Thiazolidinedione Intervention With Vitamin D Evaluation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Thiazolidinedione Intervention With Vitamin D Evaluation (NCT00879970), a randomized phase 4 study. The primary outcome is Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD).

2. Clinical Question

3. Trial Design

TIDE (Thiazolidinedione Intervention With Vitamin D Evaluation) was a Phase 4, randomized, quadruple-masked, placebo-controlled trial with a factorial model. Its official title describes a multicenter study in people with type 2 diabetes at risk for cardiovascular disease. The registry lists enrollment of 1332 participants. It records a start date of 2009-05, primary completion in 2010-11, and a terminated status.

The study addressed two distinct questions. One tested cardiovascular effects of long-term rosiglitazone or pioglitazone, when used as part of standard care, against similar standard care without either drug. The other compared long-term vitamin D supplementation with placebo on death and cancer. The registry describes pioglitazone and rosiglitazone as drug interventions, vitamin D as a dietary supplement, and placebo interventions for both treatment questions.

The descriptions state that pioglitazone began at 30 milligrams (mg) once daily and could be titrated to a maximum of 45 mg at or after the 6-month visit; after 1 year, the dose was increased to 45 mg once daily for the duration of 5.5 years. Rosiglitazone began at 4 mg once daily and could be titrated to a maximum of 8 mg at or after the 6-month visit; after 1 year, the dose was increased to 8 mg once daily for the duration of 5.5 years. A matching TZD placebo tablet was administered once daily for the duration of 5.5 years. The registry does not provide comparable dosing detail for vitamin D.

Although the record identifies randomization, masking, and a factorial model, it does not report the allocation sequence, exact factorial assignment structure, or masking procedures. The planned long-term treatment descriptions should not be taken as evidence that every participant received treatment for the full described duration. The recorded primary endpoint timeframe is from randomization at Visit 3 to the final visit, with an average of 162 days.

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: Randomization occurred subsequent to a 3-week rosiglitazone (RSG) and vitamin D Single-blind Run-in Phase to assess compliance and tolerability. Participants received an RSG tablet (4 milligrams \[mg\]) and a vitamin D tablet (1000 international units \[IU\]) once a day.

Period 1 TZD Randomization

Reasons for not completing this period:

Period 2 Vitamin D Randomization

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-Treat (ITT) Population: all randomized participants

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 the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD), measured over From Randomization at Visit 3 up to the Final Visit (average of 162 days).

The primary TZD endpoint is a composite count of participants experiencing an indicated cardiovascular event. The components are cardiovascular death for which a non-heart-related cause was not identified, non-fatal myocardial infarction, and non-fatal stroke. The registry states that an event adjudication committee adjudicated occurrences. The endpoint population is the Intent-to-Treat population, defined as all randomized participants.

A composite endpoint combines multiple clinically relevant event types into one outcome. In general, this can capture a broader range of events than any single component and can make an overall treatment comparison possible when the components are related to a common clinical question. Interpretation still depends on knowing which components occurred, how often each occurred, and whether the component results are consistent. A composite total alone can obscure differences in the types or severity of events.

The timeframe is recorded as beginning at randomization at Visit 3 and continuing to the final visit, with an average of 162 days. This is the timeframe attached to the registry outcome, not a guarantee that each participant had the same observation period. The registry record does not report the component counts, group-specific composite counts, or comparative estimates for this endpoint. Consequently, the stated outcome definition can be described, but the observed cardiovascular contrast between groups cannot be interpreted from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in the registry record is limited. It identifies a randomized factorial trial, a primary endpoint expressed as participants with events, and an Intent-to-Treat population. It does not report a statistical analysis plan, the model used for the primary comparison, any effect estimate, confidence interval, p-value, or analysis-specific denominator. The following concepts explain how such outcomes are generally interpreted; they do not describe an analysis documented for this trial.

What does a participant count represent?

For a binary outcome, each participant is classified as having or not having the event during the defined observation period. A count of participants with an event describes how many met the outcome definition. To compare groups, the counts need to be read with the corresponding denominators and follow-up context. Counts alone do not show the probability of an event in each group, and they do not quantify uncertainty around a treatment contrast. The registry lists this outcome as a participant count, but does not report the primary component or composite counts by group.

Why define a composite endpoint?

A composite combines more than one event type under a shared endpoint definition. In general, it may reflect a broader clinical outcome and can accrue events across its components. Its interpretation requires attention to each component: a composite result may be driven mainly by one component, and components can differ in importance or frequency. Here, the registry specifies cardiovascular death without an identified non-heart-related cause, non-fatal myocardial infarction, and non-fatal stroke. It notes adjudication by an event adjudication committee, but does not give event counts or component-level analyses.

What does randomization contribute?

In general, random assignment is intended to make treatment groups comparable at the start of a trial, on average, so that outcome differences can be interpreted as evidence about assigned treatment under appropriate conduct and analysis. Randomization does not by itself guarantee that follow-up is complete, that treatment is taken as intended, or that an analysis is unbiased. Those questions depend on trial conduct, outcome ascertainment, missing-data handling, and the analysis plan. The record identifies randomization but does not describe these details.

