Midodrine Use in Septic Shock: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Midodrine Use in Septic Shock (NCT03706053), a randomized phase 3 study. The primary outcome is Days Free of Vasopressors (Days).

2. Clinical Question

The clinical question is whether assignment to midodrine, compared with placebo, changes vasopressor-related outcomes in patients receiving IV vasopressors for early septic shock. The registry's brief summary focuses on time to IV vasopressor liberation, while the posted primary outcome is days free of vasopressors adjusted with mortality. These outcomes are related in subject matter but are not stated in identical terms. The record does not explain the precise adjustment for mortality or how the primary measure was constructed.

The posted results cover three groups: placebo, midodrine hydrochloride 10 mg TID, and midodrine hydrochloride 20 mg TID. The primary summaries are based on 3, 4, and 3 participants, respectively. The registry record reports group means and ranges, but does not report a formal comparison, confidence interval, or p-value. This means the record describes the observed values without establishing the precision of a treatment contrast. The small number of participants also makes the group summaries especially sensitive to the outcomes of individual participants.

3. Trial Design

The registry identifies NCT03706053 as a phase 3, randomized, parallel-group trial sponsored by the University of Virginia. Its title is “Midodrine Use in Septic Shock,” and its official title specifies hypotension requiring IV vasopressor therapy in early septic shock. The record lists triple masking. The brief summary describes the intended study as randomized, double-blind, and placebo-controlled. The exact masking roles are not reported in the registry record, so the difference in wording cannot be resolved from the record alone.

The registry lists three groups: placebo, midodrine hydrochloride 10 mg TID, and midodrine hydrochloride 20 mg TID. The arm descriptions state that in an early phase participants would be randomized among all three groups, with 15 per group. They also describe an interim safety and efficacy analysis after the first 45 participants, which would determine which experimental group remained open to further enrollment. These statements describe the registered plan; whether the interim analysis occurred or changed enrollment is not reported in the registry record. The arm descriptions are truncated, so further details about the planned transition are unavailable.

Enrollment is listed as 10. The trial status is terminated. The start date is 2018-11-05, and the primary completion date is 2022-02-11. The reason for termination is not reported in the registry record. The observed group sizes in the posted primary results are 3 for placebo, 4 for midodrine hydrochloride 10 mg TID, and 3 for midodrine hydrochloride 20 mg TID.

The design sought to compare the primary outcome across the randomized groups, but the posted record contains group summaries rather than an inferential comparison. The registry does not report the allocation procedure, the details of masking, protocol deviations, or whether the planned enrollment and interim process were carried out as described.

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

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 Days Free of Vasopressors (Days), measured over 90 days from enrollment.

The primary outcome is “Days Free of Vasopressors (Days),” measured over 90 days from enrollment. Its description says that the number of days without vasopressor is adjusted with mortality. In general, a vasopressor-free-days outcome is intended to represent time alive and free of vasopressor support over a defined observation period. Incorporating mortality can prevent deaths from being treated as though they simply produced uncomplicated time off treatment. The exact adjustment used in this trial is not reported in the registry record, so the meaning of the adjustment cannot be specified further.

The registry reports the outcome as a mean and gives a full range for each group. Placebo has a mean of 24.3 days, with a range of 24.0 to 25.0, among 3 participants. Midodrine hydrochloride 10 mg TID has a mean of 7.5 days, with a range of 0.0 to 27.0, among 4 participants. Midodrine hydrochloride 20 mg TID has a mean of 25.6 days, with a range of 24.0 to 27.0, among 3 participants.

This measure is relevant to the trial's stated interest in liberation from IV vasopressors, but it is not identical to a reported time-to-liberation analysis. The registry does not provide individual participant data, a definition of how days were counted, or an inferential estimate comparing groups. The summaries therefore describe the recorded outcome while leaving important details of its construction and comparative precision unspecified.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is summarized by group using the mean and full range. A mean gives the arithmetic average of the recorded values in a group. A range reports the lowest and highest observed values. These statistics describe the participants whose results were posted; they do not, by themselves, estimate how outcomes would vary among all eligible patients or quantify uncertainty in a treatment comparison. In this trial, the reported means are 24.3 days for placebo, 7.5 days for midodrine hydrochloride 10 mg TID, and 25.6 days for midodrine hydrochloride 20 mg TID.

What does a range tell the reader?

As a general statistical explanation, a range gives the endpoints of the observed data and does not show how observations are distributed between those endpoints. A range can be especially unstable in a small group because each participant can determine one of its endpoints. The registry labels the dispersion as full range; it does not report a standard deviation or another measure of spread. The ranges are 24.0 to 25.0 days for placebo, 0.0 to 27.0 days for midodrine hydrochloride 10 mg TID, and 24.0 to 27.0 days for midodrine hydrochloride 20 mg TID.

The participant counts attached to those summaries are 3, 4, and 3, respectively. A group mean based on a handful of observations can change substantially when an individual value changes. This is a general limitation of estimating an average from a very small sample, not evidence that any particular posted value is incorrect. The record does not provide the participant-level observations needed to inspect the distribution or verify the summary from individual records.

