Establishing a Dose-response Relationship With Accelerated Transcranial Magnetic Stimulation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Establishing a Dose-response Relationship With Accelerated Transcranial Magnetic Stimulation (NCT04243798), a randomized na study. The primary outcome is Change in Resting State Functional Connectivity of the Subgenual Anterior Cingulate Cortex (sgACC) and the Default Mode Network (DMN)..

2. Clinical Question

The primary outcome is a brain-connectivity measure assessed using magnetic resonance imaging. The registry also names secondary questions about the relationship between clinical improvement and resting-state connectivity, and between acute mood state and resting-state connectivity, comparing active and sham participants. These are association questions: they concern whether changes in symptoms or mood are related to connectivity, rather than defining additional primary endpoints.

The title refers to establishing a dose-response relationship, but the listed arms are active stimulation and sham stimulation. No multiple active-dose groups or dose levels are reported in the registry record. Therefore, the recorded design supports a question about active-versus-sham assignment; a comparison across different active doses is not described in the listed arms. Numerical results for the primary or secondary questions are not reported in the registry record, so the direction and size of any observed differences or relationships cannot be stated.

3. Trial Design

The registry describes a randomized, parallel-group study with quadruple masking. The planned enrollment is 48, and the listed conditions are treatment-resistant depression. The active arm is named Active TBS-DLPFC and is described as receiving theta-burst TMS stimulation. The comparator arm, Sham TBS-DLPFC, is described as receiving sham theta-burst TMS stimulation. The study summary characterizes the design as double-blind and sham-controlled, while the design field lists quadruple masking. The registry record does not explain the difference in those masking descriptions.

The study is listed as phase NA and as completed. Its recorded start date is 2021-06-15, and its primary completion date is 2024-06-21. Stanford University is listed as the sponsor. These administrative details describe the registered study, but do not establish how many participants completed treatment or contributed data to each endpoint. The registry record does not report the primary outcome analysis population or participant flow.

The primary measure concerns resting-state functional connectivity between the subgenual anterior cingulate cortex and the default mode network. Assessments are specified at Visit 3 (Day 1), Visit 4 (Day 2), Visit 5 (Day 3), Visit 6 (Day 4), Visit 7 (Day 5), and immediate post-treatment follow-up at Visit 8 (Day 6). This repeated-measures schedule makes time part of the outcome question: the measure is planned across treatment visits and a post-treatment assessment, rather than at a single assessment alone.

The record lists three outcome measures: the primary connectivity outcome and two secondary outcomes relating connectivity to clinical improvement and acute mood state. It lists no analysis entries. The statistical plan, analysis populations, missing-data procedures, and any protocol-level justification for the enrollment target are not reported in the registry record.

4. Participant Flow and Accounting

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

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 Change in Resting State Functional Connectivity of the Subgenual Anterior Cingulate Cortex (sgACC) and the Default Mode Network (DMN)., measured over Visit 3 (Day 1), Visit 4 (Day 2), Visit 5 (Day 3), Visit 6 (Day 4), Visit 7 (Day 5) and Immediate Post Treatment Follow Up (Visit 8 and Day 6).

The primary endpoint is change in resting-state functional connectivity between the subgenual anterior cingulate cortex (sgACC) and the default mode network (DMN). The registry says this connectivity is assessed using magnetic resonance imaging. Its stated unit is the Spearman correlation coefficient, with the outcome parameter listed as a mean and its dispersion as a standard deviation.

Functional connectivity describes statistical coupling between measured brain signals in the specified regions or networks. It is not itself a direct measure of a participant’s symptoms. The registry’s secondary outcomes address possible relationships between connectivity and clinical improvement, and between connectivity and acute mood state. That separation matters: a change in a brain measure and a change in clinical state are distinct outcomes, even if they may be related.

Repeated measurement can describe how connectivity varies over the treatment schedule and at immediate post-treatment follow-up. The listed assessment occasions run from Visit 3 (Day 1) through Visit 8 (Day 6). The registry record does not report the actual coefficient means, standard deviations, participant counts for the endpoint, or estimates comparing active and sham groups. It therefore does not establish whether connectivity increased, decreased, or differed between groups.

