Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH) (Droxi-304): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH) (Droxi-304) (NCT01132326), a na phase 3 study. The primary outcome is Patients With Treatment-emergent Adverse Events.

2. Clinical Question

3. Trial Design

This was a phase 3, multicenter, open-label study of droxidopa. The official title describes a long-term safety assessment in subjects with primary autonomic failure, dopamine beta hydroxylase deficiency or non-diabetic neuropathy and symptomatic neurogenic orthostatic hypotension. The registry lists the study as completed, with a start date of 2009-01 and primary completion in 2013-02. Chelsea Therapeutics is listed as the sponsor.

The design is single-group, with no masking and allocation listed as NA. Participants were assigned to the open-label droxidopa group; there is no separate comparator arm in this study record. The listed enrollment is 350. The record does not state whether this figure is the number enrolled, treated, or included in the primary outcome analysis, so those categories should not be treated as interchangeable.

The primary outcome is the number of participants reporting treatment-emergent adverse events, including serious adverse events and/or adverse events, over a timeframe of up to 2 years. This design can describe events observed among participants receiving droxidopa, but it cannot by itself separate treatment-related effects from events that might occur over time for other reasons. Open-label status also means the record does not describe blinded assessment.

The registry does not report a randomized comparison, an efficacy endpoint in the listed outcome measure, or the detailed statistical plan. It also does not report treatment dosing, adherence, exposure duration by participant, or the exact analysis population for the primary outcome. Those omissions limit interpretation of how the observed safety counts relate to treatment exposure and to the full enrolled group.

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 Patients With Treatment-emergent Adverse Events, measured over up to 2 years.

The primary endpoint is the number of participants reporting any treatment-emergent adverse events, described as serious adverse events and/or adverse events, during the study. Its timeframe is up to 2 years. In general, a participant count is a way to describe how many people experienced at least one event under the endpoint definition; it is not the same as a count of all event episodes. A participant with more than one event may still contribute only once to a participant-based measure, depending on the endpoint’s counting rules.

Safety endpoints are used to characterize harms observed during treatment, including events that may require particular attention because they meet serious-event criteria. They can support a descriptive account of the kinds and frequency of reported events. In a single-group open-label study, however, the endpoint does not estimate the excess risk attributable to treatment relative to a control group. Events occurring during treatment are not necessarily caused by treatment.

The registry record does not give a fuller operational definition, specify how repeated events were handled, or describe an analysis population for this endpoint. The adverse-event summary separately records 83 participants affected under serious adverse events and 178 under other adverse events, with 350 at risk in each category. Those category counts should not be treated as the primary endpoint total: the record does not establish whether the categories overlap or how they map to the endpoint’s “serious adverse events and/or adverse events” wording.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count describe?

A participant count records how many people meet an outcome definition, rather than how many event episodes occurred. This distinction matters in safety reporting: a person may experience more than one event, while a participant-based endpoint may count that person once. The registry’s primary endpoint is phrased as the number of patients reporting treatment-emergent adverse events. The adverse-event summary gives separate counts for participants affected by serious and other adverse events. The record does not explain the counting rules or whether the same participant can appear in both categories.

Each adverse-event category lists 350 at risk. That figure is the denominator recorded for the category, not proof that every participant had the same amount of follow-up or treatment exposure. The endpoint timeframe is up to 2 years, but the registry record does not report participant-level follow-up duration or exposure-adjusted event rates.

Why does the study design matter?

A single-group study can describe what was observed among participants receiving droxidopa. A comparative treatment effect requires a reference condition that allows outcomes under treatment to be contrasted with outcomes under a comparator. This study has no separate control group, and allocation is listed as NA. As a result, differences from a hypothetical untreated or differently treated group cannot be estimated from this record.

Open-label status means treatment was not masked. In general, knowledge of treatment assignment can influence reporting, monitoring or assessment of events. The extent of any such influence cannot be determined from the registry information. The design does not invalidate the event descriptions, but it limits what can be inferred from them about causation or comparative risk.

What do serious-event categories mean?

Seriousness is a regulatory classification based on the consequences of an event; it is not simply a synonym for intensity or symptom severity. A serious event and a non-serious event can each be clinically important. The record lists 83 participants affected under serious adverse events and 178 under other adverse events. It also lists serious-event terms and percentages. These should be interpreted as reported categories, not as proof of a causal relationship with droxidopa.

