Drug Treatment Validation of Functional Magnetic Resonance Imaging in Generalized Anxiety Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug Treatment Validation of Functional Magnetic Resonance Imaging in Generalized Anxiety Disorder (NCT00662259), a randomized phase 4 study. The primary outcome is Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces.

2. Clinical Question

The study asks whether alprazolam, compared with placebo, is associated with differences in brain activity measured by functional magnetic resonance imaging (fMRI) in patients with generalized anxiety disorder. The primary endpoint concerns signal change in the amygdala while participants view emotional faces. The registry description defines that signal in relation to activity while matching geometric designs.

The study also planned to examine brain activity at rest and while viewing emotional material, including emotional faces and pictures. Its listed secondary outcomes are scores on the Hamilton Anxiety Scale and the Penn State Worry Scale. These measures address clinical symptoms and worry alongside the imaging question, but their numerical results are not reported in the registry record.

The clinical question is therefore broader than whether the two groups differ on a single scan. It includes the relationship between treatment assignment and an imaging measure across the recorded time points, as well as behavioral and clinical measures. The primary endpoint is specified as a continuous measure summarized by a mean and standard deviation. However, the record does not give group means, an estimated between-group contrast, uncertainty intervals, or a test result. It is not possible to determine the direction or precision of an imaging difference from the registry information described.

3. Trial Design

The registry describes a randomized, double-blind, placebo-controlled, parallel-group phase 4 study. Participants with generalized anxiety disorder were assigned to alprazolam or placebo. In a parallel-group design, participants are assigned to a group and the groups are compared; the record does not describe a crossover between treatments. The sponsor is the University of California, San Diego. The study status is completed, with a start date of 2008-04 and a primary completion date of 2009-09.

The registry lists enrollment of 32. Its arm descriptions state that alprazolam would be administered to 24 patients and placebo to 12 patients. These descriptions are not a report of the number analyzed for the primary endpoint. The primary-outcome population description separately reports 19 out of 21 participants analyzed, with 2 withdrawing from adverse events. The registry does not explain how these figures relate to the enrollment and arm descriptions, and arm-specific primary-analysis counts are not reported in the registry record.

Double masking is intended to limit the influence of treatment knowledge on participants and study personnel, while random allocation is intended to support a fair comparison between groups. These design features do not by themselves establish that the groups were comparable in every respect or explain how the analysis handled missing measurements. Details about the randomization procedure, concealment, masking assessment, and statistical analysis plan are not reported in the registry record.

The endpoint timeframe is listed as 0,1,28 days. The registry does not define in the information recorded which time point was the principal comparison, how repeated measurements were modeled, or whether the treatment contrast used all listed time points. The primary outcome has several categories or time points and is not reduced to one comparison in the registry result description. That matters because a reader cannot identify a single numerical primary contrast from the endpoint metadata alone.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 19 out of 21 participants analyzed due to 2 withdrawing from adverse events.

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 Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces, measured over 0,1,28 days.

The primary endpoint is titled “Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces.” The measure is percent signal change in brain activity. The endpoint description defines it as the extent of brain-signal activation when matching emotional face expressions, expressed relative to the signal when matching geometric designs. The signal is the blood oxygen level dependent (BOLD) signal measured with fMRI.

As a general explanation, BOLD fMRI measures changes in the magnetic resonance signal associated with changes in blood oxygenation. It is an indirect measure of brain activity, rather than a direct count of neural firing. A within-scan contrast between emotional-face matching and geometric-design matching can provide a way to quantify a response to the emotional-face task against a comparison task. The registry does not report the detailed image-processing or region-of-interest procedures.

The endpoint is continuous and is specified to be summarized by a mean and standard deviation. Those summaries would describe the group values and their variation, but they are not reported in the registry record. The record also does not report a treatment contrast or its uncertainty. Although the endpoint timeframe is listed as 0,1,28 days, the registry information does not identify a single time point as the sole primary comparison. Consequently, the endpoint definition explains what was intended to be measured, but not what value was observed or how precisely the groups differed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods information allows the study question to be described, but not the statistical analysis to be reconstructed. The registry records a randomized, double-blind, placebo-controlled, parallel design and defines a continuous primary endpoint. It does not report a detailed analysis plan or numerical primary results.

What does a mean and standard deviation describe?

The primary endpoint is specified as a mean with a standard deviation. In general, a mean describes the average measured value in a group, while a standard deviation describes how spread out individual values are around that average. Together, they provide information about the observed distribution within each group. They do not, by themselves, quantify the uncertainty in the difference between groups. To evaluate a comparative effect, readers ordinarily need an estimate of the group contrast and an uncertainty measure, such as a confidence interval. Those statistics are not reported in the registry record.

The distinction between variation among participants and uncertainty about a group estimate is important. A standard deviation reflects participant-to-participant variation in the recorded measure. A confidence interval, in general, expresses the range of estimates compatible with the data and an assumed statistical procedure. Neither can be recovered from the endpoint definition alone, and no confidence interval is reported for this endpoint.

Why is the endpoint a contrast?

