This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for The Safety Evaluation of Aminophylline and Ambrisentan When Administered Orally Alone and in Combination to Healthy Volunteers (NCT01530464), a randomized phase 1 study. The primary outcome is Mean Number of Adverse Events Following Each Dose.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01530464 |
| Phase | Phase 1 |
| Condition | High Altitude Pulmonary Hypertension |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | None (open label) |
| Enrollment | 18 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Thies Schroeder |
| Results posted | Yes |
2. Clinical Question
Population
Healthy human volunteers. The registry record lists High Altitude Pulmonary Hypertension as a condition, but describes the study participants as healthy volunteers rather than people being treated for that condition.
Intervention
Aminophylline and ambrisentan taken together as oral doses. The combined dose is described as aminophylline 500 mg plus ambrisentan 5 mg.
Comparator
Oral aminophylline alone and oral ambrisentan alone. The dosing descriptions identify single doses of 500 mg aminophylline and 5 mg ambrisentan, respectively.
Primary question
What mean number of adverse events was observed during the 48 h following each dose, and how did the recorded safety experience compare across the three dosing conditions?
The study’s primary objective was to assess the safety and tolerability of aminophylline and ambrisentan when administered together to healthy volunteers. Its secondary objective was to assess the pharmacokinetic profiles of theophylline, identified in the registry summary with aminophylline, and ambrisentan when each was administered alone or in combination.
The registry summary states a hypothesis that the combination would be generally safe and that no drug interaction would be observed. That hypothesis is not itself a result. The registry record does not report numerical primary-endpoint results or pharmacokinetic results, so the posted information does not establish whether the observed data supported either expectation. It also does not describe a clinical efficacy question in patients with pulmonary hypertension.
3. Trial Design
This was a Phase I, randomized, open-label crossover study with three treatment periods and two sequences. The registry record reports enrollment of 18 participants. In a crossover design, participants receive more than one treatment condition over successive periods, so each participant can contribute observations under different conditions. Random allocation to sequence is intended to assign the order of those conditions rather than to create separate parallel groups.
The three conditions were aminophylline alone, ambrisentan alone, and the combination. The dose descriptions identify a single 500 mg dose of aminophylline, a single 5 mg dose of ambrisentan, and a combined single dose of aminophylline 500 mg plus ambrisentan 5 mg. The study was open-label, meaning masking was not used. The registry record does not report the sequence-specific treatment order, the duration of each period, or any washout interval between periods.
The primary objective was safety and tolerability. The primary outcome is described as the mean number of adverse events following each dose, with a 48 h timeframe. The secondary objective concerned pharmacokinetic profiles. The record identifies the study as completed, with a start date of 2012-02 and primary completion in 2012-04.
The crossover structure is relevant when interpreting comparisons: measurements within the same participant may be related, and the treatment order or period may also matter. The registry record does not report how those design features were handled in the analysis. It also does not report the statistical analysis plan, analysis populations, or any numerical primary endpoint or pharmacokinetic results.
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: The study was initiated on August 1, 2011 and stopped on August 9, 2011 after a delay in acquiring the study drug ambrisentan. None of the 24 screened subjects were randomized in this period. The trial was re-started on February 6, 2012 and completed on April 14, 2012 with the last subject being evaluated on April 30, 2012.
First Intervention (24h)
| Stage | Sequence A | Sequence B |
|---|---|---|
| STARTED | 10 | 8 |
| COMPLETED | 10 | 8 |
| NOT COMPLETED | 0 | 0 |
Washout (24h)
| Stage | Sequence A | Sequence B |
|---|---|---|
| STARTED | 10 | 8 |
| COMPLETED | 10 | 8 |
| NOT COMPLETED | 0 | 0 |
Second Intervention (24h)
| Stage | Sequence A | Sequence B |
|---|---|---|
| STARTED | 10 | 8 |
| COMPLETED | 10 | 8 |
| NOT COMPLETED | 0 | 0 |
Washout (24h)
| Stage | Sequence A | Sequence B |
|---|---|---|
| STARTED | 10 | 8 |
| COMPLETED | 9 | 8 |
| NOT COMPLETED | 1 | 0 |
Reasons for not completing this period:
| Reason | Sequence A | Sequence B |
|---|---|---|
| Withdrawal by Subject | 1 | 0 |
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.
| Characteristic | Unit | Sequence A | Sequence B | Total |
|---|---|---|---|---|
| Participants analysed | 10 | 8 | 18 | |
| Age, Categorical: <=18 years | Participants | 0 | 1 | 1 |
| Age, Categorical: Between 18 and 65 years | Participants | 10 | 7 | 17 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Sex: Female, Male: Female | Participants | 2 | 1 | 3 |
| Sex: Female, Male: Male | Participants | 8 | 7 | 15 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 6 | 8 | 14 |
| Race (NIH/OMB): White | Participants | 4 | 0 | 4 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Mean Number of Adverse Events Following Each Dose, measured over 48 h following each dose.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | Mean number of adverse events |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is titled Mean Number of Adverse Events Following Each Dose. It is a continuous outcome: the registry describes a mean and standard deviation, with the observation window defined as 48 h following each dose. In practical terms, the endpoint is intended to summarize the average number of adverse events recorded after exposure to each treatment condition.