As a general statistical point, a correlation coefficient expresses the direction and strength of an association. A Spearman coefficient is based on ranks, rather than requiring the association to be described solely through a straight-line relationship between raw values. This can be useful when the scientific question concerns monotonic association. Its interpretation still depends on the data and analysis choices; the registry record does not give enough analysis detail to assess those choices.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary measure represent?

The registered primary measure is resting-state functional connectivity between the sgACC and DMN, assessed with magnetic resonance imaging. The outcome is expressed as a Spearman correlation coefficient. In general, a correlation summarizes how two measured signals vary together. A positive association means that higher ranks in one signal tend to accompany higher ranks in the other; a negative association means that higher ranks in one tend to accompany lower ranks in the other. The strength of the association is reflected by how consistently the paired measurements follow that pattern. This general explanation does not imply any particular direction or strength in this trial, for which numerical estimates are not reported in the registry record.

A Spearman coefficient uses the rank ordering of observations. This makes it a measure of monotonic association and does not require the relationship to be represented as a straight line in the original measurement scale. Rank-based association is not free of assumptions: the measurement process, data quality, and the meaning of the paired observations still matter. The registry record does not describe how the imaging data were preprocessed, how connectivity values were derived, or how the coefficient was calculated for the reported endpoint.

Why are the mean and standard deviation named?

The record lists the parameter as a mean and the dispersion as a standard deviation. In general, a mean describes the center of a set of values, while a standard deviation describes how spread out those values are around that center. These summaries can help readers understand a group’s measured values, but they do not by themselves provide an active-versus-sham treatment contrast. A comparison also needs an estimate of the difference or other contrast and a measure of its uncertainty. Such numerical results are not reported in the registry record.

The record does not explain whether the mean is calculated over participants, visits, or another unit of analysis. Nor does it report whether the primary comparison uses a change score, a model of repeated values, or another approach. The endpoint title uses the word “change,” and the timeframe lists repeated assessments, but those details are not enough to reconstruct the statistical model. The precise method and model specification are not reported in the registry record.

What does randomization contribute?

In general, random assignment is intended to make treatment groups comparable with respect to factors known and unknown at assignment. This supports an interpretation of group differences as related to assigned intervention, provided the analysis and follow-up preserve the benefits of randomization. Randomization does not guarantee that groups will be identical in a particular study, especially for a measured characteristic, and does not resolve bias arising after assignment. The registry record identifies randomized allocation, but does not report the randomization sequence method, concealment procedures, or details of the primary analysis population.

The design is described as parallel, meaning participants are assigned to an arm and the arms are compared over the study rather than each participant receiving both assigned conditions in sequence. The record also lists quadruple masking, while its study summary describes a double-blind design. Masking can reduce the influence of expectations or knowledge of assignment on care, measurement, and assessment. The registry record does not specify which roles were masked or reconcile the two descriptions.

How should repeated assessments be understood?

The primary outcome is scheduled at Visit 3 (Day 1), Visit 4 (Day 2), Visit 5 (Day 3), Visit 6 (Day 4), Visit 7 (Day 5), and immediate post-treatment follow-up at Visit 8 (Day 6). Repeated measurements can reveal whether an outcome changes over time and whether its pattern differs between randomized groups. Measurements from the same participant are generally related, so a suitable analysis needs to account for that dependence rather than treating every measurement as unrelated. This is a general statistical consideration; the registry record does not report the model used or how within-participant correlation was handled.

Having multiple assessments also creates choices about the primary contrast. A study could focus on a particular visit, an average over visits, a change from baseline, or an overall trajectory. Those approaches answer different questions. The registry notes that the primary outcome has several categories or time points and was not reduced to one comparison. The intended primary contrast, and any approach for handling multiple comparisons across assessments, are not reported in the registry record.

What can a confidence interval or p-value add?

In general, a confidence interval presents a range of estimates compatible with the data and the method used, conveying uncertainty around an estimated effect. A p-value assesses how compatible the observed data are with a specified null model under the test assumptions; it is not the probability that the null hypothesis is true and does not measure clinical importance. Neither measure can be interpreted without knowing the estimate, analysis, and assumptions. No confidence interval or p-value for the primary outcome is reported in the registry record, so neither statistical uncertainty nor evidence against a null comparison can be assessed.