What is an Intent-to-Treat population?

In general, an Intent-to-Treat analysis retains participants in the groups to which they were randomized, regardless of subsequent treatment changes. This approach can preserve the benefits of randomization and estimates the effect of assignment rather than necessarily the effect of continuous treatment received. The registry defines the primary endpoint population as all randomized participants. It does not state how missing outcome information, treatment discontinuation, or other deviations were handled, so the label alone does not establish how the analysis was implemented.

How should uncertainty be assessed?

A confidence interval is a range of values compatible with the observed data under a specified statistical method. It communicates both the estimated contrast and its precision. A wide interval indicates substantial uncertainty; a narrow interval indicates greater precision under the model assumptions. A p-value addresses how surprising the observed data would be under a specified null hypothesis and analysis model. Neither an interval nor a p-value is reported for the primary cardiovascular outcome in the registry record, so neither statistical significance nor precision can be evaluated from that endpoint.

What does the factorial model imply?

In general, a factorial design can evaluate more than one intervention question within a trial. It may also allow evaluation of whether the effect of one intervention differs according to the other intervention, depending on the design and analysis. Such interpretation requires knowing assignment combinations, the planned contrasts, and whether interaction was assessed. The record names a factorial model and describes separate TZD and vitamin D questions, but does not report the assignment structure or interaction analysis. No interaction result should be inferred.

Why does multiplicity matter?

When many outcomes, treatment comparisons, or subgroup analyses are tested, the chance of at least one apparently notable result can increase. In general, a statistical plan may specify a primary outcome, testing order, or adjustment approach to address this issue. The record lists 15 outcome measures and 0 analyses, but does not describe a multiplicity strategy or an analysis hierarchy. It is therefore not possible to determine from the registry record which comparisons were prespecified or how any multiplicity was handled.

What can safety counts establish?

Safety counts describe observed events in the categories recorded. They are useful for documenting what was reported, but counts are not automatically estimates of comparative risk. Interpretation needs denominators, definitions, follow-up duration, and a clear understanding of whether groups overlap or represent distinct assignments. In general, rare events can also yield imprecise comparisons. The record lists serious adverse-event counts and selected event terms, but it does not provide comparative estimates or a statistical model for them.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 15 outcome measures and 0 analyses. The primary TZD endpoint is a composite cardiovascular outcome, while the study also posed a separate vitamin D question concerning death and cancer and lists secondary outcomes that include revascularization, hospitalization, microvascular outcomes, hypoglycemia, proteinuria, and fracture. With multiple outcomes and treatment questions, multiplicity is relevant: in general, testing many hypotheses can increase the chance of apparently notable findings. The record does not describe a testing hierarchy, adjustment method, or prespecified approach to multiplicity.

The record identifies the primary endpoint population as Intent-to-Treat and defines it as all randomized participants. This identifies the population concept but does not describe the actual handling of missing outcome information. Missing-data rates, reasons for missingness, imputation methods, sensitivity analyses, and the number included in each outcome analysis are not reported in the registry record. It is therefore not possible to judge whether missingness might have affected the reported outcomes.

The factorial model and separate TZD and vitamin D questions raise additional analysis questions. The record does not describe how the factorial comparisons were constructed, whether an interaction between interventions was assessed, or how any such analysis related to the primary endpoint. Interim analyses, stopping rules, and the statistical plan are not reported in the registry record. The terminated status is recorded, but the reason for termination is not reported in the registry record. These details should not be inferred from the status alone.

11. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypoglycemia (0.3%), benign prostatic hyperplasia (0.3%), bronchial disorder (0.3%), chronic obstructive pulmonary disease (0.3%), renal cancer (0.3%).

The registry lists serious adverse-event counts by treatment-group labels. The recorded counts are 7 for Placebo, 5 for Pioglitazone, 2 for Rosiglitazone, 2 for Vitamin D Placebo, and 9 for Vitamin D. These are counts of participants affected in the listed serious-event categories, not estimates of treatment effects. The displayed at-risk counts are 541, 392, 399, 614, and 607, respectively. Because the trial is described as factorial and the TZD and vitamin D groups relate to distinct treatment questions, these labels should not be assumed to represent five mutually exclusive groups.

The registry also lists six serious-event terms at 0.3%: Hypoglycemia, Benign prostatic hyperplasia, Bronchial disorder, Chronic obstructive pulmonary disease, Renal cancer, and Cholecystitis acute. These are the terms and percentages recorded; they do not describe all adverse events or establish a comparison between treatments. The record does not provide a statistical comparison, confidence interval, or adjustment for differences in follow-up. The deaths field has no reported values, so death counts are not reported in the registry record. Safety counts should be interpreted separately from the primary cardiovascular composite, whose group-specific results are not reported.

