This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta (NCT04545554), a non-randomized phase 1 study. The primary outcome is Maximum Observed Serum Concentration (Cmax) of Romosozumab.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04545554 |
| Phase | Phase 1 |
| Condition | Osteogenesis Imperfecta |
| Allocation | Non-Randomized |
| Design model | Sequential |
| Masking | None (open label) |
| Enrollment | 25 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Amgen |
| Results posted | Yes |
2. Clinical Question
Population
Children and adolescents with osteogenesis imperfecta were enrolled in two age bands: 5 to < 12 years and 12 to < 18 years. The registry record reports enrollment of 25 participants overall. The primary pharmacokinetic analysis population included participants whose data allowed at least one pharmacokinetic parameter or endpoint to be adequately tested.
Intervention
Participants received romosozumab at one of three dose levels. The study was open-label and used sequential cohorts. Calcium and vitamin D were also received by all participants, according to the arm descriptions.
Comparator
There was no randomized control group. Cohorts differed by age band and romosozumab dose level, but the registry record does not describe them as a like-for-like control comparison. Comparisons among these cohorts therefore should not be read as randomized treatment contrasts.
Primary question
The primary question concerned the pharmacokinetic profile of romosozumab after multiple subcutaneous doses. The primary endpoint was mean maximum observed serum concentration, or Cmax, with measurements presented following Days 1 and 57. Numerical Cmax results are not reported in the registry record, so the magnitude and precision of the observed concentrations cannot be assessed from that record.
3. Trial Design
This was a phase 1, open-label, non-randomized, sequential study of romosozumab in children and adolescents with osteogenesis imperfecta. The registry record gives enrollment as 25 and status as completed. It records the study start as 2021-01-21 and primary completion as 2023-03-30.
Participants were assigned to cohorts organized by age band and dose level. The two age bands were 5 to < 12 years and 12 to < 18 years; each age band had cohorts for Dose A, Dose B, and Dose C. The record says participants would receive one of three dose levels and that all participants also received calcium and vitamin D. It does not state the numerical dose levels in the information available for this description.
Because allocation was non-randomized and the study was sequential, the cohorts are not randomized comparison groups. Differences between cohorts could reflect age, dose, cohort sequence, or other factors; the registry record does not provide a basis for separating those influences. No placebo or untreated comparator is described.
The stated primary objective was to evaluate romosozumab pharmacokinetics after multiple subcutaneous doses. The primary Cmax endpoint used a pharmacokinetic analysis set defined by whether at least one pharmacokinetic parameter or endpoint could be adequately tested. The registry lists safety, antibody, bone-turnover, and bone-measure outcomes as secondary outcomes. Detailed statistical analysis plans, dose-escalation criteria, and sample-size justification are not reported in the registry record.
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: Ambulatory children (5 to \< 12 years of age) and adolescents (12 to \< 18 years of age) with osteogenesis imperfecta were enrolled to receive 1 of 3 subcutaneous (SC) dose levels of romosozumab. Specific doses are blinded due to the protection of propriety information.
Overall Study
| Stage | Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) | Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) | Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) | Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) | Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) | Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age) |
|---|---|---|---|---|---|---|
| STARTED | 4 | 4 | 4 | 5 | 4 | 4 |
| Received at Least 1 Dose Romosozumab | 4 | 4 | 4 | 5 | 4 | 4 |
| Received All Doses of Romosozumab | 4 | 4 | 4 | 4 | 4 | 4 |
| COMPLETED | 4 | 4 | 4 | 4 | 4 | 4 |
| NOT COMPLETED | 0 | 0 | 0 | 1 | 0 | 0 |
Reasons for not completing this period:
| Reason | Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) | Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) | Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) | Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) | Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) | Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age) |
|---|---|---|---|---|---|---|
| Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) Analysis Set: all participants for whom at least 1 PK parameter or endpoint could be adequately tested.
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.
Only the first 6 of 7 groups are shown.
