High Dose Vitamin D vs Standard Dose Vitamin D Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for High Dose Vitamin D vs Standard Dose Vitamin D Study (NCT01988090), a randomized phase 2 study. The primary outcome is Number of Participants With Aromatase Inhibitor Induced Arthralgia (AIA) After 12 Weeks of Therapy.

2. Clinical Question

3. Trial Design

This was a randomized, controlled, parallel-group phase 2 study comparing 50,000 IU vitamin D with 800 IU vitamin D in breast cancer survivors taking aromatase inhibitors. The registry lists an enrollment of 93. It identifies the study as having no masking, so participants and study personnel were not described as blinded to the assigned dose. The study status is terminated; the reason for termination is not reported in the registry record.

The clinical motivation was aromatase-inhibitor induced arthralgia, a joint or muscle pain concern described in the study summary. The investigators were interested in whether dose of vitamin D affected the development of AIA. The primary outcome was the number of participants meeting the AIA definition after 12 weeks of therapy. The registry also lists secondary outcomes concerning compliance with anti-cancer treatment and the association between changes in vitamin D levels and treatment.

The record describes the primary analysis population as intent-to-treat, including all patients randomized in the overall evaluation of response. That description identifies the intended population for the primary evaluation, but it does not establish how missing outcome measurements were handled. Details of follow-up completeness and the analysis population used for each secondary outcome are not reported in the registry record.

Randomization can help balance known and unknown participant characteristics between groups on average, while an open-label design can leave outcomes vulnerable to differences in expectations, reporting, or care. The AIA endpoint relied on questionnaire-based pain and function measures, so the lack of masking is relevant to interpretation. The registry record does not report details of sequence generation, allocation concealment, stratification, or other implementation features of randomization.

The record does not describe a sample-size justification, a detailed statistical analysis plan, or interim analyses. It does state assumptions for sample-size planning illustrations based on the observed effect, including a two-sided significance level of 0.05, equal allocation, and a normal approximation. Those are planning assumptions, not evidence about the study’s observed precision or power.

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.

Start Treament After Randomization

Reasons for not completing this period:

Complete Study After Start

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT population. All patients who were randomized in the study were included in the overall evaluation of response (intent-to-treat analysis).

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 Aromatase Inhibitor Induced Arthralgia (AIA) After 12 Weeks of Therapy, measured over 12 weeks.

The primary endpoint was the number of participants with aromatase-inhibitor induced arthralgia after 12 weeks of therapy. The study treated AIA as a binary outcome: a participant either met the operational definition or did not. The stated population was intent-to-treat, described as all randomized patients included in the overall evaluation of response.

AIA was assessed with a questionnaire covering pain and functioning. The HAQ-II included 20 questions scored 0-3 across 8 functioning categories: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. An average composite HAQ-II score was calculated. The visual analog scale was another component: participants marked their pain on a horizontal line, which was converted to a score from 0 to 3.

For this study, a participant met the AIA definition if the HAQ-II score increased from baseline by 0.2 or greater, or if the visual analog pain score increased by 0.3 or greater. Combining these criteria creates an event definition that can be counted across participants. Such an endpoint can be easier to interpret as a participant-level outcome than a continuous score, but it depends on the selected thresholds and the completeness and consistency of questionnaire measurement.

The registry record does not report the number meeting the AIA definition in each arm or a comparative estimate. Consequently, the endpoint definition is available, but the posted information does not establish the observed difference between dose groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a binary primary outcome and an intent-to-treat population, but it does not report the primary comparison estimate or a complete statistical analysis plan. The concepts below explain how this kind of study outcome is generally analyzed; they do not describe unreported analyses as if they were performed.

What does a binary endpoint represent?

A binary endpoint places each participant into one of two outcome categories, such as meeting or not meeting a prespecified event definition. In this study, the event was AIA according to the stated change-from-baseline criteria. Counting participants who meet the definition allows a comparison of event occurrence between the treatment groups. The count by itself, however, is not a complete comparison: interpretation also depends on the number assessed in each group, the chosen effect measure, and uncertainty around that measure.

Binary outcomes can be summarized using measures such as a difference in event proportions or a relative measure. Which measure is appropriate depends on the analysis plan and the scientific question. The registry record does not report a primary effect estimate, so no particular comparative measure should be attributed to this study. A recalculation from summary statistics would also require the relevant primary outcome counts, which are not reported in the registry record.

What does an uncertainty interval tell a reader?

In general, a confidence interval describes a range of effect values compatible with the observed data under the statistical model and its assumptions. A narrower interval indicates greater precision than a wider interval, although precision does not establish that the estimate is free of bias. An interval is especially useful alongside an effect estimate because it shows how much uncertainty remains around the estimated difference or association. No confidence interval for the primary outcome is reported in the registry record.

