Safety of Vitamin D Supplementation in Older Persons: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of Vitamin D Supplementation in Older Persons (NCT00681590), a randomized phase 3 study. The primary outcome is Number of Participants Who Develop Hypercalcemia.

2. Clinical Question

The registry also describes an interest in whether supplementation improves physical performance. However, the posted secondary outcome is change from baseline in serum 25-hydroxyvitamin D levels; a physical-performance outcome is not reported in the registry record. The distinction matters: a change in a blood marker addresses a biochemical response, while the primary endpoint concerns a safety event. Neither alone answers every question that may motivate supplementation.

The question is comparative rather than a test of supplementation against no treatment. Any interpretation therefore concerns the two assigned daily doses in the studied population and follow-up period. The registry does not report enough detail to extend the result to other doses, durations, populations, or settings.

3. Trial Design

The registry describes a Phase 3, randomized, quadruple-masked, parallel-group study sponsored by the University of Miami. The listed enrollment is 105. The study status is completed; its start is recorded as 2008-04 and primary completion as 2009-04. These registry descriptors characterize the design but do not, by themselves, establish how successfully masking was maintained or how participants were recruited and followed.

Participants were assigned to one of two active cholecalciferol regimens: 400 IU daily by mouth or 2000 IU daily by mouth. The record does not describe a placebo group. The term “parallel” indicates that the groups are compared across the intervention period rather than participants crossing between regimens, but details of the visit schedule beyond the calcium measurements are not reported in the registry record.

The primary endpoint is assessed over 6 months. Serum calcium was measured at baseline and at the end of the intervention, and the primary outcome is the number of participants who developed hypercalcemia. The registry also lists change from baseline in serum 25-hydroxyvitamin D levels, with measurements at baseline and 6 months.

The reported group counts are 34 participants in the 400 IU group and 71 in the 2000 IU group for the primary outcome. The record does not explain the unequal group sizes, whether all enrolled participants were included in each analysis, or whether any participants discontinued or had missing measurements. The planned allocation ratio, concealment procedures, detailed masking roles, eligibility criteria, and statistical analysis plan are not reported in the registry record. Randomization and masking are useful design features, but the record alone cannot confirm implementation details or remove uncertainty from the small number of primary events.

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:

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 Who Develop Hypercalcemia, measured over 6 months.

The primary endpoint is the number of participants who develop hypercalcemia during the 6-month intervention. Serum calcium was measured at baseline and at the end of the intervention. This endpoint is used to assess a potential safety outcome associated with the assigned vitamin D doses; it is not a measure of physical performance or of overall health.

Counting participants with the event gives an interpretable group-level summary: the event count is considered alongside the number of participants at risk in each group. The registry reports 0 of 34 participants in the 400 IU group and 2 of 71 in the 2000 IU group as developing hypercalcemia. With only a small number of events, the observed counts provide limited information about how frequently the event might occur beyond these participants. A zero count in a group does not establish that the event cannot occur in similar people.

The record does not specify the laboratory threshold or clinical criteria used to classify hypercalcemia, how borderline measurements were handled, or whether confirmation was required. It also does not report whether the outcome was assessed by masked reviewers. Those details would help readers judge consistency of measurement and classification. The endpoint is therefore interpretable at the level of the posted counts, but the registry record does not supply all the operational detail needed to independently reproduce its definition.

7. Results Posted in the Registry

• Vitamin D 2000 IU: 2.8% (2/71) versus 0.0% (0/34) on control; risk difference 2.8 percentage points (95% CI -1.0 to 6.7); unadjusted two-proportion z-test p = 0.323.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change From Baseline in Serum 25-hydroxyvitamin D Levels

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Vitamin D 2000 IU: mean 6.50 versus -0.50 on control; difference 7.00 (95% CI 5.56 to 8.44), standardized effect d = 1.41; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Vitamin D 2000 IU than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcome listed in the registry is change from baseline in serum 25-hydroxyvitamin D levels. The posted direction favors a larger mean increase in the 2000 IU group than in the 400 IU group, and the unadjusted comparison is statistically distinct from zero under the reported result. This is a biochemical pattern, not a direct measure of physical performance or a substitute for the primary safety endpoint.

