Safety and Efficacy of Hectorol in Pediatric Patients With Chronic Kidney Disease Stage 3 and 4 With Secondary Hyperparathyroidism Not Yet on Dialysis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Hectorol in Pediatric Patients With Chronic Kidney Disease Stage 3 and 4 With Secondary Hyperparathyroidism Not Yet on Dialysis (NCT02859896), a randomized phase 3 study. The primary outcome is Percentage of Participants Who Achieved 2 Consecutive >=30% Reductions in Intact Parathyroid Hormone From Baseline up to Week 12.

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, open-label, parallel-group study of doxercalciferol (Hectorol) and calcitriol (Rocaltrol). The trial title specifies pediatric patients with chronic kidney disease stages 3 and 4 and secondary hyperparathyroidism who were not yet on dialysis. The registry reports an enrollment of 21 and lists the status as terminated. It gives a start date of 2017-01-19 and a primary completion date of 2025-06-11. The reason for termination is not reported in the registry record.

Randomization means participants were assigned to treatment groups by a random process; the record does not report the allocation ratio or the details of that process. Open-label means treatment assignment was not masked. The parallel-group design means the two assigned treatment regimens were compared between groups, rather than each participant receiving both treatments in sequence.

The dosing schedules differed. Hectorol capsules were administered orally two to three times weekly depending on age, while Rocaltrol capsules were administered orally seven days per week. Both descriptions mention dose titration to individualize dosing for iPTH management. The registry does not report further details about the titration rules or adherence.

The primary outcome focused on repeated iPTH reductions from baseline through Week 12. Other registered outcomes included percent change in iPTH at Weeks 12 and 24, hypercalcemia events, treatment-emergent adverse events and serious adverse events, and pharmacokinetic measures for 1,25-dihydroxyvitamin D2 at Week 8 or 10. The record lists eight outcome measures and seven posted secondary outcomes. Details of other design features, including the planned sample-size justification and any interim analyses, 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: A total of 21 participants were randomized in a 2:1 ratio to receive either doxercalciferol (Hectorol®) or calcitriol (Rocaltrol®). The study was conducted to fulfill a post-marketing commitment (PMC). The study was terminated as food and drug administration (FDA) acknowledged the fulfillment of this PMC on 11 June 2025. Note: Reason for not completed = Reason for permanent treatment discontinuation.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS) consisted of all treated participants with at least 2 assessments of iPTH after use of study treatment.

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: Randomized population consisted of all participants randomized either into the doxercalciferol (Hectorol®) or calcitriol (Rocaltrol®) group.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Who Achieved 2 Consecutive >=30% Reductions in Intact Parathyroid Hormone From Baseline up to Week 12, measured over Baseline (Day 1) up to Week 12.

The primary endpoint is the percentage of participants who achieved two consecutive reductions in intact parathyroid hormone (iPTH) of at least 30% from baseline at consecutive study visits up to Week 12. Baseline is defined as the last available value before the first dose of study treatment. The endpoint applies an on-treatment strategy: the recorded response is based on qualifying measurements while treatment was being given, as described in the registry.

This is a binary outcome at the participant level. A participant either met the repeated-reduction criterion within the specified period or did not. The percentage expresses the share of the analysis group meeting that definition. Requiring consecutive measurements makes the outcome different from a single qualifying reduction; it captures a repeated pattern over consecutive assessments. That can be useful when the question concerns whether a reduction was observed more than once during the assessment period, rather than whether one measurement crossed a threshold.

The registry reports the percentage with a 95% confidence interval estimated by the Clopper-Pearson method. Such an interval communicates uncertainty around the estimated response percentage: narrower intervals indicate greater precision, while wider intervals indicate more uncertainty. The observed arm estimates are 14.3% for doxercalciferol and 71.4% for calcitriol. The corresponding intervals are 1.78% to 42.81% and 29.04% to 96.33%. Their breadth is important when interpreting the estimates, particularly because the primary analysis groups were small.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level endpoint: each participant either met the repeated iPTH reduction definition by Week 12 or did not. The reported arm percentage is the proportion meeting that definition among participants in the stated analysis population. Because the outcome is a percentage of participants with an event, interpreting it differs from interpreting a mean change in a continuous measurement. It does not summarize the size of each participant's iPTH change beyond whether the threshold criterion was met.

What does the confidence interval describe?