| Characteristic | Unit | Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) | Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) | Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) | Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) | Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) | Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age) |
|---|---|---|---|---|---|---|---|
| Participants analysed | 4 | 4 | 4 | 5 | 4 | 4 | |
| Age, Continuous | years | 14.3 (SD 1.9) | 6.0 (SD 1.4) | 14.3 (SD 0.5) | 8.4 (SD 2.4) | 14.0 (SD 1.8) | 6.5 (SD 0.6) |
| Sex: Female, Male: Female | Participants | 1 | 0 | 1 | 4 | 2 | 1 |
| Sex: Female, Male: Male | Participants | 3 | 4 | 3 | 1 | 2 | 3 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 | 2 | 1 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 4 | 4 | 4 | 3 | 3 | 4 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race/Ethnicity, Customized: Asian | Participants | 0 | 0 | 0 | 0 | 0 | 1 |
| Race/Ethnicity, Customized: White | Participants | 4 | 4 | 4 | 4 | 4 | 2 |
| Race/Ethnicity, Customized: Other | Participants | 0 | 0 | 0 | 1 | 0 | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Observed Serum Concentration (Cmax) of Romosozumab, measured over Single blood samples were taken on days 1, 8, 15, 29, 57, 64, 71, 85, 113, and 169 (end of study); pre-specified PK analysis took place on Days 1 and 57.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | μg/mL |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is maximum observed serum concentration, or Cmax, of romosozumab, reported as a mean in μg/mL. Cmax describes the highest measured concentration of a medicine in serum within the specified observation period. Pharmacokinetic measures help characterize how a medicine’s concentration changes after dosing; they are not, by themselves, measures of clinical benefit.
Blood samples were scheduled on Days 1, 8, 15, 29, 57, 64, 71, 85, 113, and 169, with Day 169 identified as the end of study. The pre-specified pharmacokinetic analysis took place on Days 1 and 57, and the endpoint description says mean Cmax values following those days are presented. The endpoint also specifies standard deviation as its dispersion measure.
Reporting a mean alongside a standard deviation can describe the group’s average concentration and the spread of individual measurements around that average. In general, concentration data can inform dose selection and pharmacokinetic characterization, but interpretation depends on the actual estimates, their variability, and the study context. Numerical means and standard deviations for Cmax are not reported in the registry record, so the endpoint’s observed values and precision cannot be characterized.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The record identifies the principal scientific focus as pharmacokinetics after multiple subcutaneous doses of romosozumab in children and adolescents with osteogenesis imperfecta. Its primary endpoint is mean Cmax following Days 1 and 57. However, the registry record does not report numerical Cmax estimates or their standard deviations. Without those results, the observed concentration levels, between-participant spread, and change across the reported study days cannot be evaluated.
The study was open-label, non-randomized, and sequential. Its six described cohorts combine two age bands with three dose levels. These features are relevant to interpretation: cohort contrasts are not randomized comparisons, and the record does not establish that groups are comparable on factors other than their stated age and dose categories. No causal conclusion about differences between dose levels or ages follows from the design information alone.
The registry record describes a pharmacokinetic analysis population based on adequate testing of at least one pharmacokinetic parameter or endpoint. This is an endpoint-specific population definition, not necessarily a statement that every enrolled participant contributed to every measurement. The record does not report the number contributing to the primary endpoint, the handling of missing concentration samples, or the specific estimation procedures.
Secondary outcomes include treatment-emergent adverse events, cranial nerve VII examination changes, anti-romosozumab antibodies, and several bone-turnover and bone-measure outcomes. The registry lists 14 outcome measures but no analysis records. Numerical results for the primary endpoint and these secondary measures are not reported in the registry record available for interpretation. Consequently, the study’s direction or magnitude of pharmacokinetic and secondary-outcome findings, and the precision of those findings, cannot be assessed from these entries.
Any sample-size illustrations associated with the posted results are planning calculations based on an observed effect, not evidence that the study was designed with those assumptions. They do not establish observed power. The record does not report the original sample-size justification or enough primary endpoint results to interpret an effect-based planning illustration independently.
9. Statistical Methods Explained
What does a mean Cmax represent?
Mean Cmax is the average of participants’ maximum observed serum concentrations under the specified measurement and analysis rules. In general, a mean gives a concise description of the center of a distribution, but it does not show how concentrated or widely dispersed the individual values are. The registry endpoint also names standard deviation, which describes dispersion around the mean. Neither statistic substitutes for seeing the actual data distribution, and both depend on which observations are included.
For this study, the endpoint description specifies mean Cmax in μg/mL and identifies Days 1 and 57 for the pre-specified pharmacokinetic analysis. Blood-sampling days are listed from Day 1 through Day 169. The registry record does not give the numerical endpoint estimates, standard deviations, or participant counts contributing to each estimate. Therefore, the actual mean and observed variability cannot be interpreted from the record.
Why do sampling days matter?
Pharmacokinetic measurements are tied to time after dosing. In general, serum concentration changes over time, so the timing of collection affects which part of that profile a sample can describe. Cmax concerns a maximum observed concentration, and the sampling schedule determines which observed values can contribute to identifying it. A maximum observed from scheduled samples is not automatically identical to an unobserved biological peak between samples. The registry record names the collection schedule and the two analysis days, but it does not report detailed concentration-time methods or how values between collection times were handled.