The primary outcome concerns participants who developed hypercalcemia, while the secondary outcome concerns a change in a blood marker. These outcomes address different questions and can show different levels of statistical precision. The secondary result does not resolve the uncertainty surrounding the small number of primary events, and the primary event counts do not negate the observed biochemical contrast. Each result must be interpreted in the context of its own measurement, analysis, and uncertainty.

The registry summary mentions physical performance as an objective, but a physical-performance outcome is not reported in the registry record. The posted secondary outcome therefore cannot be taken as evidence about functional performance. Further outcomes, their results, and any reasons for not reporting them are not described.

The secondary p-value is unadjusted. When several outcomes or comparisons are examined, the chance of at least one apparently strong result can increase. The registry does not report how many analyses were planned, whether other outcomes were measured but omitted, or whether any multiplicity adjustment was prespecified. For that reason, an unadjusted secondary finding generally carries less confirmatory weight than a clearly prespecified primary analysis with a documented plan. The record does not report such a plan, so the degree of prespecification cannot be assessed.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change From Baseline in Serum 25-hydroxyvitamin D Levels

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: each participant is classified according to whether hypercalcemia occurred. For a binary outcome, the event risk is the number of participants with the event divided by the number at risk in that group. The group counts and denominators are reported as 0 of 34 for 400 IU and 2 of 71 for 2000 IU. A risk difference expresses the absolute contrast between those group risks. Positive values in the posted comparison indicate a higher event risk in the 2000 IU group relative to the 400 IU group; negative values indicate a lower risk in that group.

The posted risk difference is 0.028, and its confidence interval ranges from -0.010 to 0.067. The interval communicates uncertainty in the estimated contrast, not a range that contains a specified percentage of individual participant outcomes. Because it crosses zero, it includes no difference as a plausible value under the method used. The unadjusted p-value of 0.323 is a measure of how inconsistent the observed data are with a no-difference null model under the test assumptions. It is not the probability that the null hypothesis is true, nor a measure of clinical importance.

The registry does not report the precise statistical test, confidence-interval method, any covariate adjustment, or a detailed analysis plan. Accordingly, readers should avoid attributing a particular model or procedure to the investigators. The registry comparison is unadjusted, and the record does not describe any adjusted primary estimate. Whether adjustment would have been planned or appropriate is not reported in the registry record.

Why do few events matter?

When events are uncommon in the observed sample, estimates of group risks and their difference can be unstable. A change in the classification of a small number of participants can materially alter the apparent contrast. This is why event counts should be read together with denominators and confidence intervals. The absence of events in the 400 IU group is an observation in this sample, not evidence that risk is exactly zero in the broader population.

Over-dispersion is a general concern when a model assumes less variability than the data contain. In binary-outcome analyses, the more immediate issue in this record is the small event count and consequent uncertainty; no over-dispersion model or related adjustment is reported. It would not be justified to assert that over-dispersion was tested or corrected.

How should the secondary comparison be read?

The secondary outcome is continuous: change from baseline in serum 25-hydroxyvitamin D levels, expressed in ng/ml. The reported group means are -0.5 in the 400 IU group and 6.5 in the 2000 IU group, with standard deviations of 1.0 and 6.0, respectively. The posted mean difference is 7.0, with a confidence interval from 5.564 to 8.436 and an unadjusted p-value of <0.001. A mean difference describes the contrast between group averages; it does not imply that every participant had a change of that size.

The standard deviation describes variability among participant measurements, whereas a standard error describes uncertainty in an estimated mean. These quantities answer different questions and should not be interchanged. The registry lists standard deviations for the outcome and does not report a separate investigator analysis. No adjustment for baseline values or other covariates is reported in the registry record.

What do the planning illustrations mean?

The sample-size illustrations are calculations based on the observed secondary-outcome effect, not the trial's own design justification. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between groups, and a normal approximation. They estimate participants per arm for 80% power and participants per arm for 90% power when planning for 100% of the observed effect, 75% of the observed effect, or 50% of the observed effect. The associated values are listed as 8 and 11, 15 and 19, and 32 and 43, respectively.

These are planning illustrations, not observed power and not evidence that the trial was designed to detect those effects. They rely on the observed effect, which is itself uncertain, and use assumptions that may differ from the actual trial design. The registry does not report the trial's sample-size justification, target effect, planned power, or allocation assumptions. The calculations therefore cannot fill those gaps.