The registry defines the fMRI outcome by comparing signal during emotional-face matching with signal during geometric-design matching. In general, using a comparison task can help distinguish responses associated with the task of interest from responses also present during a reference task. The endpoint is expressed as percent signal change, and the measured signal is BOLD. This operational definition is specific to the imaging task; it should not be interpreted as a direct measure of anxiety severity or as a direct count of neural activity.

The endpoint description names the amygdala and emotional faces, but it does not report the image-processing steps, the method used to define the measured region, quality-control procedures, or how unusable scans were handled. Those details are not reported in the registry record. They can affect how an imaging measure is produced and how reproducible it is, so they would be needed to fully evaluate the measurement methods.

How should repeated time points be considered?

The endpoint timeframe is listed as 0,1,28 days. Repeated measurements on the same participant are generally correlated: a participant’s values at different visits are not necessarily independent observations. In general, an analysis of repeated measurements needs to account for this correlation, for example through a model that represents within-participant dependence or through a prespecified comparison at a selected time point. The registry information does not state which approach was used, whether all time points contributed to the primary analysis, or how the time course was summarized.

The record indicates that the primary outcome has several categories or time points and is not reduced to one comparison. This limits interpretation because a reader cannot identify a single primary contrast from the recorded endpoint information. The record does not state whether the key question was a difference at a particular time, a difference in change over time, or an overall pattern across visits.

What would randomization and masking contribute?

In general, random allocation can reduce systematic differences between treatment groups at the time of assignment, while double masking can reduce influences from treatment expectations on behavior, assessment, or study conduct. These protections depend on implementation and do not remove uncertainty due to chance, missing observations, or analytic choices. The registry does not describe the randomization sequence, allocation concealment, or whether masking was maintained.

A randomized comparison is usually interpreted through the assigned groups, but the record does not state whether the primary analysis followed an intention-to-treat principle or used another analysis population. It also does not provide an adjusted or unadjusted treatment estimate. The registry entries therefore do not support a claim about the particular statistical model or estimand used.

What is not available for statistical assessment?

There is no reported primary comparison, standard error, confidence interval, or p-value. The registry lists five outcome measures and zero analyses, but does not provide an explanation of the analysis count or a statistical plan. It does not report handling of multiple outcomes or time points, interim analyses, sample-size justification, missing-data methods, or model diagnostics. These omissions prevent assessment of whether the analysis matched a prespecified plan, how uncertainty was quantified, and whether the reported endpoint would be robust to analytic assumptions.

As a general principle, an estimate should be read together with its uncertainty and with a clear description of the population and analysis method. In this record, the outcome definition and study design are available, while the numerical estimate and several method details are not reported in the registry record. Statistical interpretation must therefore remain at the level of describing the planned measurement and the limits of the available results.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures, including the primary imaging outcome and secondary Hamilton Anxiety Scale and Penn State Worry Scale scores. It does not report a statistical analysis plan describing how multiple outcomes were handled, whether any outcome hierarchy was applied, or whether significance thresholds were adjusted. The number of analyses listed is zero. This does not establish that no analyses occurred; the analysis details are not reported in the registry record.

The primary endpoint timeframe is 0,1,28 days, and the registry indicates that the outcome has several categories or time points and is not reduced to one comparison. It does not identify a single primary time-point contrast or state how multiplicity across time points was considered. In general, examining multiple outcomes or time points can increase the chance of observing an apparently unusual result by chance if the analysis does not account for the number of comparisons. Without the analysis plan and results, the extent of that issue cannot be assessed.

For the primary outcome, the population description reports 19 out of 21 participants analyzed and says that 2 withdrew from adverse events. The record does not give arm-specific analysis counts or describe whether missing scans were excluded, imputed, or handled by a model. It also does not report whether those withdrawals occurred before or after any specific scan time point. The enrollment and arm descriptions do not resolve these missing-data questions.

The analysis population is not otherwise defined in the registry record. There is no reported intention-to-treat, per-protocol, or other population definition, and no account of sensitivity analyses for missing outcomes. As a result, the relationship between the randomized groups and the primary endpoint analysis cannot be fully evaluated.

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 non-serious adverse event terms

The registry safety figures list zero participants with serious adverse events in the alprazolam group and zero in the placebo group. The corresponding safety denominators are 21 for alprazolam and 11 for placebo. The serious adverse event terms list is empty. These entries describe what is recorded in the registry; they do not provide event narratives or further detail about how serious events were defined or collected.

Other adverse events are reported for 2 participants in the alprazolam group and 0 in the placebo group, using the same respective safety denominators. The registry does not identify the nature, severity, timing, or relationship to treatment of those events. The death counts are not reported in the registry record.

Safety counts are descriptive. A count of zero serious adverse events in a group does not establish that a treatment has no risk, and the groups’ different safety denominators matter when interpreting raw counts. These figures also do not explain the primary-outcome description that 2 participants withdrew from adverse events; the registry does not report whether those withdrawals correspond to the other adverse events or provide a participant-level link between the records. The safety entries should therefore be read as limited registry counts, not as a complete comparative safety analysis.