What would an inferential comparison add?

In general, an inferential comparison estimates how far apart group outcomes are and describes the uncertainty around that estimate. A confidence interval is one common way to express such uncertainty. A p-value, when calculated under a specified model, addresses compatibility between the observed data and a stated null hypothesis. Neither measure is reported for the primary outcome in the registry record. The means alone cannot show whether an apparent separation is precise, whether it is compatible with chance variation, or how a result might generalize beyond the enrolled participants.

The record states that the outcome is adjusted with mortality, but does not explain the adjustment method. For example, the record does not specify the rule for assigning or combining outcome values when death occurs. This matters because different rules can lead to different interpretations of a mortality-adjusted outcome. No method should be assumed from the endpoint label alone.

Why does the planned design matter?

Randomization is intended, in general, to create comparable groups at assignment by using a chance process. The record identifies the trial as randomized, but does not describe the randomization sequence or concealment procedure. The group counts in the posted results are small, and randomization in a small study does not guarantee that all prognostic characteristics will be balanced. Baseline characteristics are not reported in the registry record, so the comparability of the groups cannot be assessed in the registry record recorded.

The registered arm descriptions refer to an early phase with 15 participants per group and an interim safety and efficacy analysis after the first 45 participants. The record does not state whether that interim analysis took place, how it was conducted, or what decision rules applied. Interim analyses can affect how evidence is interpreted if they influence stopping or continuation; without the analysis plan and its execution details, no adjustment or decision process can be reconstructed.

The trial is listed as phase 3, randomized, parallel, and triple masked, while its brief summary calls it double-blind. In general, masking means keeping specified people unaware of assigned treatment to limit certain biases. Which people were masked, and how the masking was maintained, are not reported in the registry record. The two descriptions should therefore be treated as registry wording rather than reconciled into a more detailed account.

How should significance and sample size be understood?

No p-value or confidence interval is posted for the primary comparison, and no analysis record is listed. Consequently, there is no reported test of statistical significance to interpret. General statistical significance is not the same as clinical importance, and a non-significant result would not by itself establish that groups are equivalent. In this record, neither equivalence nor a definitive difference has been demonstrated by a reported comparative analysis.

The registry record does not report the trial's sample-size justification or a completed power analysis. The registered early-phase allocation description is not a substitute for a documented sample-size rationale. Any sample-size illustration based on observed effects would be a planning exercise, not observed power and not a measure of how likely this completed trial was to detect an effect. No such numerical illustration is included in the registry record described for these results.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary outcome and 8 secondary outcomes: central venous catheter free days; ICU length of stay; hospital length of stay; 30-day mortality; 90-day mortality; in-hospital mortality; ICU mortality; and need to re-initiate IV vasopressors 2 or more hours after discontinuation. The registry record does not report numerical secondary outcome results in the information available for this trial. It also does not provide a statistical analysis plan or any analysis records.

Multiplicity arises when several outcomes or comparisons are examined. In general, testing many hypotheses can increase the chance of finding an apparently notable result by chance if no adjustment or prespecified interpretation is used. Whether multiplicity adjustments were planned or used is not reported in the registry record. Because no comparative tests are reported for the primary outcome, there are no posted p-values to interpret in relation to multiple testing.

Missing-data handling is also not reported in the registry record. The record does not state whether any enrolled participants lacked a primary outcome, how missing observations were handled, or whether sensitivity analyses were planned. The reported group counts are the counts attached to the primary outcome summaries; the record does not explain whether these represent all randomized participants or a particular analysis population.

The analysis population is not reported in the registry record. There is no statement about whether the results follow intention-to-treat, per-protocol, or another principle. These distinctions matter in general because exclusions after randomization can affect the comparability created by random assignment. No conclusions about exclusions or adherence can be drawn from the posted group summaries alone.

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.

The registry reports serious adverse events and other adverse events by group. For serious adverse events, 0 affected participants are listed among 3 at risk in the placebo group, 0 among 4 at risk in the midodrine hydrochloride 10 mg TID group, and 0 among 3 at risk in the midodrine hydrochloride 20 mg TID group. For other adverse events, the corresponding figures are 0 among 3, 0 among 4, and 0 among 3. No serious adverse event terms are listed.

These are counts of participants reported as affected, not a detailed account of event types, timing, severity beyond the serious-event category, or relationship to treatment. The registry does not report the definitions or collection procedures for these categories. Zero affected participants in these small groups should not be read as proof that no adverse events could occur or as a precise estimate of safety in a broader population. In general, safety estimates based on few participants are highly uncertain.

Deaths are reported separately: 2 in placebo, 1 in the 10 mg TID group, and 0 in the 20 mg TID group. These death counts should not be treated as a comparison of mortality risk without a specified analysis and appropriate uncertainty estimates. The record does not report a statistical comparison for deaths or explain how the deaths relate to the mortality-adjusted primary outcome.