11. Confidence Intervals and Precision

The primary risk-difference estimate is 0.028, with a confidence interval from -0.010 to 0.067. In general, a confidence interval presents a range of estimates compatible with the observed data and the method's assumptions. It reflects statistical uncertainty in the estimated group contrast; it does not describe the spread of individual outcomes or guarantee that the true value lies inside the interval.

For this endpoint, the interval includes zero and extends in both directions from it. The result therefore does not pinpoint whether the underlying event risk is higher in the 2000 IU group, lower in that group, or similar across groups. The interval's width should be read in light of the low number of observed events: sparse event data tend to leave considerable uncertainty even when group counts and denominators are available. The p-value of 0.323 is consistent with the interval not providing a clear distinction from zero under the reported unadjusted comparison.

Precision is not the same as importance. A narrow interval can still contain effects of little practical importance, while a wide interval may include effects that warrant further study. The registry does not state a threshold for a clinically important difference in hypercalcemia risk, so the practical interpretation of values across this interval cannot be resolved from the record alone.

The secondary mean-difference interval, from 5.564 to 8.436 ng/ml, is more concentrated around its estimate than the primary interval in its own units. It describes uncertainty for a different outcome and cannot be used to make the primary safety result more precise. Comparing interval widths across outcomes with different units and scales is not meaningful. The analysis details and any adjustments behind the posted intervals are not reported in the registry record.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and a secondary outcome, but it does not provide a full statistical analysis plan. In particular, multiplicity procedures are not reported in the registry record. When investigators test multiple outcomes or conduct multiple analyses, the chance of obtaining a nominally notable result can rise. Adjustments or a prespecified hierarchy can help address that issue, but it is not possible to determine from this record whether such procedures were planned or used.

The secondary comparison is explicitly unadjusted in the posted results. That designation does not establish whether it was the only secondary analysis undertaken. The record does not report a broader list of planned analyses, subgroup analyses, interim analyses, or any strategy for controlling multiplicity. Their use or absence should not be inferred.

Missing-data handling is also not reported in the registry record. The posted outcome denominators are 34 and 71 for the primary endpoint, but the record does not state whether these represent all randomized participants, all participants with complete follow-up, or a particular analysis population. It does not describe withdrawals, loss to follow-up, imputation, or sensitivity analyses. The registry does not report an intention-to-treat, per-protocol, or safety analysis population definition.

These gaps limit assessment of whether the posted estimates preserve the benefits of randomization and how robust they are to missing measurements or analytic choices. The study is marked completed, but completion status does not supply the missing details. The registry also does not report a protocol-based sample-size justification or the planned handling of protocol deviations. As a result, the statistical certainty and confirmatory status of the comparisons cannot be fully judged from the registry record.

13. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures list 0 affected participants among 34 at risk in the 400 IU group and 0 among 71 at risk in the 2000 IU group. These are observed counts during the recorded safety reporting period, and they indicate that no serious adverse events were recorded in either group in these figures. With no events observed, the results do not establish that serious events are impossible or that the groups have identical underlying risk.

For other adverse events, the registry lists 0 affected participants among 34 at risk in the 400 IU group and 2 among 71 at risk in the 2000 IU group. Specific serious adverse event terms are not reported in the registry record. Death counts are not reported in the registry record. The record does not give event descriptions, severity grading details, timing, relatedness assessments, or whether the affected participants had more than one event.

These safety figures should be read as descriptive counts, not as proof of causation or as a complete safety profile. They cover the groups and reporting captured in the registry, while the short follow-up and limited number of participants constrain the information available about uncommon events.

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

The primary result describes the observed number of participants who developed hypercalcemia during the 6-month comparison of 400 IU and 2000 IU daily cholecalciferol. The point estimate is higher in the 2000 IU group, but the confidence interval includes zero and the unadjusted p-value is 0.323. The comparison does not provide statistically clear evidence of a difference in this sample. It also does not prove that the doses have equal risks or exclude differences that the data estimate imprecisely.

The result applies to the recorded groups and the follow-up described in the registry. It should not be generalized automatically to other populations, dosing schedules, durations, or treatment settings. Additional eligibility details and baseline characteristics are not reported in the registry record, which further limits judgments about how closely other populations resemble these participants.

