Long-Term Extension Study of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Long-Term Extension Study of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH) (NCT02312687), a na phase 2 study. The primary outcome is Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious AEs (SAEs), and AEs Leading to Discontinuation or Death.

2. Clinical Question

In statistical terms, this study chiefly describes events observed while participants received KRN23 over an extended period. Because it has one treatment group and no concurrent control, the posted counts do not estimate a between-group treatment effect. They also cannot distinguish events associated with treatment from events that would have occurred in the same participants without treatment.

3. Trial Design

The registry identifies NCT02312687 as a Phase 2 study and gives its official title as a Phase 2b, open-label, long-term extension study of KRN23 in adults with XLH. The study is recorded as completed. The listed start date is 2015-01-30, and the primary completion date is 2018-11-30. Enrollment is recorded as 20.

This is a single-group study. Allocation is not applicable, masking is none, and the intervention arm is KRN23. Participants received subcutaneous injections every 4 weeks. Starting doses were based on their last dose in one of two referenced studies, and doses could be titrated to achieve a target peak serum phosphorus range. The registry record does not report the actual doses or how often titration occurred.

The primary outcome is a count of participants with AEs, TEAEs, SAEs, and AEs leading to discontinuation or death. Its stated observation period runs from screening through the end of study plus 4-8 weeks. The record reports a mean duration of burosumab exposure of 165.6 weeks, with a range of 68-184 weeks. Burosumab is the name used in that exposure description; the intervention is listed as KRN23.

The record describes broader objectives covering serum phosphorus, several measures of phosphate handling and mineral metabolism, bone biomarkers, and anti-KRN23 antibodies. These objectives place the study in a long-term safety and pharmacodynamic context, but results for them are not reported in the registry record. No randomized comparison is available: the study’s design supports description of outcomes in the treated group, not causal comparison with an untreated or alternative-treatment group.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious AEs (SAEs), and AEs Leading to Discontinuation or Death, measured over Screening through the end of study plus 4-8 weeks. The mean duration of burosumab exposure was 165.6 weeks (range: 68-184 weeks)..

The primary endpoint counts participants experiencing AEs, TEAEs, SAEs, and AEs leading to discontinuation or death. An AE is defined as any untoward medical occurrence, whether or not considered drug related. A TEAE is an AE occurring on or after the first burosumab dose. The registry defines an SAE or serious suspected adverse reaction through outcomes such as death, a life-threatening event, hospitalization or its prolongation, persistent or significant incapacity, congenital anomaly or birth defect, or another important medical event.

These counts serve a descriptive safety purpose: they indicate how many participants in the study group had events in the reported categories during the specified observation period. The record says AEs were graded from 1 (mild) through 5 (death), and investigators classified them as possibly, probably, or definitely related. The available results do not provide the event-level grades or relatedness classifications.

Counting participants is useful for communicating how widely an event category occurred within the observed group. It is not the same as counting every event, because one participant may have more than one event. Nor does a participant count alone convey when an event occurred, how long it lasted, or whether exposure time differed between participants. The registry record does not report those details for the posted counts.

The stated study objectives also include the proportion reaching normal serum phosphorus and long-term pharmacodynamic and immunogenicity measures. Those objectives are not the primary endpoint described in the posted outcome record, and their results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

A participant count records whether people experienced an event category during the defined observation period. It is different from an event count: a person with repeated events may still contribute one participant to a count of people affected. This distinction matters when reading safety results because counts of participants do not indicate how many episodes occurred. The registry lists the primary endpoint as a count of participants, and its description defines AE, TEAE, and SAE categories.

What can a single-group design estimate?

In general, a single-group study describes outcomes observed in the participants who received the intervention. It can document the experience of that group, but without a concurrent comparator it cannot directly estimate what would have happened to comparable participants under a different treatment or no treatment. Differences between treated and untreated outcomes cannot be established by the posted counts because the study has no control group. The record explicitly identifies a single-group model and no randomized comparison.

Why does the open-label design matter?

In general, open-label means treatment assignment is not masked from participants or study personnel. Knowledge of treatment can affect some aspects of care, reporting, assessment, or decisions to investigate an event. This does not mean reported events are invalid; it means the design context should accompany their interpretation. The record identifies masking as none. The detailed procedures used to assess or adjudicate events are not reported in the registry record.

What does “treatment-emergent” mean?

The record defines a TEAE as an AE that occurred on or after the first burosumab dose. This is a timing definition, not a statement that the treatment caused the event. An event can meet the timing definition without being judged related. The record says investigators classified AEs as possibly, probably, or definitely related, but results by these classifications are not reported in the registry record.

Why consider time at risk?

In general, longer observation creates more opportunity for events to be recorded. Participant counts do not adjust for differences in time under observation. A rate analysis can account for person-time, but interpreting one requires event and exposure-time information in a compatible form. The registry reports a mean burosumab exposure of 165.6 weeks and a range of 68-184 weeks; it does not report a participant-level distribution of exposure or time-specific event rates. The counts should therefore be understood as observed participant counts over the stated follow-up, not as exposure-adjusted rates.