A small p-value, if reported, would not by itself show that an effect is large or important. Conversely, a result that does not meet a chosen threshold would not prove that there is no effect. Effect estimates and uncertainty are needed to distinguish the observed magnitude from the precision of the evidence. Since the registry record gives no numerical primary outcome result, these interpretations cannot be made for this trial.

What does the planning illustration mean?

The record describes sample-size assumptions as a planning illustration computed from an observed effect, using a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. In general, a sample-size calculation asks how much information might be needed to detect an effect under specified assumptions. An illustration based on an observed effect is not the same as the trial’s original design justification, and it does not describe the probability that the completed study detected an effect. The assumptions do not establish that the same analysis was used for the registered endpoint.

Planning calculations are sensitive to the assumed effect and to the statistical model. A smaller target effect generally requires more information to detect with the same planned operating characteristics; a larger target effect can require less. That is a general relationship, not a calculation for this study. The effect estimates and individual planning outputs are not reported in the registry record. Any sample-size illustration should therefore be read as a conditional planning exercise, not as an observed result, proof of adequacy, or observed power.

10. Multiplicity, Missing Data and Analysis Populations

The primary connectivity outcome is scheduled across multiple visits, and the registry explicitly notes that it has several categories or time points and was not reduced to one comparison. Repeatedly testing outcomes across visits can increase the chance of finding an apparently unusual result by chance if no plan addresses multiplicity. General approaches include defining a single primary contrast in advance, adjusting inference across comparisons, or using a model that tests an overall trajectory. The registry record does not report which approach, if any, was planned or used.

The record lists three outcome measures: the primary connectivity outcome and secondary outcomes concerning connectivity’s relationship with clinical improvement and acute mood state. It lists zero analysis entries. This indicates that analysis details are not available in the registry record; it does not establish whether analyses were or were not conducted. No adjustment for testing multiple outcomes, visits, or relationships is reported.

Missing data can affect both the estimate and its uncertainty, especially when participants with missing measurements differ from those with observed measurements. General methods may rely on assumptions about why data are missing, and those assumptions should be considered alongside the analysis. The registry record does not report the amount or pattern of missing outcome data, imputation methods, sensitivity analyses, or reasons for missingness.

The record does not identify whether analyses followed intention-to-treat principles, used a per-protocol population, or applied another analysis population definition. It also does not report outcome-specific denominators. The planned enrollment and the adverse-event denominators do not establish the number of participants contributing to the connectivity analysis. These omissions prevent assessment of whether the outcome analysis retained the benefits of randomization or how missing observations affected the results.

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 0% reporting threshold.

For serious adverse events, the registry lists 24 participants at risk in the Active TBS-DLPFC group and 24 at risk in the Sham TBS-DLPFC group, with zero affected in each. For other adverse events, it likewise lists 24 at risk in each group and zero affected in each. Deaths are listed as zero in both groups, and no top serious-event terms are listed.

These entries describe what the registry reports for the safety categories and denominators shown. They do not provide event-level descriptions, timing, duration, severity grading beyond the serious-versus-other classification, or an account of how safety information was collected. The registry record does not report such details.

In general, an adverse-event count is interpreted in relation to its reporting definition, observation period, and participants monitored. A zero count in a registry entry should not be treated as proof that an intervention has no risks or that no events of any kind occurred. Here, the record reports zero participants affected in the listed serious and other adverse-event categories and zero deaths. Those entries alone do not characterize risks beyond the recorded groups and reporting information.

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

The record establishes that a randomized, parallel comparison of active theta-burst stimulation and sham stimulation was registered for people with treatment-resistant depression. Its primary outcome is a repeated assessment of resting-state functional connectivity between the sgACC and DMN. These registry entries describe the research question and design, not the outcome of the comparison.

Numerical findings for the primary and secondary outcomes are not reported in the registry record. Consequently, it is not possible to state whether the active group’s connectivity differed from the sham group, whether connectivity changed over the scheduled assessments, or whether connectivity was related to clinical improvement or acute mood state. The record also does not supply estimates and uncertainty measures needed to judge the precision of any effect.