The secondary biochemical result has a different meaning from the primary safety outcome. A change in serum 25-hydroxyvitamin D does not establish a change in physical performance, and a physical-performance result is not reported in the registry record. Nor should a biochemical result be treated as evidence that all potential benefits or harms have been measured.

The absence of serious adverse events in the posted counts is reassuring only as a description of what was recorded in this sample; it cannot rule out uncommon events. Similarly, zero hypercalcemia events in the lower-dose group does not imply zero risk in the population. Low event counts and limited follow-up make careful attention to uncertainty essential.

The registry result is therefore best understood as a descriptive, imprecise comparison, not a definitive statement that the regimens are equivalent, that one is safer, or that supplementation changes clinical outcomes. The unreported analysis plan, outcome definitions, missing-data methods, and participant-level follow-up details further constrain the strength of conclusions that can be drawn.

15. Why This Trial Matters Statistically

This trial illustrates why a randomized comparison can still yield an uncertain answer about a safety endpoint. Random allocation is intended to support a fair comparison between groups, and masking can reduce some forms of bias, but neither feature guarantees precision. The primary outcome has few recorded events, so the estimate is sensitive to sparse data and its interval remains compatible with differing underlying risks.

It also shows why the outcome scale matters. A risk difference communicates an absolute contrast between the event risks, while the count of affected participants makes the underlying evidence visible. The p-value alone cannot convey the direction, size, or uncertainty of the comparison. Reading the estimate, interval, event counts, and denominators together gives a more complete statistical interpretation.

The separation between the primary safety endpoint and the secondary biochemical measure is equally important. A clear contrast in a laboratory marker does not settle uncertainty about hypercalcemia, and it cannot answer the registry's stated interest in physical performance when that outcome is not reported. Statistical evidence is outcome-specific.

Finally, the record demonstrates the value of transparent methods reporting. Without the analysis plan, missing-data handling, analysis-population definitions, multiplicity procedures, and sample-size justification, readers cannot fully evaluate whether the posted analyses match the intended design. Planning illustrations based on observed effects can help frame future study design, but they are not substitutes for the original trial's design rationale or evidence of its achieved power.

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 endpoint definition is incomplete in the registry record. Serum calcium was measured at baseline and at the end of the intervention, but the threshold for hypercalcemia, confirmation rules, and event-adjudication procedures are not reported. These details could affect how consistently the outcome was classified.

The primary comparison is based on few recorded events, and the confidence interval is compatible with a range of contrasts that includes no difference. The study's reported enrollment is 105, but the record does not explain the unequal outcome denominators of 34 and 71 or clarify whether those are the randomized groups, the analyzed groups, or participants with complete outcome data. Follow-up completeness and missing-data procedures are not reported.

Although the registry identifies the study as randomized and quadruple-masked, it does not describe the allocation procedure, masking roles, or whether masking remained effective. Baseline participant characteristics, detailed eligibility criteria, and reasons for discontinuation are not reported in the registry record. These omissions restrict assessment of applicability and the conduct of the trial.

The statistical analysis plan, sample-size justification, analysis populations, interim analyses, and multiplicity procedures are not reported. The secondary outcome has an unadjusted comparison, and the registry does not clarify whether other secondary analyses were planned or conducted. The stated objective includes physical performance, but no physical-performance outcome is posted. Follow-up is limited to the stated 6-month intervention for the primary outcome, so the record does not address longer-term safety.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Safety of Vitamin D Supplementation in Older Persons — NCT00681590.
• Registry record last updated 2017-01-26; status last verified 2016-12.
• Results first posted 2016-03-07.
• 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

The registry record describes a completed, randomized, quadruple-masked, parallel-group Phase 3 study of cholecalciferol in men and women age 65 and older with vitamin D deficiency. Enrollment was 105, and the study compared 400 IU daily with 2000 IU daily over 6 months. The primary outcome was the number of participants who developed hypercalcemia, assessed with serum calcium measurements at baseline and at the end of the intervention.

The posted primary counts are 0 of 34 in the 400 IU group and 2 of 71 in the 2000 IU group. The risk-difference estimate is 0.028, with a confidence interval from -0.010 to 0.067 and an unadjusted p-value of 0.323. The secondary outcome is change in serum 25-hydroxyvitamin D levels. The registry does not report a physical-performance outcome, detailed analysis methods, missing-data handling, or the trial's sample-size justification.