Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI (NCT02352753), a na phase 3 study. The primary outcome is Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months.

2. Clinical Question

3. Trial Design

This was a prospective, multicenter, single-arm Phase 3 study in children with OI. The registry record lists enrollment of 153 and describes an open-label design with no masking. It also identifies the study model as sequential. Allocation is listed as NA, consistent with the record’s description of a single-arm study rather than a randomized comparison.

Participants received denosumab on a Q6M regimen, described as 1 mg/kg up to a maximum of 60 mg by subcutaneous administration for up to 36 months. The record says early efficacy and pharmacokinetic data from Q6M dosing supported a change to Q3M dosing. Participants enrolled and still receiving denosumab were included in the regimen adjustment, but the description ends before specifying the full details. Details not included in the record are not reported in the registry record.

The primary endpoint was change from baseline in lumbar spine BMD Z-score at 12 months. The stated primary analysis population required participants to be in the FAS, have both baseline and Month 12 DXA assessments, and be on the Q3M regimen for the lumbar spine assessment. A central imaging vendor provided the assessment. This population definition is narrower than the overall enrollment count, so enrollment should not be interpreted as the number contributing to the primary endpoint.

The study status is terminated. The start date is 2015-06-24, and the primary completion date is 2022-03-26. The registry record does not report why the study was terminated. It lists 16 outcome measures and no analysis entries. The record does not report the protocol’s planned analysis details, sample-size justification, or interim-analysis approach.

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.

6-Month Dosing Period

Reasons for not completing this period:

3-Month Dosing Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: DXA Analysis Set included all participants in the FAS with Baseline and Month 12 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: The full analysis set (FAS) included all participants who enrolled into the study.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months, measured over Baseline and 12 months.

The primary endpoint was change from baseline in lumbar spine bone mineral density (BMD) Z-score at 12 months. Lumbar spine BMD was measured by dual-energy X-ray absorptiometry (DXA), adjusted for age, sex, and race/ethnicity, and converted to a Z-score. The record defines the Z-score as the number of standard deviations from the reference population, with 0 equal to the reference mean. A positive change from baseline is described in the record as an improvement in lumbar spine BMD.

A change score summarizes how a continuous measurement differs between baseline and a later assessment. In general, this can be useful for describing the direction and magnitude of change in the measured outcome over the specified period. It does not, by itself, establish that a treatment caused the change. In a single-arm study, there is no randomized concurrent control group to distinguish treatment-related change from other possible explanations.

The endpoint was defined for a particular analysis population: participants in the FAS with baseline and Month 12 DXA assessments on the Q3M regimen, using central imaging-vendor data. The registry record names the intended summary as a least-squares mean with a standard error, but it does not report the numerical endpoint result. The estimate, its standard error, and any confidence interval are therefore not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a least-squares mean represent?

The primary outcome is identified as a least-squares mean, a model-based estimate of an average. In general, least-squares means are calculated from a statistical model and can reflect adjustments or structure specified in that model. They are not automatically identical to a simple arithmetic average. The registry record does not report the model specification, covariates used in the primary analysis, or other details needed to reproduce or fully interpret the estimate.

The record identifies a standard error as the dispersion measure. In general, a standard error describes the statistical uncertainty around an estimated quantity under the assumptions of the analysis. It is not a measure of how much individual participants vary from one another; that is a different kind of variability. The numerical standard error for this endpoint is not reported in the registry record, so its precision cannot be assessed.

How should a confidence interval be understood?

In general, a confidence interval gives a range of values compatible with an estimate under the statistical model and its assumptions. A narrower interval indicates greater precision than a wider interval, while the interval’s location indicates the values most consistent with the data under that framework. The registry record does not report a confidence interval for the primary endpoint. A confidence interval should not be inferred from the stated standard-error method when the numerical estimate and standard error are not reported.

Even when available, an interval describes statistical uncertainty, not all sources of uncertainty. It does not correct for limitations in study design, measurement, missing observations, or the applicability of the analyzed population. In this study, the absence of a randomized control group remains important regardless of the precision of a within-group estimate.

What does the Z-score measure?

The outcome is based on lumbar spine BMD measured by DXA and converted to a Z-score after adjustment for age, sex, and race/ethnicity. As a general statistical concept, standardization expresses a measurement relative to a reference distribution in units of standard deviations. The record defines 0 as the reference mean and positive change from baseline as indicating an improvement in lumbar spine BMD. A change in this score is a change in the standardized measure; it is not, by itself, a direct estimate of a treatment effect against a control group.

The endpoint is a continuous measure, meaning it can take a range of numerical values rather than falling only into categories. Continuous outcomes can be summarized by averages and measures of uncertainty, but those summaries do not show the full distribution of individual responses. The registry record does not report individual-level outcome data or the distribution of participant changes.

Why does the analysis population matter?