The title’s dose-response wording should not be mistaken for evidence of a dose-response pattern. The registered arms list active stimulation and sham stimulation, without listing multiple active-dose levels. A difference between active and sham, if one were reported, would address that comparison; it would not by itself show how outcomes vary across different active doses.

The completed status and planned enrollment of 48 do not reveal the analyzed sample or resolve the lack of outcome estimates. The registry record also does not state how missing repeated measurements, multiple visits, or the secondary outcomes were handled. Those details are important for evaluating the reliability and scope of an analysis.

In general, a study result is best interpreted through its estimated effect, uncertainty, analysis methods, and relevance to the question it was designed to address. The available record supports describing the registered design and outcomes, but not drawing a conclusion about efficacy, lack of efficacy, or dose response. No medical recommendation follows from these registry entries.

13. Why This Trial Matters Statistically

This study is statistically notable for combining a randomized active-versus-sham comparison with a brain-connectivity outcome assessed repeatedly during treatment and at immediate follow-up. Repeated outcomes can provide richer information than a single measurement, because they can describe both differences between groups and variation over time. They also make the analysis more demanding: observations from the same participant are related, and the choice of time contrast affects the question being answered.

The registered primary measure is a Spearman correlation coefficient summarized using a mean and standard deviation. That combination calls for careful attention to what the coefficient represents and how it was aggregated. The registry record does not explain those analytic details or provide the estimates, so the scientific question is more clearly documented than its statistical answer.

The record also lists secondary questions linking connectivity to clinical improvement and acute mood state. Distinguishing these associations from the primary connectivity outcome is important. An association between a brain measure and a clinical measure is not automatically a treatment effect, and a treatment-group comparison does not itself establish that connectivity explains clinical change.

Finally, the title invokes dose response while the listed intervention groups comprise active stimulation and sham. That contrast can address active treatment versus a sham procedure, but the registered arms do not describe comparisons across active doses. The distinction illustrates why a study title, the design, and the estimand need to be read together. Without numerical results and a reported analysis plan, the record cannot establish either the size of a group difference or a dose-response relationship.

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.

A central limitation of interpretation is that numerical primary and secondary outcome results are not reported in the registry record. There are no estimates, uncertainty intervals, or test results with which to evaluate magnitude, direction, or precision. The completed status therefore cannot be treated as evidence of a particular result.

The primary outcome is assessed at several scheduled visits, and the registry notes that it was not reduced to one comparison. The record does not identify a primary time contrast, explain how repeated observations were modeled, or report how multiplicity was handled. Without those details, it is unclear which statistical question would take priority if results across visits differed.

The record lists active stimulation and sham stimulation, but no several-dose active comparison. This limits what can be inferred about dose response from the registered arm structure. The registry also does not report the stimulation dose, detailed eligibility criteria, outcome-analysis population, participant flow, or endpoint-specific denominators. These gaps make it difficult to assess applicability and the contribution of missing observations.

Although the record lists a mean and standard deviation for the continuous endpoint, it does not describe how the correlation coefficients were derived or summarized. Imaging processing, handling of incomplete scans, and the statistical model are not reported. The two masking descriptions—quadruple in the design field and double-blind in the study summary—are not reconciled. Finally, the adverse-event entries provide category counts but not event-level details or the safety observation procedures.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Establishing a Dose-response Relationship With Accelerated Transcranial Magnetic Stimulation — NCT04243798.
• Registry record last updated 2026-03-30; status last verified 2026-03.
• Results first posted 2026-03-30.
• 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

NCT04243798 is a completed, randomized, parallel-group study sponsored by Stanford University, with planned enrollment of 48 and treatment-resistant depression listed as the condition. Its arms are active theta-burst TMS directed at the DLPFC and sham theta-burst stimulation. The record lists quadruple masking; the study summary also describes the study as double-blind.

The primary outcome is change in resting-state functional connectivity between the sgACC and DMN, assessed by magnetic resonance imaging across Visit 3 (Day 1) through Visit 8 (Day 6). The registry lists two secondary questions linking connectivity with clinical improvement and acute mood state. Numerical outcome results and analysis details are not reported in the registry record.

Safety entries list zero serious adverse events, zero other adverse events, and zero deaths in each group, with 24 participants at risk per group for the adverse-event categories. These entries do not substitute for detailed outcome or safety reporting.