimeters per year, with a 95% confidence interval from -1.411 to 0.210 and an unadjusted p-value of 0.147. The numerical estimates differ because one is reported from ANCOVA and the other is a simple comparison of summary statistics. The registry does not provide enough model detail to reproduce the sponsor's analysis.

The record does not flag a discrepancy, but the recalculated result should not be substituted for the sponsor's analysis. The non-inferiority margin, model covariates, and decision rule are not reported in the registry record. Consequently, the reported estimate and interval can be stated, while a complete independent assessment of the non-inferiority claim is not possible from the registry information.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates several outcomes, time points, or comparisons. With each additional statistical test, the chance of at least one apparently unusual result under a null setting can increase. Prespecified outcome hierarchies or adjustments can control how evidence is interpreted across a family of tests. The registry lists 29 outcome measures and 2 analyses, but the multiplicity strategy is not reported in the registry record. It is therefore not possible to determine whether the secondary analyses were adjusted, sequenced, or treated as exploratory.

The primary endpoint is identified, and the sponsor's primary comparison is labeled as non-inferiority. However, the non-inferiority margin and detailed decision rule are not reported. These are central to evaluating a non-inferiority analysis because the question is whether the data exclude an unacceptable loss relative to a chosen margin, not merely whether a difference from zero is statistically detectable.

The registry describes the primary population as the full analysis set, including all randomized participants. It does not provide detailed information about participant flow, endpoint availability, exclusions from a particular analysis, or methods for handling missing height measurements. The primary endpoint's in-trial observation period ends at visit 7 or last trial contact, whichever came first; the record does not explain the consequences of that rule for missingness or unequal follow-up.

Missing-data methods can matter if the chance of having an observed outcome is related to treatment or to the outcome itself. Complete-case analysis, imputation, and model-based approaches rely on different assumptions. The registry's endpoint description alone does not identify which approach was used. It would be inappropriate to infer a method or its assumptions.

The record also does not report interim analyses, the full statistical analysis plan, or the original sample-size justification. Their reporting status limits independent assessment of prespecification and analysis choices. This absence does not show that these procedures were not conducted; it means that their details are not reported in the registry record.

16. 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: tonsillar hypertrophy (2.9%), gastroenteritis (1.5%), adenoidal hypertrophy (1.5%), adrenocortical insufficiency acute (1.5%), blood creatine phosphokinase increased (1.5%).

The registry reports serious adverse events by treatment and follow-up period, with the number at risk and the number affected. During weeks 0–52, serious adverse events were reported for 7 of 132 participants in the somapacitan group and 2 of 68 in the Norditropin group. No deaths were reported in either group during that period.

For weeks 52–208, the somapacitan/somapacitan group had 11 serious adverse events among 131 at risk, and the Norditropin/somapacitan group had 4 among 68 at risk. No deaths were reported in these groups. For the period after week 208, the registry lists 1 serious adverse event among 35 at risk in the Norditropin/somapacitan group and 4 among 68 at risk in the somapacitan/somapacitan group; no deaths were reported in either group.

These are descriptive counts within the registry's named groups and periods, not an adjusted comparison of safety between treatments. After week 52, both extension groups received somapacitan, and the original randomized treatment contrast no longer applies in the same way. The record lists tonsillar hypertrophy at 2.9%, gastroenteritis at 1.5%, adenoidal hypertrophy at 1.5%, adrenocortical insufficiency acute at 1.5%, blood creatine phosphokinase increased at 1.5%, and COVID-19 at 1.5% among the top serious-event terms. The registry figures alone do not establish causation or comparative risk.

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

The primary result is an estimate of average height velocity over the defined main-trial observation period. The posted group means were 11.8 centimeters per year for Norditropin and 11.2 centimeters per year for somapacitan. The sponsor's adjusted estimate was -0.5 centimeters per year, with a 95% confidence interval from -1.1 to 0.2. These figures describe the trial's measured outcome; they do not by themselves settle whether the treatments meet a non-inferiority criterion.

The record labels the sponsor analysis non-inferiority, but does not report the margin required to interpret that claim. Without the margin and decision rule, the estimate cannot be translated into a complete formal conclusion from the registry information alone. The confidence interval includes zero, but that does not establish that the regimens are equivalent. Nor does an interval crossing zero prove that there is no meaningful difference.

The endpoint concerns mean growth rate during the main trial period, not every aspect of growth, development, or health. It does not describe each participant's response, and group averages can conceal individual variation. The posted standard deviations indicate variability around the means, but the registry summaries do not show the distribution of individual responses.