A p-value, in general, describes how unusual data at least as inconsistent with a null hypothesis would be if that hypothesis and the analysis assumptions were correct. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The record does not report a primary p-value or enough primary outcome information to reconstruct one. Statistical significance therefore cannot be assessed from the available primary endpoint information.

Why does the endpoint definition matter?

The AIA outcome depends on changes from baseline in either the HAQ-II score or the visual analog pain score, using the stated thresholds. Such thresholds turn continuous measurements into a participant-level event. This can make the result more directly interpretable as the occurrence of a defined worsening, but categorizing a score also discards information about the magnitude of changes. A small change around a threshold can alter the event classification, while differences in measurement or missing questionnaire items can affect whether the endpoint can be assigned.

These are general considerations, not claims that such problems occurred in this trial. The record describes the questionnaire and the event definition, but it does not report measurement completeness, scoring procedures for incomplete questionnaires, or sensitivity analyses around the thresholds.

Why can over-dispersion matter?

Over-dispersion is a general issue in models for count data when observed variability is greater than the model expects. It can lead to uncertainty estimates that are too small if the model assumes less variability than the data contain. The primary outcome is described as a participant count for a binary event, rather than a repeated event-rate outcome, so over-dispersion should not be presumed to be a feature of the reported primary analysis. If count-based secondary outcomes were modeled, the model choice and diagnostics would matter; those details are not reported in the registry record.

What does randomization contribute?

In general, random assignment aims to make treatment groups comparable at the start of a trial, reducing systematic differences in measured and unmeasured characteristics on average. It does not guarantee exact balance in a particular study, and it does not protect against all bias after assignment. In an open-label trial, awareness of assigned dose may influence subjective symptom reporting, participant behavior, or other aspects of follow-up. That consideration is relevant because the primary outcome includes self-reported pain and functioning. The record identifies the study as randomized and unmasked but does not report allocation concealment or the methods used to generate the sequence.

What do the planning assumptions mean?

Sample-size planning illustrations are prospective calculations about how many participants might be needed under specified assumptions. The registry states that its illustrations use the observed effect, a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. Such values are planning illustrations, not observed power and not a substitute for the trial’s actual uncertainty estimates. The numerical illustration values are not reported in the information available for this analysis, and the primary effect itself is not reported, so no planning quantity can be interpreted.

The record does not report the trial’s own sample-size justification, whether any interim analyses occurred, or a full statistical plan. Those omissions limit assessment of whether the analysis choices were prespecified, how multiplicity was handled, and how missing outcomes were treated. The registry’s enrollment figure cannot resolve these methodological questions.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary outcome and secondary outcomes concerning compliance with anti-cancer treatment and changes in vitamin D levels. It also reports four outcome measures and two analyses, but does not provide enough detail to determine the full family of statistical tests or how the analyses relate to those outcomes. A multiplicity adjustment or other strategy for controlling the risk of false-positive findings is not reported in the registry record.

In general, testing several outcomes, time points, or contrasts can increase the chance of finding an apparently notable result by chance if each test is interpreted separately. A prespecified hierarchy, adjustment method, or clear distinction between primary and exploratory analyses can help readers understand the evidential weight of results. The record does not describe such a strategy, so no specific multiplicity procedure should be assumed.

The primary population is described as intent-to-treat, with all randomized patients included in the overall evaluation of response. This identifies the intended analysis population, but does not explain how missing outcome measurements were handled. The record does not report the extent of missing primary endpoint data, reasons for missingness, imputation methods, or sensitivity analyses. It is therefore not possible to assess how incomplete questionnaires or unavailable follow-up may have affected the primary comparison.

These gaps do not establish that missing data or multiplicity problems occurred. They indicate that the registry information does not allow readers to evaluate those aspects of the analysis. The primary outcome comparison itself is not reported in the registry record, further limiting assessment of the statistical evidence.

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: skin infection (2.3%), renal and urinary disorders - other, specify (2.3%).

The registry lists serious adverse events by treatment group. In the high-dose arm, 2 participants were affected among 44 at risk; in the 800 IU arm, 0 were affected among 43 at risk. It also reports other adverse events affecting 35 participants in the high-dose arm and 36 in the 800 IU arm. These are descriptive counts. They should not be treated as proof that a treatment caused an event or that the groups have meaningfully different safety profiles.

The listed serious-event terms are Skin infection at 2.3% and Renal and urinary disorders - Other, specify at 2.3%. The record does not show which treatment arm each listed term belongs to in the information available for this analysis. The terms also do not, by themselves, provide details about severity, timing, recurrence, or relatedness to treatment.

General interpretation of adverse-event counts requires attention to the event definitions, observation period, collection procedures, and follow-up completeness. Comparative conclusions also require an analysis that accounts for the group sizes and uncertainty. Those details and a comparative safety analysis are not reported in the registry record. The counts are useful as a record of reported events, but they are not a standalone assessment of causality or comparative risk.