Safety and tolerability are central questions in an early-phase study of drugs administered alone and together. Counting events can describe the amount of recorded event experience, while the standard deviation describes how much individual observations vary around the mean. These summaries can help characterize the observed safety data, but they do not, on their own, establish why an event occurred or whether one treatment caused more events than another.
The registry record includes the endpoint definition and timeframe, but does not report the mean values, standard deviations, or a statistical comparison for this endpoint. It also does not report details of how events were collected, coded, or counted for this measure. Consequently, the posted information describes what the endpoint was meant to measure, but does not provide its numerical results.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted adverse-event figures list no serious adverse events among the 18 participants at risk in each of the three treatment conditions. For other adverse events, the record lists 7 affected participants in the aminophylline-only condition, 5 in the ambrisentan-only condition, and 6 in the combined condition, with 18 at risk in each. These are descriptive counts, not estimates of comparative treatment effects.
Because this was a crossover study, the same participants may contribute to more than one treatment condition. The figures for the conditions therefore should not automatically be read as counts from independent groups. The registry record does not provide participant-level data or an analysis that accounts for within-participant pairing, sequence, or period. It is not possible to determine from the posted counts whether the same participants experienced events in more than one condition.
The primary outcome is defined as a mean number of adverse events during the 48 h after each dose. Its numerical results are not reported in the registry record. The counts of participants affected by other adverse events are a different summary: they do not give the total number of events, the mean number of events, or the variability of that mean. They therefore cannot substitute for the missing primary-endpoint summaries.
No p-value, confidence interval, or formal comparison for the primary outcome is reported in the registry record. No pharmacokinetic results are reported either. Without these results, the posted information does not quantify the precision of a treatment contrast or show whether a difference between conditions was compatible with chance variation. The descriptive counts alone do not establish that the treatments have the same safety profile, nor do they establish that the combination caused an increase or decrease in adverse events.
The serious-event counts are reassuring only as a description of what was recorded in this study’s observed participants and follow-up. A zero count is not proof that serious events cannot occur. The registry record does not report longer-term safety follow-up, and the primary endpoint’s stated observation window is limited to 48 h following each dose. These features constrain what can be concluded from the posted safety information.
9. Statistical Methods Explained
What does a mean and standard deviation describe?
As a general statistical explanation, a mean summarizes the average value of a measured outcome across observations. For an event-count endpoint, the mean is an average number of recorded events. It can be useful for comparing overall event burden, but it may conceal differences between participants: some may have no events while others have several. The standard deviation describes the spread of observations around the mean. A larger spread indicates greater variation among the observations, but does not by itself indicate whether the mean is estimated precisely.
The registry record identifies the primary measure as a mean number of adverse events and names standard deviation as its dispersion measure. It does not report the actual mean or standard deviation for any treatment condition. Nor does it explain the specific event-counting rules. Those details matter because the same participant could have multiple events, and the summary of event totals differs from the summary of participants with at least one event.
How does a crossover design affect comparisons?
As a general statistical point, a crossover design can make within-participant comparisons possible because each participant receives multiple conditions. Measurements from the same person are often related. An analysis that accounts for this relationship may differ from one that treats all treatment observations as independent. Treatment order and period can also be relevant: outcomes may vary over time, and earlier exposure could affect a later observation if an adequate washout is not present.
This trial is described as randomized, open-label, and crossover, with three periods and two sequences. The registry record does not report the treatment order within each sequence, the washout schedule, or whether the analysis accounted for participant, sequence, or period. The registry record also does not report an analysis model, so it is not possible to assess whether the posted statistical approach used the crossover structure appropriately.
What would a confidence interval or p-value add?
As a general explanation, a confidence interval communicates the range of effect estimates that are reasonably compatible with the observed data under the method’s assumptions. Its width indicates precision: a wide interval reflects substantial uncertainty, while a narrow interval reflects more precise estimation. A p-value measures how unusual data at least as discrepant as those observed would be under a specified null hypothesis and model. Neither statistic, by itself, measures clinical importance or proves that a treatment effect is present or absent.