What would a confidence interval add?

In general, a confidence interval expresses the statistical uncertainty around an estimate under a specified method and assumptions. For a proportion, it gives a range of values compatible with the data and method; it does not remove uncertainty caused by selection, measurement, or lack of a control group. Confidence intervals for the safety counts are not reported in the registry record. No precision estimate should be inferred from the counts alone.

Why do event definitions matter?

An SAE is defined by seriousness criteria, such as death, a life-threatening event, or hospitalization, and is not synonymous with an event that is severe in intensity. The record separately describes severity grading from 1 (mild) to 5 (death). In general, seriousness and severity answer different questions: seriousness concerns outcomes or consequences specified by the definition, while severity concerns intensity. The registry entries do not give participant-level grades, so the serious-event count cannot be used to infer how many events were severe.

How should planning illustrations be interpreted?

In general, a sample-size illustration based on an observed effect describes a hypothetical future design under stated assumptions. The record’s stated illustration assumptions include a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of an observed effect. Such calculations are planning aids, not outcomes observed in this study and not evidence of “observed power.” The registry record does not report the study’s own sample-size justification or statistical plan. Since this trial has one group and no randomized comparison, a hypothetical two-arm planning calculation should not be mistaken for the design actually used.

What does multiplicity mean in general?

When many outcomes or analyses are examined, the chance of at least one apparently unusual result can increase if each is tested separately. Methods for addressing multiplicity may include prespecifying a primary analysis or adjusting inference across tests. The registry reports 25 outcome measures and 96 analyses, but the multiplicity strategy is not reported in the registry record. Those counts alone do not establish which analyses were confirmatory, how they were ordered, or whether adjustment was used.

What is not recoverable from counts alone?

Aggregate counts cannot establish event chronology, recurrence, duration, exposure-adjusted rates, or individual clinical courses. They also cannot show whether missing outcome information affected estimates. A registry summary is useful for identifying what was recorded, but interpretation of detailed safety patterns would require information not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The study lists multiple objectives: long-term safety, the proportion of participants reaching the normal serum phosphorus range, pharmacodynamic changes across several laboratory and bone measures, and anti-KRN23 antibody status. The registry records 25 outcome measures and 96 analyses. These registry entries indicate a broad set of outcomes and analyses, but do not reveal which were designated as confirmatory or how inference across them was handled.

Multiplicity refers, in general, to the increased chance of false-positive findings when many statistical comparisons are made without accounting for their number or structure. A prespecified hierarchy, adjustment method, or distinction between confirmatory and exploratory analyses can clarify interpretation. The multiplicity strategy is not reported in the registry record. The stated analysis plan, including whether any adjustment was applied, is not reported in the registry record.

Missing-data handling is also not reported in the registry record. The registry entries do not describe missing observations, exclusions, imputation, or sensitivity analyses. The Safety Analysis Set is named as the population for the primary endpoint, but the rules defining membership in that set are not reported in the registry record. It is not possible to determine from the posted counts how incomplete follow-up or missing assessments were handled.

The registry lists enrollment of 20 and reports safety counts for the KRN23 group. Those values do not establish that every participant contributed complete information to every outcome or analysis. No claim about completeness or the effect of missing data should be inferred from the group counts alone. The detailed statistical analysis plan and sample-size justification are not reported in the registry record.

11. 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: hereditary non-polyposis colorectal cancer syndrome (5.0%), small intestinal obstruction (5.0%), cholecystitis acute (5.0%), medical device site joint infection (5.0%), musculoskeletal chest pain (5.0%).

The serious adverse-event results are participant counts from the KRN23 group: 9 participants are listed in the serious-event category, and the record reports 0 deaths. The record also lists 20 participants in the other adverse-event category. These counts describe people recorded in the respective categories during the study; they do not give the total number of event episodes.

Six serious-event terms are listed, each with 5.0%: Hereditary Non-Polyposis Colorectal Cancer Syndrome, Small Intestinal Obstruction, Cholecystitis Acute, Medical Device Site Joint Infection, Musculoskeletal Chest Pain, and Osteoarthritis. The terms should not be treated as a complete account of every event or as evidence of causation. The record’s AE definition includes events whether or not considered drug related.

The record states that events were graded and that investigators classified relatedness, but those detailed results are not reported in the registry record. Seriousness is defined by specified consequences or importance, and should not be read as the same thing as severity of intensity. Because this study has no control group, the counts cannot establish how these events compare with an alternative treatment or with what would otherwise have occurred.

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

The registry record documents the safety experience observed during a long-term, single-group extension study of KRN23 in adults with XLH. It reports participant counts for adverse-event categories and identifies several serious-event terms. The reported mean burosumab exposure was 165.6 weeks, with a range of 68-184 weeks. These details provide context for the period over which safety was observed.