The primary population was the DXA Analysis Set: participants in the FAS with a baseline and Month 12 lumbar spine DXA assessment on the Q3M regimen, based on central imaging-vendor data. This definition conditions the endpoint on having the required measurements and being on the specified regimen. In general, estimates from a selected analysis population describe that population and may not represent all enrolled participants if some do not meet its criteria.

The registry enrollment is 153, but the size of the DXA Analysis Set is not reported in the registry record. The record does not report how many participants lacked a baseline or Month 12 DXA assessment, how participants entered the FAS, or how missing outcome data were handled. These omissions limit assessment of how representative the analyzed group may be.

What can the dosing groups establish?

The record describes Q6M and Q3M dosing groups and explains that early efficacy and pharmacokinetic data supported adjustment from Q6M to Q3M. In general, when a regimen changes during a study, a comparison between regimen groups can be affected by differences in timing, participant availability, or study participation. The registry record does not describe randomized assignment to the two regimens, so they should not be interpreted as independent randomized arms. A direct causal comparison between them is not established by the design information reported.

The Q6M and Q3M groups also appear in the safety record, with separate numbers at risk and numbers affected by events. These are descriptive counts. Without a randomized, like-for-like comparison and further analysis details, they do not estimate a controlled difference in risk between regimens.

How should planning illustrations be read?

Sample-size calculations are planning exercises, not observations from participants. The planning assumptions described for this study use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They consider an effect defined as a stated fraction of the observed effect. For time-to-event outcomes, the planning convention is a total number of events; for other outcomes, it is participants per arm.

These assumptions are explicitly described as a planning illustration computed from the observed effect, not as the trial’s own design. They do not establish that the single-arm study was designed with two equal randomized arms, and they are not evidence of observed power. Sample-size planning values cannot replace a reported endpoint estimate, standard error, or confidence interval. The registry record does not report the trial’s own sample-size justification.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Denosumab 3-Month Dosing Regimen")
n   <- c(45)
m   <- c(1.009)
sp  <- c(0.119)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Denosumab 3-Month Dosing Regimen  45  1.009  0.798  0.769  1.249

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 16 outcome measures, including the primary lumbar spine BMD Z-score outcome and secondary outcomes covering other BMD measures, fracture outcomes, and a health questionnaire score. It does not report a multiplicity strategy for interpreting results across these outcomes. Multiplicity refers, in general, to the statistical issue that arises when several hypotheses or outcomes are examined; without a stated approach, the intended control of false-positive findings across outcomes is not reported in the registry record.

The record lists no analysis entries and does not provide numerical results for the primary endpoint. It does not report a statistical analysis plan, the model specification, hypothesis-testing procedures, or any adjustment for multiple comparisons. The registry record also does not report whether interim analyses were planned or conducted. These details should not be inferred from the sequential study model or from the statement that early efficacy and pharmacokinetic data supported a regimen adjustment.

Missing-data handling is not reported in the registry record. The primary DXA Analysis Set required baseline and Month 12 measurements, but the record does not say how missing assessments were treated, whether any imputation method was used, or what assumptions were made about participants without the required measurements. It also does not report the size of the DXA Analysis Set.

The FAS is mentioned as the source population for the primary DXA Analysis Set, but its full definition is not reported in the registry record. The endpoint population was further restricted to participants with the specified DXA assessments on the Q3M regimen. Readers therefore cannot determine from the record how the analysis population relates to all enrolled participants beyond the criteria stated, or how exclusions and missing assessments might affect the estimate.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypercalcaemia (13.3%), femur fracture (9.8%), tibia fracture (6.5%), humerus fracture (5.2%), fibula fracture (4.6%).

The safety record gives separate counts for the Q6M and Q3M dosing-regimen groups. In the Q6M group, 153 participants were at risk for serious adverse events, and 52 were affected; 153 were at risk for other adverse events, and 141 were affected. Deaths were 0. In the Q3M group, 60 participants were at risk for serious adverse events, and 12 were affected; 60 were at risk for other adverse events, and 38 were affected. Deaths were 0.

These are descriptive counts, not results from a randomized comparison. The registry record describes a single-arm study and a dosing-regimen adjustment; it does not establish that the Q6M and Q3M groups are comparable. The figures should therefore be read as event reporting within each regimen group, not as evidence of a causal difference between regimens.

The listed serious adverse event terms include Hypercalcaemia at 13.3%, Femur fracture at 9.8%, Tibia fracture at 6.5%, Humerus fracture at 5.2%, Fibula fracture at 4.6%, and Lumbar vertebral fracture at 3.3%. The registry record does not provide further details about the denominators or analysis underlying these percentages. The listed terms should not be treated as a complete account of all safety outcomes.