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

The record establishes that TIDE was a randomized, quadruple-masked, placebo-controlled Phase 4 trial with a factorial model, enrollment of 1332, and two separate intervention questions. It also supplies a clear definition of the primary TZD cardiovascular composite and identifies the intended population as all randomized participants. Those features allow readers to understand what the trial set out to examine and which events were included in the primary endpoint.

However, the registry record does not report the primary endpoint results by group. It gives no participant counts for the composite or its components, no effect estimate, and no confidence interval or p-value. The record therefore does not establish the direction, magnitude, or precision of any difference between TZD treatment and its comparator. It also does not report results for the vitamin D question about death and cancer. The safety counts describe observed serious adverse events but do not resolve either efficacy question.

In general, a randomized design can support a causal interpretation of treatment comparisons when the analysis follows the design, outcome data are sufficiently complete, and relevant assumptions are appropriate. That general principle is not a substitute for trial results. Here, the analysis details, missing-data handling, treatment adherence, and factorial comparison structure are not reported in the registry record. The trial's terminated status alone does not explain why it ended or what its unreported results might have been.

Thus, the appropriate interpretation is limited: the record documents the trial's design and outcome definitions, but it does not provide enough comparative outcome information to judge the primary cardiovascular result or the vitamin D result. No conclusion about benefit, lack of benefit, harm, or equivalence follows from the absence of these results in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable because it addressed two intervention questions within a randomized factorial design. Factorial trials can be efficient ways to study more than one intervention, but their interpretation depends on the treatment assignment structure and analysis strategy. When effects may depend on the other intervention, interaction assessment can matter. The registry record names the factorial model yet does not report the assignment combinations, the statistical analysis plan, or any interaction analysis.

The primary cardiovascular outcome is also a composite. Combining cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke creates an overall endpoint that spans several event types. Statistical interpretation would ideally consider both the composite and its components, because a combined result can conceal differences in which events contributed most. The registry record defines the components and mentions event adjudication, but does not report their counts or comparative estimates.

The record illustrates why trial registration details and result reporting answer different questions. The design description explains the intended comparisons, while outcome data and inferential statistics are needed to assess the observed evidence. Here, there are no primary endpoint results or analyses listed, despite an enrollment of 1332 and a specified endpoint timeframe. The record also indicates 15 outcome measures, making a transparent multiplicity plan useful for interpreting any collection of comparisons; that plan is not reported.

Finally, the gap between the long-term treatment descriptions and the primary endpoint timeframe, from randomization at Visit 3 to the final visit with an average of 162 days, makes careful attention to actual follow-up important. The record does not report participant-level follow-up or analysis denominators. These are not reasons to infer a result, but they identify what is needed to evaluate the precision and general meaning of any eventual comparison.

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 registry record has major limitations for interpreting efficacy. Although it defines the primary TZD composite, it does not report component counts, group-specific composite counts, effect estimates, confidence intervals, or p-values. It lists 0 analyses. Consequently, the size and precision of the primary comparison cannot be assessed. The vitamin D question is described, but results for its stated outcomes of death and cancer are not reported in the registry record.

Important design and conduct details are also absent. The record does not report the exact factorial allocation structure, statistical analysis plan, interim analyses, multiplicity approach, missing-data methods, or reasons for termination. It identifies the Intent-to-Treat population but does not give analysis-specific denominators or explain how participants with missing outcomes were handled. Baseline characteristics, adherence, withdrawals, and participant-level follow-up are not reported.

The primary outcome timeframe is recorded as running from randomization at Visit 3 to the final visit, with an average of 162 days, while the treatment descriptions refer to longer treatment periods. The record does not explain the relationship between those descriptions and the observed endpoint follow-up. It also does not report details needed to interpret whether follow-up was complete or comparable across groups.

Safety reporting is limited to listed serious-event counts, at-risk counts, and selected event terms. Comparative safety estimates and statistical uncertainty are not reported. The deaths fields contain no values, so death counts are not reported in the registry record. These limitations constrain conclusions to the trial description and the particular safety figures recorded; they do not justify inferring unreported outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Thiazolidinedione Intervention With Vitamin D Evaluation — NCT00879970.
• Registry record last updated 2017-04-18; status last verified 2017-03.
• Results first posted 2011-12-13.
• 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

TIDE was a Phase 4 randomized, quadruple-masked, placebo-controlled factorial trial in people with type 2 diabetes at risk for cardiovascular disease. The registry records enrollment of 1332, a start date of 2009-05, primary completion in 2010-11, and terminated status. Its two questions concerned TZD treatment and vitamin D supplementation.

The primary TZD endpoint was a composite of cardiovascular death without an identified non-heart-related cause, non-fatal myocardial infarction, and non-fatal stroke, in the Intent-to-Treat population. Its timeframe ran from randomization at Visit 3 to the final visit, with an average of 162 days. The registry record does not report primary endpoint results, comparative estimates, or a statistical analysis. It also does not report results for the vitamin D question. Selected serious adverse-event counts are listed, but comparative safety analyses are not reported.