The registry reports 95% confidence intervals for each arm using the Clopper-Pearson method. In general, a confidence interval describes the uncertainty around an estimate under a specified statistical procedure and its assumptions. It is not a range containing every participant's response, and it is not a probability statement that the true value has a particular chance of lying within the calculated interval. A narrow interval indicates a more precise estimate; a wide interval indicates less precision. The reported intervals are broad, which is consistent with substantial uncertainty around the arm percentages.

The Clopper-Pearson method is an exact method for binomial proportions. In general, exact methods can be useful when the number of observations is limited or when the observed proportion is near an endpoint such as zero or one. They do not remove uncertainty due to a small analysis group, nor do they account automatically for design or missing-data issues. The intervals describe the arm percentages under the stated method; they do not on their own give an interval for every possible contrast between treatments.

How should the treatment contrast be read?

The registry reports a percentage difference of -52.9, with a 95% confidence interval from -99.90 to -5.98, and labels the analysis as superiority. This is the reported comparison, not a newly calculated subtraction of the arm estimates. The registry does not state a p-value for it. A confidence interval for a contrast describes uncertainty in that contrast under its analysis method. Interpreting the sign requires knowing the comparison's direction and definition; readers should use the registry's stated contrast rather than assume a direction from the order in which arm results are displayed.

In general, a contrast can be expressed on different scales, including a difference in percentages or a relative measure. Those scales answer different questions and can have different numerical interpretations. The registry labels this estimate as a percentage difference but does not report a calculation method in the analysis entry. No alternative recalculated contrast is available for this binary percentage endpoint in the posted comparison material. That absence means it is not appropriate to construct a replacement estimate from the displayed arm summaries.

What does open-label randomization imply?

In general, randomization aims to make assigned groups comparable at the start of a trial in expectation, reducing the influence of systematic allocation choices. It cannot ensure balance in every small trial, and it does not resolve problems that arise after randomization, such as missing assessments or departures from assigned treatment. Open-label treatment means participants and investigators were not masked to treatment assignment. Knowledge of treatment can potentially influence care, reporting, or assessment. The primary endpoint is based on laboratory iPTH measurements, but the registry record does not describe procedures for blinded laboratory assessment or other safeguards.

The parallel-group structure compares outcomes across assigned treatment groups. The regimens also differed in frequency: doxercalciferol was administered two to three times weekly depending on age, and calcitriol seven days per week. Both used individualized dose titration. The record does not provide further details about how adherence, dose changes, or treatment discontinuation were incorporated into the primary analysis beyond its stated on-treatment strategy.

Why can over-dispersion matter in general?

For a binary endpoint, a simple binomial model assumes that outcomes follow the model's specified probability within the relevant group. In general, over-dispersion means observed variation is greater than the model expects. If over-dispersion is present and not accounted for, standard errors may be too small and confidence intervals may be too narrow. Whether over-dispersion is relevant depends on the data structure and analysis model. The registry does not report an over-dispersion assessment or describe a model-based method for the primary outcome; the arm intervals are identified as Clopper-Pearson intervals.

What can planning illustrations tell readers?

Sample-size calculations are planning illustrations, not observed evidence and not observed power. In general, a planning calculation asks how many participants per arm might be needed for a chosen significance level and power under specified assumptions about the effect and allocation. The stated planning approach uses a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects defined as fractions of the observed effect. It specifies participants per arm for non-time-to-event outcomes. These assumptions describe an illustrative calculation, not the trial's own design rationale. The registry does not report its sample-size justification or the assumptions used when planning the trial.

Such illustrations depend on the effect chosen for planning and on modeling assumptions. An observed effect can be an uncertain basis for future planning, especially when the trial groups are small. A planning calculation should not be interpreted as showing that the study had a particular observed probability of finding a result. The registry record does not report the design's intended power or enough information to verify its original planning assumptions.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Doxercalciferol (Hectorol®)", "Calcitriol (Rocaltrol®)")
n      <- c(14, 7)
events <- c(2, 5)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Doxercalciferol (Hectorol®)  14  2  14.3  1.8  42.8  4.0  39.9  4.3  40.5
ARM  Calcitriol (Rocaltrol®)  7  5  71.4  29.0  96.3  35.9  91.8  34.9  91.5

11. Analyses Reported by the Sponsor

The registry's own primary comparison is reported as a percentage difference of -52.9, with a 95% confidence interval from -99.90 to -5.98, and is labeled a superiority analysis. The arm-level estimates are 14.3% for doxercalciferol and 71.4% for calcitriol. These are distinct presentations: the arm percentages describe each analysis group, while the sponsor's reported contrast summarizes a comparison using its stated measure.