What does the design imply for comparisons?
In general, random allocation helps balance measured and unmeasured factors between treatment groups, on average. This study is recorded as non-randomized and sequential, with no masking. Its cohorts are organized by age band and dose level. Thus, a difference between cohort summaries would be descriptive unless additional methods and assumptions supported a comparative interpretation. The registry record does not report adjusted comparisons, a control group, or a statistical model for separating dose effects from age or cohort effects.
The record describes multiple doses and an ascending-dose study in its official title. It does not report the operational rules for moving between dose levels, nor does it provide a detailed statistical plan. Those details should not be inferred from the study title or cohort labels.
How should dispersion and uncertainty be understood?
In general, standard deviation describes variability among observations, whereas a confidence interval describes uncertainty about an estimated quantity under a specified statistical procedure. A confidence interval’s width depends on factors such as variability, sample size, and the method used. The registry endpoint names standard deviation, but no confidence interval for Cmax is reported in the registry record. With neither numerical estimates nor uncertainty intervals, the precision of the primary endpoint cannot be judged.
Over-dispersion is a general issue for count data when variability exceeds what a chosen model expects. In such cases, a model that ignores the extra variability can give uncertainty estimates that are too small. This concept may matter in general when analyzing adverse-event counts, but the registry record does not report a model for those outcomes. It would be inappropriate to attribute any particular model or correction to this study.
What do the planning calculations mean?
In general, a sample-size calculation estimates how many participants a future design would need under specified assumptions about an effect, variability, significance level, allocation, and statistical method. The planning assumptions described for the posted calculations use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. For time-to-event outcomes, the calculation is described as a total event count using the Schoenfeld method; other calculations are described in participants per arm.
These are planning illustrations based on an observed effect, not the trial’s own design justification. They are not observed power and do not show that the study had a particular probability of detecting an effect. The registry record does not report an original sample-size justification. Because the primary numerical effect is not reported in the registry record, no effect magnitude or calculated sample size should be inferred from the planning assumptions alone.
What statistical details are absent?
The registry lists zero analysis records. This means the registry record does not provide registered analysis entries to describe; it does not, by itself, establish what analyses were performed outside the registry. The statistical analysis plan, model specifications, handling of multiplicity, missing-data procedures, and confidence-interval methods are not reported in the registry record. Interpretation should remain limited to the design, endpoint definitions, and safety counts that the record actually states.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists 14 outcome measures, including the primary pharmacokinetic endpoint and secondary outcomes covering adverse events, examination findings, antibodies, and bone-related measures. When several outcomes or repeated measurements are evaluated, the chance of at least one apparently notable result can increase. In general, multiplicity procedures can control or characterize that issue, but the appropriate approach depends on the planned questions and analysis structure. The record does not report whether any multiplicity adjustment was planned or used.
The registry lists zero analysis records. A detailed statistical analysis plan, including any hierarchy among outcomes or adjustment for multiple testing, is not reported in the registry record. As a result, the relative inferential status of the listed outcomes cannot be established beyond the designation of Cmax as the primary endpoint and the others as secondary outcomes.
Missing-data handling is also not reported in the registry record. The primary pharmacokinetic analysis set includes participants for whom at least one pharmacokinetic parameter or endpoint could be adequately tested. That definition does not state how many participants contributed to each endpoint, how incomplete sample series were treated, or whether any observations were excluded. It also does not describe missingness assumptions or sensitivity analyses.