The results do not, by themselves, show that KRN23 caused any particular event. An AE is defined irrespective of whether it is considered drug related, and there is no concurrent comparator group. The counts also do not show how event frequency would differ under another treatment or no treatment. They should not be interpreted as a causal estimate or as proof that the intervention either produces or prevents an outcome.

The counts are not event rates and do not describe event timing, recurrence, duration, or individual trajectories. Although severity grading and investigator judgments of relatedness are described, those results are not reported in the registry record. The record also does not report confidence intervals for the posted counts.

The study’s stated objectives extend beyond safety to serum phosphorus, pharmacodynamic measures, bone biomarkers, and immunogenicity. Results for those outcomes are not reported in the registry record. Consequently, the available information does not establish whether participants reached the target serum phosphorus range or how the listed laboratory measures changed over time.

In general, a registry outcome is one component of an evidence assessment. It should be read in light of its definitions, study design, follow-up, and the degree of statistical uncertainty that is reported. Here, the design supports a descriptive account of the treated group, while comparative effectiveness, causal attribution, and several planned biochemical outcomes remain unanswered by the posted results.

13. Why This Trial Matters Statistically

Long-term extensions address a statistical question that differs from a short, controlled comparison: what outcomes were recorded while participants continued under observation over an extended period? This study reports a mean burosumab exposure of 165.6 weeks, with a range of 68-184 weeks, and describes adverse-event counts over the stated follow-up. Such duration is relevant context when considering accumulated safety observations.

The study also illustrates why design and estimand matter. A single-group extension can describe the treated participants’ experience, but it cannot separate treatment effects from underlying disease course, background risks, or other influences. The lack of a randomized comparator is not a flaw in the descriptive question, but it limits what causal or comparative conclusions the counts can support.

The record distinguishes event categories and defines seriousness, treatment emergence, severity grading, and investigator-assessed relatedness. These distinctions are statistically important because different definitions answer different questions. A count of affected participants does not equal a count of event episodes, and a serious event is not automatically the same as a severe event.

Finally, the record states several biochemical, pharmacodynamic, and immunogenicity objectives in addition to safety. That breadth makes transparent reporting of outcomes, missingness, analysis populations, and multiplicity important. Those details and results are not reported in the registry record. The available information therefore has value as a structured account of safety observations, while underscoring the limits of drawing comparative conclusions from an uncontrolled extension.

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.

This study is a single-group, open-label extension with no concurrent comparator. Observed adverse-event counts therefore cannot isolate an intervention effect from other causes, background risks, or changes over time. The record explicitly notes that this is not a randomized comparison and that the arms are not a like-for-like control comparison.

Participant counts provide limited detail. They do not show total event episodes, recurrence, timing, duration, or exposure-adjusted rates. The record gives mean exposure and a range, but not participant-level exposure information or rates by follow-up time. Severity grades and investigator assessments of relatedness are described, but the corresponding results are not reported in the registry record.

The listed serious-event terms and their percentages are not accompanied in the registry entries by event narratives or further clinical context. They should not be interpreted as evidence of a causal relationship. The registry record does not report confidence intervals or other measures of statistical precision for the safety counts.

Although the study states objectives for serum phosphorus, pharmacodynamic measures, bone biomarkers, and immunogenicity, their results are not reported in the registry record. The analysis population is identified as the Safety Analysis Set, but its membership rules are not reported. Missing-data methods, the multiplicity strategy, the statistical analysis plan, and the sample-size justification are also not reported in the registry record.

These limitations constrain interpretation to a descriptive account of recorded events in the study group. They do not negate the observed counts, but they prevent the counts from answering comparative, causal, or several planned biochemical questions.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Long-Term Extension Study of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH) — NCT02312687.
• Registry record last updated 2024-05-06; status last verified 2024-05.
• Results first posted 2019-12-16.
• 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.

18. Record Summary

NCT02312687 is a completed Phase 2, open-label, single-group extension study of KRN23 in adults with XLH. The official title describes it as a Phase 2b study. The record lists enrollment of 20, subcutaneous KRN23 injections every 4 weeks, and possible dose titration toward a target peak serum phosphorus range.

The primary outcome counts participants with AEs, TEAEs, SAEs, and AEs leading to discontinuation or death. The safety results report 9 participants in the serious-event category, 20 in the other adverse-event category, and 0 deaths. The record lists six serious-event terms, each with 5.0%. Mean burosumab exposure was 165.6 weeks, with a range of 68-184 weeks.

The study also states objectives for serum phosphorus, pharmacodynamics, bone biomarkers, and immunogenicity. Results for those objectives, the detailed statistical plan, missing-data handling, and multiplicity strategy are not reported in the registry record. The single-group design supports descriptive interpretation, not a randomized treatment comparison.