No recalculated two-arm comparison is available for this binary percentage endpoint in the posted material. The absence of a recalculated contrast should not be filled by subtracting the arm percentages or constructing a different estimate from the summaries. The reported contrast's method is not specified in the registry entry, and no p-value is listed. The registry does not flag a discrepancy between its own analysis and a recalculation. Where a discrepancy is flagged, the sponsor's own analysis takes precedence; that situation is not indicated in this record.

Accordingly, the sponsor's reported comparison should be read as the registry's stated analysis, with its uncertainty and method limitations in view. It is not possible to use the posted summaries to validate the contrast independently or determine the exact derivation of its confidence interval.

12. Multiplicity, Missing Data and Analysis Populations

The trial lists multiple outcomes. Besides the primary repeated iPTH reduction outcome through Week 12, the registry describes percent change in iPTH at Weeks 12 and 24, hypercalcemia events, treatment-emergent adverse events and serious adverse events, and pharmacokinetic measures at Week 8 or 10. The record lists eight outcome measures and seven posted secondary outcomes. When several outcomes or analyses are examined, the chance of at least one apparently notable result can increase. In general, multiplicity procedures can address that issue by controlling a chosen error rate across a family of tests, but the appropriate approach depends on the prespecified analysis plan.

Multiplicity handling, any hierarchy among outcomes, and any adjustment to significance thresholds are not reported in the registry record. The available information therefore does not establish whether the primary comparison was treated as the sole confirmatory test or how secondary analyses were interpreted. The secondary outcomes should not be treated as confirmatory evidence without details about prespecification and multiplicity management.

The primary population is defined as treated participants with at least two post-treatment iPTH assessments. The outcome definition specifies an on-treatment strategy. These descriptions clarify which participants and measurements are considered for the primary endpoint, but they do not explain how missing assessments were handled, whether participants with insufficient assessments were excluded, or how discontinuation and other intercurrent events were treated. Those details are not reported in the registry record.

The record also does not report a full participant flow, the number randomized to each group, or reasons participants may not have contributed to the primary analysis. The primary arm counts are 14 and 7, but they should not be assumed to describe every enrolled or randomized participant. The reason the trial was terminated is not reported. Without these details, readers cannot fully assess the potential impact of missing data, analysis-population selection, or early termination on the estimates.

13. 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: hypertensive urgency (7.1%), bronchial hyperreactivity (7.1%), end stage renal disease (7.1%).

The safety summary reports serious adverse events in 3 of 14 participants in the doxercalciferol group and 0 of 7 participants in the calcitriol group. It also reports other treatment-emergent adverse events in 11 of 14 and 6 of 7 participants, respectively. No deaths are listed in either group. These are counts of participants with events as reported, not estimates that can establish a comparative safety profile on their own.

The listed serious adverse event terms are hypertensive urgency, bronchial hyperreactivity, and end stage renal disease, each shown as 7.1%. The registry does not attach those terms to a particular treatment group in the posted term list, so they should not be interpreted as group-specific rates. A participant may also have experienced more than one event; the record does not provide enough detail to infer participant-level overlap from the listed terms.

In general, safety counts from small groups are imprecise and can be sensitive to the occurrence of a small number of events. The registry does not provide enough information to evaluate event timing, duration, severity beyond the serious classification, relatedness to treatment, or comparative risk. These figures describe the posted safety results and should not be used alone to draw a broad conclusion about safety.

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

The primary result describes the percentage meeting a defined laboratory response criterion: two consecutive iPTH reductions of at least 30% from baseline at consecutive study visits through Week 12. The reported percentages were 14.3% for doxercalciferol and 71.4% for calcitriol. The estimates are accompanied by broad 95% confidence intervals, so their precision is limited. The registry's reported percentage-difference contrast is -52.9, with a 95% confidence interval from -99.90 to -5.98.

These results do not tell readers how much iPTH changed for each participant, whether a response persisted after Week 12, or whether other secondary outcomes followed the same pattern. The primary endpoint reduces each participant's measurements to whether a repeated threshold was met. It does not capture every aspect of the trajectory of iPTH values. The listed secondary outcomes have separate definitions and assessment times, and their results are not included in the primary figures.