The original treatment comparison was during the 52-week main period. Participants completing that period were assigned weekly somapacitan during the extension regardless of their original group. Long-term extension observations therefore do not provide a continued randomized comparison of weekly somapacitan against daily Norditropin. They should not be interpreted as evidence about a long-term contrast between those original regimens.

Safety counts describe recorded events in named groups and follow-up periods. They do not show that a treatment caused an event, and the registry does not provide an adjusted between-group safety analysis. Taken together, the record supports a careful description of the measured outcomes and their uncertainty, not a broad claim about benefit, equivalence, or long-term comparative safety.

18. Why This Trial Matters Statistically

This trial illustrates why a registry result needs to be read at the level of its estimand and analysis. The primary endpoint is a growth rate over the main 52-week period, while the sponsor's reported result is an adjusted ANCOVA treatment difference. A simple recalculation from group summaries answers a related but not identical question. Keeping these analyses distinct prevents a summary-based calculation from being mistaken for the trial's own primary model.

It also illustrates the importance of the decision framework. A non-inferiority analysis is not interpreted in the same way as a conventional superiority test. The estimate and confidence interval are informative, but the margin and decision rule determine what degree of difference the analysis was designed to exclude. Because those details are not reported in the registry record, the statistical label alone is not enough to reconstruct the full conclusion.

The design has a clear randomized treatment contrast during the main period, followed by an extension in which both groups receive weekly somapacitan. That change matters for interpretation: the extension can contribute information about longer exposure and recorded events, but it does not maintain the original randomized comparison of the two regimens.

Finally, the secondary outcomes and planning illustrations show how statistical interpretation extends beyond a single estimate. Multiple outcomes raise multiplicity questions, and planning estimates depend on assumptions about the target effect and analysis. Reporting the outcome definitions, model details, missing-data methods, multiplicity strategy, and non-inferiority margin would make the result easier to evaluate and reproduce.

19. 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 does not report the non-inferiority margin, despite labeling the primary analysis as non-inferiority. Without this information, the sponsor's interval cannot be assessed against the threshold that would define an acceptable loss. The model covariates and further ANCOVA details are also not reported, which prevents reproduction of the sponsor's adjusted estimate.

The trial was open-label. The primary outcome is based on height measurements, but the registry does not state whether measurement assessors were masked or give detailed measurement quality procedures. Knowledge of treatment assignment can affect aspects of study conduct, even when the endpoint is not a subjective rating.

The record describes the full analysis set as including all randomized participants, but does not give detailed participant flow or endpoint-specific missing-data handling. The posted primary endpoint counts differ between the groups, and the reason is not reported. The in-trial endpoint definition allows observation to end at the last trial contact before visit 7, but the record does not explain how this affects the analysis.

The post-week-52 extension has no continuing randomized contrast between somapacitan and Norditropin because participants in both extension groups received weekly somapacitan. Consequently, extension observations cannot be read as a long-term head-to-head comparison of the initial regimens. Safety counts are descriptive, with no comparative inferential analysis reported.

The registry does not report the multiplicity approach, interim analyses, original sample-size justification, or the full statistical analysis plan. These omissions limit assessment of prespecification and the conditions behind the reported analyses. The planning illustrations use observed effects and stated assumptions; they are not evidence of the trial's original design rationale or observed power.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Research Study in Children With a Low Level of Hormone to Grow. Treatment is Somapacitan Once a Week Compared to Norditropin® Once a Day (REAL4) — NCT03811535.
• Registry record last updated 2026-10-22; status last verified 2026-09.
• Results first posted 2023-08-04.
• 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.

23. Record Summary

NCT03811535, REAL4, was a completed randomized phase 3 parallel-group trial comparing weekly somapacitan with daily Norditropin in children with growth hormone deficiency. The study was open-label. The primary endpoint was height velocity from baseline to week 52, expressed in centimeters per year.

The sponsor reported an ANCOVA treatment difference of -0.5 centimeters per year, with a 95% confidence interval from -1.1 to 0.2, and labeled the analysis non-inferiority. The non-inferiority margin and detailed model specification are not reported in the registry record. An unadjusted recalculation from posted summaries estimated a difference of -0.6 centimeters per year, with a 95% confidence interval from -1.411 to 0.210.

The main treatment comparison lasted 52 weeks. Participants completing the main period were to receive weekly somapacitan during a 3-year extension. Secondary outcomes cover growth and metabolic measures. Safety results are reported as counts by group and period; they are descriptive and do not constitute an adjusted comparative safety analysis.