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

The study addresses a focused clinical research question: whether AIA after 12 weeks differed between breast cancer survivors assigned to 50,000 IU vitamin D and those assigned to 800 IU vitamin D. The registry record establishes that the study was randomized, parallel-group, and open-label, and it describes how AIA was defined using questionnaire-based changes from baseline.

What the posted information does not establish is the primary outcome result. No arm-specific AIA counts, comparative effect estimate, confidence interval, or primary p-value are reported in the registry record. The endpoint definition alone cannot show whether AIA was more or less common in either group. It also cannot show how large or precise a difference may have been.

The available safety counts describe events recorded in the two arms, including serious adverse events and other adverse events. These data do not establish that an event was caused by vitamin D or that one dose is safer than the other. The listed serious-event terms are not linked to treatment arms in the information available for this analysis.

In general, a statistically nonsignificant result, if reported, would not prove that treatments are equivalent; an equivalence or noninferiority question requires an appropriate design and prespecified criteria. No such conclusion can be drawn here, because the primary comparative result is not reported. Likewise, the study’s terminated status does not explain why it ended, and the reason is not reported in the registry record.

The appropriate reading is therefore limited but clear: the record describes the question, the endpoint, the study design, and selected safety counts, while leaving the main comparative efficacy result unavailable. No claim about benefit, lack of benefit, equivalence, or treatment choice follows from the posted information alone.

13. Why This Trial Matters Statistically

This trial illustrates why a clearly defined endpoint and a reported comparative result are both needed for statistical interpretation. The registry specifies a participant-level AIA outcome based on changes in function and pain measures. That definition allows readers to understand what counted as an event, but it does not reveal how often the event occurred in either arm or how uncertain a comparison would be.

It also highlights the importance of reporting effect estimates with measures of uncertainty. Counts can be informative, particularly for safety, but they do not by themselves show the size or precision of a between-group effect. The serious adverse-event counts are sparse in the sense that the record reports only a small count in one arm and none in the other; without a comparative analysis and uncertainty measure, the strength of any safety inference remains unclear.

The open-label design is statistically relevant because pain and functioning were assessed through participant reports. Randomization helps address baseline confounding, but it does not remove the possibility that awareness of assignment influences reporting or follow-up. This is a general interpretive concern rather than evidence that bias occurred in this study.

The registry also distinguishes trial results from planning calculations. A sample-size illustration based on an observed effect and specified assumptions is not observed power and cannot replace the actual effect estimate and its uncertainty. Here, the primary result needed to interpret such an illustration is not reported in the registry record.

More broadly, this study shows that registry records can document design and outcome definitions while leaving readers unable to evaluate the principal comparison. Transparent reporting of outcome counts, analysis methods, missing-data handling, and uncertainty is essential for separating a well-defined question from an interpretable answer.

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 central limitation for interpreting this trial is that the primary outcome comparison is not reported in the registry record. Although the AIA endpoint and its assessment criteria are described, the number meeting the definition in each arm and the comparative estimate are unavailable. This prevents assessment of the direction, magnitude, and precision of the primary result.

The study was open-label, and the endpoint included participant-reported pain and functioning. In general, awareness of assignment can influence subjective assessment. Randomization remains a strength of the design, but the registry record does not report allocation concealment or enough implementation detail to assess all potential sources of bias.

Important analysis details are also not reported: the full statistical plan, treatment of missing outcome data, completeness of follow-up, and any multiplicity strategy. The stated intent-to-treat population does not by itself explain how participants without an observed endpoint were handled. The record does not provide enough information to assess whether the analysis followed prespecified procedures.

The registry lists safety counts and event terms, but not enough detail to determine the relationship of events to treatment, their timing, or a comparative safety estimate. The reason for the terminated status is not reported in the registry record. These limitations constrain interpretation; they do not establish that a particular bias, missing-data problem, or safety concern occurred.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: High Dose Vitamin D vs Standard Dose Vitamin D Study — NCT01988090.
• Registry record last updated 2021-08-09; status last verified 2021-08.
• Results first posted 2019-03-19.
• 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

The record describes NCT01988090, a randomized, controlled, open-label, parallel-group phase 2 study of high-dose versus standard-dose vitamin D for aromatase-inhibitor induced arthralgia in breast cancer survivors. Enrollment was 93, and the study status is terminated. The reason for termination is not reported in the registry record.

The arms received 50,000 IU and 800 IU vitamin D. The primary outcome was the number of participants with AIA after 12 weeks, defined through specified changes in HAQ-II or visual analog pain scores. The primary population was described as intent-to-treat. The primary comparative outcome result is not reported in the registry record.

Reported safety information includes serious and other adverse-event counts by arm and two listed serious-event terms. The record also lists secondary outcomes on compliance with anti-cancer treatment and changes in vitamin D levels. Details of multiplicity handling, missing-data methods, and the complete statistical plan are not reported in the registry record.