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

The registry record documents a randomized study of placebo and two midodrine regimens in early septic shock, with the stated aim of examining vasopressor liberation. The posted primary outcome is days free of vasopressors adjusted with mortality over 90 days from enrollment. It reports group means and ranges for 10 participants: 3 assigned to placebo, 4 to midodrine hydrochloride 10 mg TID, and 3 to midodrine hydrochloride 20 mg TID.

The reported values are descriptive. The registry provides no confidence intervals, p-values, or formal primary comparison, so the precision of a group contrast is not established. The small group sizes and the spread in the 10 mg TID group make it particularly important not to treat the means as stable estimates for a broader population. The record also does not explain the mortality adjustment, which limits interpretation of the endpoint itself.

These results do not establish that one assignment is better or worse than another. They also do not establish equivalence or rule out differences. The data describe the participants and outcome summaries posted for this trial, rather than providing a conclusive comparative estimate. The safety counts likewise cannot establish the presence or absence of risk beyond the observed participants: no serious or other adverse events are listed as affecting participants, while deaths are reported separately in the groups.

The status is terminated and enrollment is listed as 10. The reason for termination is not reported in the registry record, and the record does not say whether the planned interim safety and efficacy analysis took place. These missing details prevent attributing the enrollment or status to any particular outcome or safety finding. The results should therefore be read as a limited record of a small terminated trial, with substantial uncertainty and important analytic details absent.

13. Why This Trial Matters Statistically

This trial illustrates an important distinction between a randomized design and an informative comparative result. Randomization is valuable because it aims to make treatment groups comparable, but a randomized study with very few participants can still provide imprecise estimates. Here, the primary summaries are based on 3, 4, and 3 participants. Such small groups leave little information for distinguishing a treatment-related pattern from ordinary variation among participants.

The endpoint also raises a measurement issue. The stated primary outcome combines vasopressor-free days with a mortality adjustment, but the method is not described. This kind of outcome may be useful for incorporating death into an assessment of time free from treatment, yet its interpretation depends on the exact rule used. A clear endpoint definition and analysis method are necessary for readers to understand what the resulting mean represents.

The registry describes a planned interim safety and efficacy analysis and a design with three initial groups, while the completed enrollment is listed as 10. Whether the interim analysis occurred and how the registered plan was implemented are not reported. This makes the record a useful example of why planned design features and completed analyses need to be distinguished. A planned interim analysis should not be presumed to have been conducted merely because it appears in an arm description.

Finally, reporting only group means and ranges leaves readers without an estimate of comparative uncertainty. Confidence intervals and a defined analysis population would help clarify what the results can support; the registry record does not report them. The trial therefore matters statistically as an illustration of how endpoint definition, sample size, analysis transparency, and complete reporting all shape interpretation, even when a study is randomized.

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 primary limitation for interpreting this trial is the very small enrolled sample. The registry lists enrollment of 10, and the posted primary outcome summaries include 3 participants in placebo, 4 in midodrine hydrochloride 10 mg TID, and 3 in midodrine hydrochloride 20 mg TID. Individual observations can have substantial influence on summaries at these group sizes. The reported range in the 10 mg TID group, 0.0 to 27.0 days, also indicates that observed values in that group varied widely.

The trial is listed as terminated, but the reason is not reported in the registry record. The arm descriptions refer to an early allocation plan and an interim safety and efficacy analysis, but the record does not report whether that analysis occurred or whether enrollment continued according to the described plan. The arm descriptions are truncated, leaving further design details unclear.

The primary outcome's mortality adjustment is not defined. The record also lacks a comparative analysis, confidence intervals, p-values, baseline characteristics, an analysis population, missing-data methods, and a sample-size justification. It does not report protocol deviations or treatment adherence. These omissions limit assessment of both the endpoint and the reliability or generalizability of the group summaries.

There is also differing masking language: the registry identifies triple masking, while the brief summary describes a double-blind trial. The specific people masked and the procedures used are not reported in the registry record. Finally, secondary outcomes are listed, but their numerical results are not included in the registry record described for this trial. These limitations mean the posted results offer only a narrow descriptive account, rather than a complete basis for evaluating the trial's planned and executed analyses.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Midodrine Use in Septic Shock — NCT03706053.
• Registry record last updated 2025-09-24; status last verified 2025-09.
• Results first posted 2025-09-24.
• 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

NCT03706053 is a phase 3, randomized, parallel-group trial sponsored by the University of Virginia and listed as terminated. It concerns midodrine use for hypotension requiring IV vasopressor therapy in early septic shock. The record lists placebo, midodrine hydrochloride 10 mg TID, and midodrine hydrochloride 20 mg TID. Enrollment is 10; the start date is 2018-11-05, and the primary completion date is 2022-02-11.

The primary outcome is days free of vasopressors adjusted with mortality over 90 days from enrollment. Reported group means are 24.3 days for placebo, 7.5 days for the 10 mg TID group, and 25.6 days for the 20 mg TID group, with full ranges and group sizes also reported. No inferential comparison is posted. Serious and other adverse events are listed as affecting 0 participants in each group; deaths are reported as 2, 1, and 0, respectively. The reason for termination, analysis methods, and secondary outcome results are not reported in the registry record.