In general, missing observations can affect estimates when the chance of a measurement being absent is related to participant characteristics or outcomes. The extent and direction of any such effect depend on the missingness pattern and analysis method; neither is documented. The registry record’s total enrollment does not establish the analysis population size for each outcome. Accordingly, numerical outcome estimates, denominators, and uncertainty measures would be needed to assess completeness and precision, but are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) | 0 | 4 | 0.0% |
| Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) | 1 | 4 | 25.0% |
| Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) | 0 | 4 | 0.0% |
| Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) | 1 | 5 | 20.0% |
| Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) | 0 | 4 | 0.0% |
| Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age) | 0 | 4 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) | 0 of 4 |
| Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) | 0 of 4 |
| Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) | 0 of 4 |
| Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) | 0 of 5 |
| Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) | 0 of 4 |
| Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age) | 0 of 4 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) | 1 of 4 |
| Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) | 0 of 4 |
| Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) | 2 of 4 |
| Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) | 4 of 5 |
| Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) | 1 of 4 |
| Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age) | 3 of 4 |
Most frequent serious adverse event terms
| Event term | Organ system | Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) | Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) | Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) | Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) | Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) | Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age) |
|---|---|---|---|---|---|---|---|
| Femur fracture | Injury, poisoning and procedural complications | 0 of 4 | 0 of 4 | 0 of 4 | 1 of 5 | 0 of 4 | 0 of 4 |
| Lower limb fracture | Injury, poisoning and procedural complications | 0 of 4 | 1 of 4 | 0 of 4 | 0 of 5 | 0 of 4 | 0 of 4 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) | Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) | Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) | Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) | Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) | Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age) |
|---|---|---|---|---|---|---|---|
| Pain in extremity | Musculoskeletal and connective tissue disorders | 0 of 4 | 0 of 4 | 0 of 4 | 1 of 5 | 0 of 4 | 2 of 4 |
| Injection site erythema | General disorders | 0 of 4 | 0 of 4 | 0 of 4 | 0 of 5 | 1 of 4 | 1 of 4 |
| Injection site swelling | General disorders | 0 of 4 | 0 of 4 | 0 of 4 | 0 of 5 | 1 of 4 | 1 of 4 |
| Pyrexia | General disorders | 0 of 4 | 0 of 4 | 0 of 4 | 1 of 5 | 0 of 4 | 1 of 4 |
| COVID-19 | Infections and infestations | 0 of 4 | 0 of 4 | 0 of 4 | 1 of 5 | 1 of 4 | 0 of 4 |
| Nasopharyngitis | Infections and infestations | 0 of 4 | 0 of 4 | 0 of 4 | 1 of 5 | 0 of 4 | 1 of 4 |
| Upper respiratory tract infection | Infections and infestations | 0 of 4 | 0 of 4 | 0 of 4 | 0 of 5 | 0 of 4 | 2 of 4 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 0 of 4 | 0 of 4 | 0 of 4 | 1 of 5 | 0 of 4 | 1 of 4 |
| Back pain | Musculoskeletal and connective tissue disorders | 0 of 4 | 0 of 4 | 1 of 4 | 1 of 5 | 0 of 4 | 0 of 4 |
| Headache | Nervous system disorders | 0 of 4 | 0 of 4 | 0 of 4 | 0 of 5 | 0 of 4 | 2 of 4 |
Serious events with the highest arm-level rate: lower limb fracture (25.0%), femur fracture (20.0%).
The registry safety entries give serious-event counts and counts for other adverse events separately for each cohort. Cohort 1, Dose A, ages 12 to < 18 years, lists 0 of 4 participants with a serious event and 1 of 4 with another adverse event. Cohort 2, Dose A, ages 5 to < 12 years, lists 1 of 4 with a serious event and 0 of 4 with another adverse event. Cohort 3, Dose B, ages 12 to < 18 years, lists 0 of 4 with a serious event and 2 of 4 with another adverse event.
Cohort 4, Dose B, ages 5 to < 12 years, lists 1 of 5 with a serious event and 4 of 5 with another adverse event. Cohort 5, Dose C, ages 12 to < 18 years, lists 0 of 4 with a serious event and 1 of 4 with another adverse event. Cohort 6, Dose C, ages 5 to < 12 years, lists 0 of 4 with a serious event and 3 of 4 with another adverse event. Each cohort lists 0 deaths.
The serious-event terms listed most prominently are lower limb fracture, 25.0%, and femur fracture, 20.0%. The registry record does not explain the denominator or whether these terms overlap, so these percentages should not be converted into participant counts. These small, non-randomized cohorts do not support direct causal comparisons of safety between dose levels or age bands.
12. What the Result Does, and Does Not, Mean
The study’s stated focus is pharmacokinetic characterization of romosozumab after multiple subcutaneous doses in children and adolescents with osteogenesis imperfecta. It also records safety and other secondary outcomes. The registry record gives the design, endpoint definitions, and cohort-level safety counts, but does not report numerical results for the primary Cmax endpoint. Therefore, it does not allow a reader to determine the observed serum concentration levels or how precisely they were estimated.
The record also does not establish comparative efficacy. It describes a phase 1, open-label, non-randomized, sequential study without a randomized control group. The listed secondary outcomes include bone mineral density, bone mineral content, lumbar spine bone area, and bone-turnover markers, but their numerical findings are not reported in the registry record. Outcome names alone do not indicate whether a measure increased, decreased, or changed meaningfully.