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

The registry record establishes that a multicenter, prospective, single-arm study evaluated denosumab in children with OI and specified change in lumbar spine BMD Z-score at 12 months as the primary endpoint. It also describes the DXA measurement approach, the analysis population criteria, and safety counts by dosing regimen. These details explain what the study set out to measure and how the primary population was defined.

The record does not report a numerical primary endpoint result, standard error, or confidence interval, and it lists no analysis entries. Therefore, the magnitude and precision of the primary outcome cannot be assessed from the registry record. The outcome definition says that a positive change from baseline indicates an improvement in lumbar spine BMD, but the direction of an observed change cannot be established without a reported estimate.

Even if a within-group change were reported, the single-arm design would limit causal interpretation. Without a randomized concurrent control group, an observed change could not be separated from other explanations using the trial comparison alone. The record’s Q6M and Q3M regimens should not be interpreted as randomized treatment arms: it describes an adjustment from Q6M to Q3M based on early efficacy and pharmacokinetic data.

The safety counts document participants affected by serious and other adverse events within the two regimen groups, as well as deaths. They are descriptive and do not provide a controlled comparison of safety between regimens. The record does not report enough analysis detail to determine how event timing, exposure, or other factors were incorporated into comparisons.

Accordingly, the registry information supports a description of the study design, endpoint, analysis-population definition, and posted safety counts. It does not support a numerical interpretation of the primary efficacy outcome or a causal conclusion about treatment effects. Missing details about the analysis plan, missing data, and the reason for termination further constrain interpretation.

14. Why This Trial Matters Statistically

This study raises several statistical issues that matter when interpreting clinical research. First, the primary endpoint is a continuous, standardized measure of lumbar spine BMD, but the registry record does not report its numerical estimate or uncertainty. Knowing the outcome definition is useful, yet it cannot tell readers the size or precision of the change actually observed.

Second, the single-arm design makes the distinction between observed change and treatment effect especially important. A within-group change can describe the analyzed participants over time, but it cannot provide the same controlled contrast as a randomized comparison. The Q6M and Q3M regimen groups do not resolve this limitation because the record describes a regimen adjustment, not randomized allocation between regimens.

Third, the primary endpoint population is narrower than overall enrollment: it requires the FAS, baseline and Month 12 DXA assessments, and the Q3M regimen. In general, the way participants enter an analysis population can affect how representative an estimate is. The size of this DXA Analysis Set and the handling of missing assessments are not reported in the registry record, leaving important questions about the analyzed population unanswered.

Finally, the registry record lists multiple outcomes but does not report a multiplicity strategy or analysis entries. Such information helps readers understand how a study planned to interpret results across outcomes and how uncertainty was handled. The record also labels sample-size calculations as planning illustrations rather than the trial’s own design, an important distinction: planning scenarios are not observed power and do not supply evidence about the trial’s endpoint result. Together, these features make transparent reporting of the analysis and its uncertainty essential for interpretation.

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 primary limitation for statistical interpretation is that the registry record does not report the numerical primary endpoint result, its standard error, or a confidence interval. It lists no analysis entries, so the magnitude and precision of the primary outcome cannot be evaluated from the record.

The study was single-arm, with no randomized comparator. This prevents a controlled estimate of the difference attributable to denosumab. Although the record describes Q6M and Q3M regimens, it says the regimen changed following early efficacy and pharmacokinetic data; it does not describe randomization between these regimens. The groups are therefore not a like-for-like control comparison.

The primary analysis population required baseline and Month 12 DXA assessments on the Q3M regimen and inclusion in the FAS. The size and full definition of that population are not reported in the registry record. Nor does the record report how missing DXA data were handled, whether participants without the required assessments were excluded, or how missingness could affect the estimated change.

The record lists multiple outcome measures but does not report a multiplicity plan, detailed statistical analysis methods, or interim-analysis information. The sample-size assumptions are described as a planning illustration and not as the trial’s own design or justification. The record also states that the study was terminated but does not report the reason. These limitations leave the endpoint’s statistical interpretation and the context for study completion uncertain.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI — NCT02352753.
• Registry record last updated 2022-12-28; status last verified 2022-11.
• Results first posted 2022-12-28.
• 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 NCT02352753 as a prospective, multicenter, single-arm Phase 3 study of denosumab in children with OI aged 2 to 17 years at screening. Enrollment was 153. The listed status is terminated; the start date is 2015-06-24, and the primary completion date is 2022-03-26.

The primary outcome was change from baseline in lumbar spine BMD Z-score at 12 months, measured by DXA. Its analysis population required FAS participants with baseline and Month 12 assessments on the Q3M regimen. The record describes an initial Q6M regimen and a subsequent adjustment to Q3M.

The record lists 16 outcome measures and no analysis entries. It does not report a numerical primary endpoint result, its standard error, or a confidence interval. Safety counts are listed by dosing-regimen group, but those groups are not a randomized comparison.