The result also does not establish the clinical importance of the measured response. The registry describes the endpoint and the observed percentages but does not provide a threshold linking this specific outcome to clinical benefit. It would therefore be inappropriate to translate the response percentages into advice or a treatment recommendation.

Interpretation is limited by the small analysis groups, the open-label design, and incomplete registry information about missing data, participant flow, analysis details, and the reason for termination. Randomization is a design strength, but it does not remove uncertainty or resolve limitations in reporting. The findings apply to the recorded study population and endpoint; they should not automatically be extended to other populations, treatment schedules, or outcome definitions.

15. Why This Trial Matters Statistically

This trial is statistically useful as an example of how a binary response endpoint can produce strikingly different point estimates while still leaving substantial uncertainty. The primary outcome is not simply a one-time threshold crossing. It requires two consecutive qualifying iPTH reductions, which makes the outcome depend on repeated assessments and the rule used to classify each participant.

The confidence intervals draw attention to precision, not just the displayed percentages. The intervals are broad, emphasizing that small analysis groups provide limited information about the underlying response percentages. Reporting a percentage without its interval would obscure that uncertainty. The registry also reports a contrast with its own confidence interval, but does not state the method used for that comparison or give a p-value.

The record illustrates the distinction between an arm estimate and a treatment contrast. Arm percentages describe outcomes within each group; a contrast answers a comparative question and depends on how the comparison is defined and calculated. A reader should not substitute a newly constructed contrast for the sponsor's reported analysis when the necessary method details are absent.

Finally, a registered trial can leave important interpretation questions unanswered. Here, details about multiplicity, missing-data handling, interim analyses, sample-size justification, and the reason for termination are not reported in the registry record. Recognizing these gaps is part of statistical interpretation: the reported estimates can be described, while conclusions requiring unreported design or analysis information must remain limited.

16. 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 analysis groups were small: 14 participants in the doxercalciferol group and 7 in the calcitriol group. The resulting arm estimates have broad confidence intervals, making their precision limited. The registry reports enrollment of 21, but does not give a full account of randomization, treatment allocation, follow-up, or participant disposition. The analysis counts should not be taken as a complete description of trial flow.

The trial was open-label, with no masking reported. The primary endpoint uses laboratory assessments, but the registry does not describe whether laboratory evaluation or other aspects of outcome assessment were blinded. The two treatment regimens also differed in administration frequency, and both used dose titration. The record does not provide adherence information or detailed rules for dose changes.

The endpoint's analysis population required at least two post-treatment iPTH assessments, and its definition uses an on-treatment strategy. The registry does not explain how missing values, insufficient assessments, treatment discontinuation, or other events affecting measurement were handled. The sponsor's reported comparison is not accompanied by a stated method or p-value, and no independent recalculated contrast is available for this endpoint.

The record lists multiple secondary outcomes, but does not report how multiplicity was handled. The sample-size justification, interim analyses, and rationale for the planned design are not reported in the registry record. The trial status is terminated, but the reason for termination is not reported. These omissions limit assessment of how the study's conduct and analysis may affect the primary result.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Safety and Efficacy of Hectorol in Pediatric Patients With Chronic Kidney Disease Stage 3 and 4 With Secondary Hyperparathyroidism Not Yet on Dialysis — NCT02859896.
• Registry record last updated 2026-07-02; status last verified 2026-06.
• Results first posted 2026-07-02.
• 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.

20. Record Summary

NCT02859896 is a randomized, open-label, parallel-group phase 3 trial in pediatric patients with chronic kidney disease stages 3 and 4 and secondary hyperparathyroidism who were not yet on dialysis. It compared oral doxercalciferol (Hectorol), given two to three times weekly depending on age, with oral calcitriol (Rocaltrol), given seven days per week. Both regimens used individualized dose titration.

The primary outcome was the percentage achieving two consecutive iPTH reductions of at least 30% from baseline at consecutive visits through Week 12. The reported percentages were 14.3% and 71.4%, with broad 95% confidence intervals. The registry reports a percentage-difference contrast of -52.9, with a 95% confidence interval from -99.90 to -5.98.

The registry lists the trial as terminated and does not report the reason. Important details about missing-data handling, multiplicity, and the primary comparison method are not reported in the registry record.