The safety entries show that serious events were recorded in some cohorts and not in others, with no deaths listed for any cohort. These counts should be read as descriptive observations in the stated cohorts. The cohort structure and lack of randomization limit interpretation of apparent differences, and the entries do not establish that an event was caused by romosozumab. The record’s listed serious-event terms and percentages also lack denominator details needed for further interpretation.
More broadly, pharmacokinetic, safety, and bone-measure outcomes answer different questions. Concentration measurements characterize exposure; safety counts describe reported events; bone measures describe specified outcomes. None alone establishes a clinical benefit or a treatment effect. The registry record does not report a statistical plan, missing-data procedures, or analysis entries that would clarify how the results were evaluated. The evidence described in the record is therefore limited to study structure and the reported safety counts, rather than a complete account of numerical outcome findings.
13. Why This Trial Matters Statistically
This trial is statistically notable because it addresses pharmacokinetics in children and adolescents across two age bands and three dose levels, while using a sequential, non-randomized design. Such a design can organize dose evaluation across cohorts, but it does not provide the protection against confounding that random allocation can offer. Any comparison across age or dose cohorts needs to be interpreted as descriptive unless a suitable analysis and its assumptions are reported.
The primary endpoint is a concentration measure rather than a clinical outcome. Mean Cmax and its standard deviation can describe central tendency and dispersion, but they do not by themselves show clinical effects. The distinction matters when reading pharmacokinetic studies: exposure information can be scientifically relevant without answering whether health outcomes change.
The registry also illustrates why reporting completeness matters. It specifies the primary endpoint, sampling schedule, analysis population definition, and multiple secondary outcomes, yet the numerical Cmax estimates and detailed analysis methods are not reported in the registry record. Without estimates and measures of uncertainty, readers cannot assess the magnitude or precision of the primary finding. Without analysis details, they cannot determine how missing observations, multiple outcomes, or cohort differences were handled.
Finally, the safety counts are organized by cohort, which preserves context about age band and dose category. Their descriptive value is constrained by the small cohort sizes and non-randomized structure. The trial’s statistical contribution cannot be fully judged from design labels alone; clear numerical outcome reporting and transparent analysis methods are necessary for evaluating what the study observed and how confidently it can be interpreted.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The primary limitation for interpreting outcomes from the registry record is that numerical Cmax results, including means and standard deviations, are not reported. The record therefore does not support an assessment of the primary endpoint’s magnitude or precision. Numerical results for the listed secondary outcomes are also not reported in the registry record.
The non-randomized, open-label, sequential design has important interpretive limits. Cohorts were organized by age band and dose level, but the record does not describe a randomized control group. Differences between cohorts cannot be attributed to dose or age alone on the basis of the registry description. The record also does not provide the numerical dose levels, dose-escalation rules, or detailed cohort assignment procedures.
The registry reports total enrollment, but does not give endpoint-specific analysis counts or explain how incomplete measurements were handled. The pharmacokinetic analysis-set definition indicates that at least one parameter or endpoint had to be adequately testable, but does not clarify the data available for each analysis. Missing-data methods and sensitivity analyses are not reported in the registry record.
The record lists 14 outcome measures and zero analysis records. It does not report a statistical analysis plan, multiplicity handling, model specifications, or confidence-interval methods. These omissions limit assessment of how outcome estimates were generated and how uncertainty was quantified. The safety entries are descriptive, and the listed serious-event percentages lack denominator information in the record. No sample-size justification is reported; planning illustrations based on an observed effect should not be mistaken for the study’s original design rationale.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta — NCT04545554.
- Registry record last updated 2024-04-15; status last verified 2023-10.
- Results first posted 2024-04-15.
- 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.
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18. Record Summary
NCT04545554 is a completed phase 1 study of romosozumab in children and adolescents with osteogenesis imperfecta. The registry describes an open-label, non-randomized, sequential study with two age bands and three dose levels; participants also received calcium and vitamin D. Enrollment is recorded as 25.
The primary objective was pharmacokinetic characterization after multiple subcutaneous doses. The primary outcome was mean maximum observed serum concentration, measured in μg/mL, with Days 1 and 57 specified for pharmacokinetic analysis. The registry defines the pharmacokinetic analysis set but does not report numerical Cmax results or their standard deviations.
Secondary outcomes cover adverse events, examination findings, antibodies, and bone-related measures. The record lists 14 outcome measures and zero analysis records. Cohort-level serious-event and other-adverse-event counts are recorded, with zero deaths listed in each cohort. Statistical analysis details, missing-data methods, multiplicity handling, and the original sample-size justification are not reported in the registry record.