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

This trial addresses a focused statistical question: whether randomized assignment to alprazolam rather than placebo is associated with a difference in an amygdala fMRI signal during an emotional-face task among patients with generalized anxiety disorder. Its parallel, double-blind design and defined imaging contrast clarify what the researchers intended to compare. The listed symptom scales indicate that the study also included clinical and behavioral outcomes.

The registry information does not report numerical results for the primary endpoint or the secondary outcomes. It therefore does not establish the direction, size, or precision of any group difference. No claim that alprazolam increased, decreased, or left unchanged the measured signal can be supported from the recorded endpoint description alone. Likewise, no conclusion about changes in anxiety or worry scores can be drawn from the outcome names.

An fMRI signal is a measurement generated under a particular task and imaging definition. As a general point, an observed difference in an imaging measure would not by itself show that a clinical symptom changed, explain a mechanism, or demonstrate that a measure can validate treatment effects in other settings. Those interpretations would require numerical findings and additional evidence about measurement validity, reproducibility, and links between imaging and clinical outcomes. The registry’s title refers to validation, but the registry entries recorded do not report evidence sufficient to assess validation.

The primary-outcome population description notes withdrawals due to adverse events, but does not give enough information to evaluate their effect on the comparison. The safety counts likewise are limited and do not supply a detailed account of event types or treatment relationships. Thus, the record is informative about the study’s design and intended measures, while leaving the principal efficacy and safety comparisons unresolved.

13. Why This Trial Matters Statistically

The study is statistically interesting because it places an imaging measure within a randomized, double-blind, placebo-controlled comparison. Randomization and masking are relevant design protections when the aim is to compare groups, while the fMRI endpoint is defined through a specific task contrast rather than a general impression of brain activity. The study also lists clinical symptom measures, which could have allowed readers to consider how imaging findings relate to patient-relevant outcomes.

At the same time, the record illustrates why an endpoint definition is not a result. The amygdala signal, its percent-change scale, and the task contrast are described, but numerical group summaries and a treatment contrast are not reported. Without an estimate and its uncertainty, there is no statistical basis in the registry record to judge how large or precise the observed difference was. A completed study status does not fill this gap.

Repeated time points and multiple outcomes raise important analytic questions. The endpoint timeframe lists 0,1,28 days, and the registry notes that the primary outcome is not reduced to one comparison. The record does not explain how time points or outcomes were prioritized or how any multiplicity was addressed. Nor does it describe the analysis population or missing-data approach, despite noting withdrawals related to adverse events in the primary-outcome population description.

These features make the record useful for understanding the planned measurement and for identifying what would be needed to interpret its evidence: a clearly specified contrast, arm-level outcome summaries, uncertainty estimates, analysis methods, and transparent handling of missing observations. In their absence, the central contribution available for statistical review is a defined research question and an incomplete account of its results, not an estimable treatment effect.

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 most immediate limitation is the absence of numerical primary and secondary outcome results in the registry record. Without group summaries and comparative estimates, the treatment effect and its precision cannot be assessed. The endpoint is described at multiple time points, but the primary comparison is not specified as one contrast. This leaves uncertainty about which estimand readers should use to interpret the study question.

The record also does not report the statistical analysis plan, the model used for repeated measurements, any covariate adjustment, or the handling of multiple outcomes and time points. The registry lists five outcome measures and zero analyses, but does not explain the analysis count. Details of sample-size justification and interim analyses are not reported in the registry record.

The primary-outcome population description reports 19 out of 21 participants analyzed and 2 withdrawals due to adverse events. The record does not provide arm-specific primary-analysis counts, explain the relation between this description and the enrollment or arm descriptions, or state how missing scan values were handled. These gaps prevent a full assessment of potential missing-data bias.

Further limitations concern measurement and safety detail. Image-processing methods, region-of-interest procedures, and scan-quality rules are not reported in the registry record. The safety entries give counts but no adverse-event terms, narratives, or treatment relationships; death counts are also not reported. These omissions restrict both reproducibility assessment and interpretation of the safety profile.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Drug Treatment Validation of Functional Magnetic Resonance Imaging in Generalized Anxiety Disorder — NCT00662259.
• Registry record last updated 2019-07-25; status last verified 2019-06.
• Results first posted 2019-07-25.
• 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 registry record describes a completed, randomized, double-blind, placebo-controlled, parallel-group phase 4 study of alprazolam versus placebo in generalized anxiety disorder. The sponsor is the University of California, San Diego. The recorded study start is 2008-04, and primary completion is 2009-09. Enrollment is listed as 32.

The primary endpoint is percent signal change in the amygdala during emotional-face matching relative to geometric-design matching, measured with BOLD fMRI. Its timeframe is 0,1,28 days. Hamilton Anxiety Scale and Penn State Worry Scale scores are listed as secondary outcomes.

Numerical outcome comparisons and detailed analysis methods are not reported in the registry record. The primary-outcome population description reports 19 out of 21 participants analyzed, with 2 withdrawing due to adverse events. Safety entries record zero serious adverse events in both groups and other adverse events in 2 alprazolam participants and 0 placebo participants. The nature of those other events is not reported.