General statistical interpretation also distinguishes the number of participants with an event from the number of events. The registry provides participant counts for the categories, but the detailed event-level totals and counting conventions are not reported in the registry record. The counts cannot establish how often events recurred within a participant.

What can uncertainty estimates add?

In general, a confidence interval describes the range of values compatible with an estimate under a specified statistical model and indicates its precision. A hypothesis test addresses compatibility with a null hypothesis under that model. Neither type of result is recorded for the analyses in this study record: the record lists zero analyses and does not provide confidence intervals or p-values. A reader therefore cannot use the posted results to assess the statistical uncertainty around a comparative effect.

Statistical significance, when reported, would not by itself establish clinical importance or causation. Conversely, a non-significant result would not prove that two conditions are equivalent. Those distinctions are general; this record does not report a treatment comparison to which such a test could be applied.

How should planning illustrations be understood?

General sample-size calculations depend on assumptions about the effect to be detected, the significance level, allocation, and the statistical model. The planning description associated with this study uses a two-sided significance level of 0.05, equal allocation between two hypothetical arms, and a normal approximation; it describes effects as fractions of an observed effect. These are planning assumptions, not a description of the actual single-group trial design.

Such planning values are illustrations of what a future comparison might require under stated assumptions. They are not observed power, evidence that the trial was designed around those assumptions, or a retrospective measure of whether the study could detect a safety difference. The registry record does not report the trial’s sample-size justification or a sample-size calculation in its own design plan.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Droxidopa")
n      <- c(350)
events <- c(263)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Droxidopa  350  263  75.1  70.3  79.6  70.4  79.4  70.4  79.4

11. Multiplicity, Missing Data and Analysis Populations

The record lists one outcome measure and zero analyses. It does not report a multiplicity adjustment or explain how multiple outcomes, event categories or statistical tests would have been handled. Because no analyses are listed, there is no reported family of hypothesis tests from which to judge control of false-positive findings. The serious-event terms and their percentages are descriptive entries, not a set of reported inferential tests.

Missing-data methods are not reported in the registry record. The record does not explain how participants with incomplete follow-up, missing outcome assessments or unknown event status were handled. Although the adverse-event categories each list 350 at risk, that entry does not establish complete outcome ascertainment for every participant throughout the timeframe of up to 2 years.

The analysis population is also not reported in the registry record. The enrollment figure is 350, but the available description does not say whether the primary endpoint used all enrolled participants, only those who received treatment, or another defined group. It does not report exclusions, withdrawals or a participant flow. These details matter when interpreting denominators and comparing outcome counts.

There is no reported statistical analysis plan, interim analysis approach or adjustment for covariates. Their absence should be treated as unreported information, not evidence that a particular method was or was not used outside the registry record. With no analysis entries or uncertainty estimates, the posted safety counts remain descriptive.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: syncope (2.9%), pneumonia (2.0%), dehydration (2.0%), fall (1.1%), respiratory failure- (1.1%).

The serious adverse-event summary lists 83 participants affected, with 350 at risk. The other adverse-event summary lists 178 participants affected, also with 350 at risk. These are separate categories in the registry record. The record does not report whether participants could be counted in both, so the figures should not be combined or interpreted as mutually exclusive groups.

The listed serious-event terms and percentages are syncope, 2.9%; pneumonia, 2.0%; dehydration, 2.0%; fall, 1.1%; respiratory failure-, 1.1%; and transient ischaemic attack, 0.9%. They identify reported terms, not necessarily treatment-related events. The record does not state the denominator or follow-up basis for each term in the available summary.

In general, a serious adverse event is classified by seriousness criteria, which differ from a simple rating of symptom intensity. A listed serious event does not on its own establish that the treatment caused it. Because this study has no control group, the figures cannot show whether event occurrence was higher or lower than it would have been under another condition. Deaths are not reported in the adverse-event summary.

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

The results do show that adverse events were recorded among participants in the open-label droxidopa group. The registry lists separate participant counts for serious adverse events and other adverse events, along with a set of serious-event terms and percentages. These observations describe the safety experience captured in this study record over a timeframe of up to 2 years.

They do not show that droxidopa caused the recorded events. Adverse events can occur during treatment for reasons unrelated to treatment, and this single-group design provides no control group to help distinguish those possibilities. Open-label conduct also means the record does not describe blinded assessment. The posted figures therefore cannot establish a comparative safety effect or a causal risk.