No confidence interval or p-value for a treatment comparison is reported in the registry record. The record lists no analysis results, and the primary outcome has several categories or time points that were not reduced to one comparison. Thus, there is no posted inferential result with which to assess precision or statistical evidence for a difference.
Why might event counts need careful modelling?
As a general statistical point, event counts are non-negative and may be unevenly distributed. Some participants can have no events, while a smaller number have multiple events. A simple mean and standard deviation remain descriptive summaries, but the distribution can affect the suitability of a model used for comparisons. Over-dispersion occurs when the variability in event counts exceeds what a chosen model assumes. If present, it can make standard errors too small and confidence intervals too narrow unless the method accounts for it.
The registry record does not report the distribution of the event counts or a model used to analyse them. It is therefore not possible to determine whether over-dispersion was assessed or whether a count-data model was used. This is a general methodological consideration, not a finding about this study’s data.
What can planning calculations establish?
As a general distinction, a sample-size calculation is a planning exercise based on assumptions about a target effect, variability, significance level, allocation, and analysis method. It does not describe the power achieved after a study has finished. An illustration based on an observed effect is also not a substitute for the trial’s original design justification.
The registry record lists assumptions for planning illustrations, including a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It does not report the trial’s original sample-size justification. The registry record also does not provide a numerical comparison for the primary endpoint from which to assess any observed effect. Any planning illustration should therefore be read as a hypothetical planning exercise, not as an observed study result or evidence of achieved power.
10. Multiplicity, Missing Data and Analysis Populations
The primary outcome is described as having several categories or time points, and it was not reduced to one comparison. When a study assesses multiple outcomes, contrasts, or time points, the chance of obtaining at least one apparently unusual result can increase. Statistical methods for multiplicity can address that issue, but the appropriate approach depends on the planned questions and analysis.
The registry record does not report a multiplicity strategy or identify a single primary comparison among the listed outcome components. It does not report p-values or confidence intervals for the primary outcome. Therefore, the posted information does not permit an assessment of whether multiplicity was controlled or how any multiple comparisons should be interpreted.
The registry record does not report how missing observations were handled, how many observations were missing, or whether participants were excluded from any analysis. The analysis populations and the rules for including participants in each endpoint analysis are not reported in the registry record. Although enrollment is listed as 18, that number alone does not establish how many participants contributed usable data to every endpoint or treatment period.
The record lists zero analysis records. This means the posted results do not include a reported inferential analysis for the primary endpoint. It does not establish what analyses may have been planned or conducted outside the registry record. The statistical analysis plan, including missing-data methods and any prespecified hierarchy of outcomes, is not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Aminophylline Only | 0 | 18 | 0.0% |
| Ambrisentan Only | 0 | 18 | 0.0% |
| Combined Aminophylline and Ambrisentan | 0 | 18 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Aminophylline Only | 7 of 18 |
| Ambrisentan Only | 5 of 18 |
| Combined Aminophylline and Ambrisentan | 6 of 18 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Aminophylline Only | Ambrisentan Only | Combined Aminophylline and Ambrisentan |
|---|---|---|---|---|
| Headache | Nervous system disorders | 2 of 18 | 5 of 18 | 2 of 18 |
| Cramping | Musculoskeletal and connective tissue disorders | 2 of 18 | 3 of 18 | 2 of 18 |
| Tremors | Nervous system disorders | 4 of 18 | 0 of 18 | 2 of 18 |
| Urinary Frequency | Renal and urinary disorders | 0 of 18 | 1 of 18 | 4 of 18 |
| Dizziness/ lightheadedness | Nervous system disorders | 2 of 18 | 0 of 18 | 2 of 18 |
| Nausea | Gastrointestinal disorders | 3 of 18 | 0 of 18 | 1 of 18 |
| Palpitations and Tachycardia | Cardiac disorders | 2 of 18 | 0 of 18 | 2 of 18 |
| Facial flushing and hot flashes | General disorders | 0 of 18 | 1 of 18 | 1 of 18 |
| Sweaty clammy hands and feet | General disorders | 0 of 18 | 0 of 18 | 2 of 18 |
| Anxiety and restlessness | Nervous system disorders | 1 of 18 | 0 of 18 | 1 of 18 |
The registry lists 18 participants at risk for serious adverse events in each treatment condition and 0 affected by serious adverse events in each. These are serious-event counts for the aminophylline-only, ambrisentan-only, and combined conditions. Death counts are not reported in the registry record.
For other adverse events, the registry lists 7 affected participants in the aminophylline-only condition, 5 in the ambrisentan-only condition, and 6 in the combined condition; 18 participants are listed at risk in each condition. These are counts of affected participants, not a count of all events. A participant may have experienced more than one event, and the record does not provide details that would allow the total event count or overlap across conditions to be determined.