The counts also do not answer whether droxidopa improves symptoms or changes clinical outcomes. The listed primary endpoint is a safety measure, and the registry record does not include a reported efficacy analysis. Nor does it provide confidence intervals or hypothesis tests for a treatment contrast. The precision of any comparative effect is therefore not available from the record.

The serious and other adverse-event counts should be read separately. The registry does not report whether they overlap, how repeated events were counted, or whether every participant had the same observation period. The figures cannot be added to infer a count of participants with any event, and the listed enrollment should not be assumed to equal the primary endpoint analysis population without further information.

In statistical terms, this is a descriptive account of events recorded in the study, not a controlled estimate of benefit or harm. The absence of a reported comparison is not evidence that no difference exists. It means that the registry results do not quantify a difference against an alternative treatment or no treatment.

14. Why This Trial Matters Statistically

Long-term safety studies address a question that is distinct from whether a treatment changes a clinical outcome: what adverse events are recorded while people receive treatment over an extended timeframe? This study’s primary outcome is framed around treatment-emergent adverse events, with a timeframe of up to 2 years. Its results therefore contribute descriptive information about events documented in the droxidopa group.

The statistical design sets clear limits on that information. With a single group and no masking, the study can report observed counts but cannot provide a randomized contrast. A control group is important for interpreting whether event occurrence differs from what might happen without the study treatment or under another treatment. Without one, background events and treatment effects cannot be separated using the posted counts alone.

The record also illustrates why definitions and analysis details matter in safety reporting. Serious and other adverse events appear as distinct categories, but the registry does not explain possible overlap or the exact counting rules. Follow-up and analysis-population details are not reported. Those omissions affect how confidently readers can connect counts to the primary endpoint and the study’s enrolled population.

Statistically, the value of the record lies in its descriptive safety observations, not in a causal or comparative estimate. The absence of reported analyses and uncertainty estimates leaves precision unquantified. Keeping that distinction in view prevents a count of events from being mistaken for a treatment effect and helps define what further controlled evidence would be needed to answer comparative questions.

15. 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 important design limitation is the lack of a comparator. A single-group, open-label study cannot establish how event occurrence compares with another treatment or with no treatment. It also cannot distinguish treatment effects from events that would have occurred for other reasons. The registry record does not describe blinded event assessment.

The safety summaries have limited detail. The record lists 83 participants affected under serious adverse events and 178 under other adverse events, with 350 at risk in each category, but does not report whether those categories overlap. It does not describe how repeated events were counted or give event-level totals. The listed serious-event terms and percentages are not accompanied by a reported denominator or participant-level follow-up basis in the available summary.

The primary outcome timeframe is up to 2 years, but the registry record does not report how long participants were followed individually, their treatment exposure, or whether exposure differed. It also does not report the analysis population, participant flow, withdrawals, missing-data handling or completeness of outcome ascertainment. The enrollment figure cannot resolve these questions.

No statistical analyses are recorded. Confidence intervals, p-values, adjusted estimates, a statistical analysis plan, interim analyses and a sample-size justification are not reported in the registry record. The available counts therefore do not quantify statistical uncertainty or support an inferential comparison. Finally, deaths are not reported in the adverse-event summary; their absence from that summary should not be interpreted as evidence about whether deaths occurred.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH) (Droxi-304) — NCT01132326.
• Registry record last updated 2024-02-09; status last verified 2024-02.
• Results first posted 2014-04-21.
• 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.

19. Record Summary

The registry describes NCT01132326, titled “Clinical Study of Droxidopa in Patients With Neurogenic Orthostatic Hypotension (NOH) (Droxi-304).” It is a completed phase 3, multicenter, open-label, single-group study sponsored by Chelsea Therapeutics. The listed enrollment is 350; the study start date is 2009-01 and primary completion is 2013-02.

The study assessed long-term safety of droxidopa in participants with primary autonomic failure, dopamine beta hydroxylase deficiency or non-diabetic neuropathy and symptomatic neurogenic orthostatic hypotension. Its primary outcome is the number of participants reporting treatment-emergent adverse events, including serious adverse events and/or adverse events, over up to 2 years.

The adverse-event summary lists 83 participants affected under serious events and 178 under other events, with 350 at risk in each category. The record lists serious-event terms and percentages but no analyses. It does not report a comparator, statistical uncertainty estimates, missing-data methods or the primary endpoint analysis population. The results are descriptive and do not provide a comparative treatment effect.