Because the study used a crossover design, participants may appear in the risk group for more than one condition. The counts should not be treated as independent groups or as a formal comparison. They describe the recorded adverse-event experience, but do not establish causal attribution or characterize risks beyond the study’s reported observation window.
12. What the Result Does, and Does Not, Mean
The registry record establishes that a randomized, open-label crossover study was conducted in healthy volunteers to examine aminophylline and ambrisentan alone and together. It defines a safety endpoint based on the mean number of adverse events during the 48 h following each dose and lists participant counts for serious and other adverse events. Those details help identify the questions the study was designed to address and the scope of the posted safety information.
The record does not provide numerical results for the mean adverse-event endpoint, its standard deviations, or a formal comparison across treatment conditions. It also does not provide pharmacokinetic results. The descriptive affected-participant counts therefore cannot answer the full primary question or establish whether the combination changed event experience relative to either drug alone.
Zero serious adverse events were recorded among the participants listed at risk in each condition. That observation describes this study; it does not demonstrate that serious adverse events are impossible or rule out less common events. Likewise, the counts of participants with other adverse events do not show whether events were related to treatment, how severe they were, or whether any participant had events under more than one condition.
The study’s stated hypothesis about safety and drug interaction should be distinguished from the evidence posted in the registry. Without numerical endpoint and pharmacokinetic findings, it is not possible to determine from this record whether the hypothesis was supported. The study also involved healthy volunteers, so its results, even if fully reported, would not automatically describe outcomes in people with High Altitude Pulmonary Hypertension.
13. Why This Trial Matters Statistically
This trial is statistically notable because its crossover design is suited to questions about treatment conditions administered to the same participants. Such a design can support within-participant comparisons, but interpretation depends on the treatment sequence, period structure, and handling of possible carryover. The registry record identifies the crossover structure without reporting those analytical details.
The endpoint also illustrates the difference between a mean event-count outcome and the number of participants affected by an event. The primary measure is the mean number of events, accompanied by a standard deviation, while the adverse-event listing reports affected-participant counts. These summaries answer different descriptive questions. The available counts cannot reconstruct the missing mean, variability, or comparison.
Finally, the record separates a stated study hypothesis from reported results. It includes a rationale and objectives, but the numerical primary endpoint and pharmacokinetic findings are not reported. For statistical interpretation, a design description and a set of descriptive safety counts are not substitutes for an effect estimate and an account of its uncertainty. This distinction is especially important in an early-phase study where the posted information is limited to observed counts and endpoint definitions.
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 describes a study in healthy volunteers, not a therapeutic trial in people with High Altitude Pulmonary Hypertension. Its findings therefore would have limited direct relevance to patients with that condition, even if the complete outcome results were available. The record also lists enrollment of 18, which limits the amount of information available for characterizing uncommon events.
The stated safety observation window is 48 h following each dose. The registry record does not report longer-term safety follow-up. It also does not report the primary endpoint’s numerical mean or standard deviation, the total number of events, event-level descriptions, or formal comparisons. The posted affected-participant counts cannot fill those gaps.
Open-label administration means treatment masking was not used. The registry record does not describe how adverse events were elicited, assessed, or attributed. It does not report treatment order, period-specific results, washout intervals, or methods for handling possible period or carryover effects. Those omissions limit assessment of how well the reported design features were reflected in the analysis.
The registry record does not report analysis populations, missing-data methods, a statistical analysis plan, multiplicity handling, or numerical pharmacokinetic findings. It also does not report the trial’s original sample-size justification. These limitations concern the information available in the registry record; they do not establish what procedures may have been used outside it.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: The Safety Evaluation of Aminophylline and Ambrisentan When Administered Orally Alone and in Combination to Healthy Volunteers — NCT01530464.
- Registry record last updated 2014-01-16; status last verified 2013-11.
- Results first posted 2014-01-16.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
This completed Phase I study enrolled 18 healthy volunteers in a randomized, open-label crossover design with three treatment periods and two sequences. It examined aminophylline alone, ambrisentan alone, and the combined drugs. The listed single doses were 500 mg aminophylline and 5 mg ambrisentan, including those doses together in the combination condition.
The primary endpoint was the mean number of adverse events during the 48 h following each dose, with standard deviation identified as the measure of dispersion. The registry record does not report numerical results for that endpoint or for the secondary pharmacokinetic objective. It lists 0 serious adverse events among 18 at risk in each condition and other adverse events affecting 7, 5, and 6 participants, respectively. These are descriptive counts, not a formal comparison. Analysis methods, missing-data handling, and the original sample-size justification are not reported in the registry record.