Safety Study of Albuterol Spiromax® in Subjects With Asthma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety Study of Albuterol Spiromax® in Subjects With Asthma (NCT01698320), a randomized phase 3 study. The primary outcome is Participants With Adverse Experiences During Weeks 0-12 (Double-Blind Period).

2. Clinical Question

In statistical terms, this is a question about event occurrence during a defined follow-up window, rather than a question about symptom improvement or a measure of treatment benefit. The safety focus is consistent with the study’s stated purpose of evaluating Albuterol Spiromax® over 52 weeks. The initial placebo-controlled period allows a blinded comparison of the assigned groups during the first 12 weeks; the later open-label period follows both groups while participants receive Albuterol MDPI. Because treatment assignment and blinding differ between periods, the later counts answer a different descriptive question and should not be read as an extension of the original placebo-controlled contrast.

3. Trial Design

This was a Phase 3, randomized, quadruple-masked, parallel-group study in subjects with asthma. The registry record lists enrollment of 364 and study status as completed. The sponsor was Teva Branded Pharmaceutical Products R&D, Inc. The study began in 2012-10, and primary completion was recorded in 2013-12.

The planned study structure had two periods over 52 weeks. The first was a 12-week, double-blind, placebo-controlled period with QID dosing. Participants in the Albuterol MDPI group took 2 inhalations of albuterol MDPI, identified as Spiromax®, 90 mcg/inhalation, four times daily, at approximately 7:00 AM, 12:00 PM, 5:00 PM, and bedtime. The stated total daily dose was 720 micrograms per day. Participants assigned to placebo MDPI took 2 inhalations on the same four-times-daily schedule.

The double-blind period was followed by a 40-week open-label period with PRN dosing. The arm descriptions identify participants in both original groups as receiving Albuterol MDPI during this later period, and distinguish them by their earlier assignment. That change in treatment and masking means the later period is not another randomized placebo comparison. The study also set out to evaluate device performance through the life of the device, but specific device-performance findings are not reported in the registry record.

Random allocation and masking help reduce systematic differences in treatment assignment and expectations during the blinded period. These design features do not, by themselves, establish that all potential sources of bias were prevented. Details of the randomization procedure, allocation concealment, or the roles of each masked party are not reported in the registry record. Nor are the reasons for the enrollment target or a formal sample-size justification reported.

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: Of the 33 patients who were screened but not enrolled, 28 were excluded on the basis of inclusion/exclusion criteria, 2 patients withdrew consent, and 3 patients were lost to follow-up before the baseline visit.

Run-In Period (Week -1 to Day 0)

Reasons for not completing this period:

12-Week Double-Blind Period

Reasons for not completing this period:

40-Week Open-Label Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population

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.

Population: Full analysis set of randomized subjects

6. Primary Endpoint

The registry lists the primary outcome as Participants With Adverse Experiences During Weeks 0-12 (Double-Blind Period), measured over Day 1 to Week 12.

The primary outcome is the number of participants with adverse experiences during Weeks 0-12, within the safety population. Its timeframe is Day 1 to Week 12. The registry description defines the events as treatment-emergent: an adverse event must have begun or worsened after study drug treatment to be included in the summarized outcome. An adverse event is an untoward medical occurrence that develops or becomes more severe during a clinical study; the definition does not require a causal relationship to study drug.

The measure is useful in a safety study because it describes how many participants experienced at least one event during a specified treatment period. The accompanying severity categories reflect investigator ratings of mild, moderate, or severe, with severe defined as an event that prevents normal daily activities. The investigator also determined the relation of an event to treatment. These are distinct judgments: whether an event occurred, how severe it was, and whether it was considered related to treatment.

The endpoint is a participant count, not a count of all event episodes or a measure of time to the first event. A participant may have more than one event, while the participant-level outcome counts that person once for the relevant category. The registry record notes that the primary outcome has several categories or time points and is not reduced to one comparison. Consequently, the posted adverse-event counts provide a descriptive view of safety, but no single estimate of the primary comparison or its precision is reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is binary at the participant level: a participant either had an event in a specified category and period or did not. The registry’s primary outcome is presented as a number of participants, and the adverse-event results report counts alongside the number at risk. This format preserves the observed event totals and the group denominators. It is not itself a statistical test or an estimate of the difference between treatment groups.

What does a confidence interval add?

General statistical explanation: a confidence interval describes the range of values reasonably compatible with an estimate under a stated analysis and its assumptions. It communicates precision, rather than only whether a result passes a threshold. A narrow interval indicates greater precision under that model; a wide interval indicates less precision. The registry record does not report confidence intervals for the primary safety comparison. Therefore, the precision of any group contrast cannot be read from the posted counts alone.

Why is the participant count distinct from the event count?

The endpoint counts participants with an event, not every occurrence of every event. If a participant has multiple adverse events, a participant-level count can still register that person once for a particular category. Event-level summaries answer a different question, such as how many separate occurrences were recorded. The registry description includes multiple categories, including serious events and other events, so their counts should be understood within those categories rather than added together or treated as mutually exclusive without further information. The registry record does not report the detailed event-level data needed to examine recurrence or overlap between categories.

Why does the study period affect the comparison?

During the first 12 weeks, the study was randomized, double-blind, and placebo-controlled. That design supports a comparison of the originally assigned groups for this period, subject to the prespecified analysis and its assumptions. During the subsequent 40 weeks, the study was open-label and both original groups received Albuterol MDPI. The later counts describe adverse events during continued follow-up under that open-label treatment arrangement. They do not preserve a concurrent placebo group and therefore answer a different question. General statistical principle: treatment contrasts depend on the comparison being made, the period of follow-up, and whether assignment remains randomized between distinct treatments.

What do planning calculations mean?

The record describes sample-size planning illustrations based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also states that the effect to detect is a stated fraction of the observed effect. Such calculations are planning illustrations, not evidence that the trial was designed around those assumptions, and not an account of the study’s actual power. The registry record does not report the trial’s own sample-size justification. No numerical planning result is included in the registry record used for this explanation, so no target group size can be stated.

General statistical explanation: power is a design property under specified assumptions about the effect, variability, analysis, and sample size. It is not a probability that a finding is true, and a calculation based on the observed effect after a study is not “observed power.” A planning calculation can help describe what a future study might need under its assumptions, but it cannot substitute for a confidence interval or an analysis of the current trial’s outcomes.

What is not available for inferential interpretation?

The registry record reports no analyses for the primary outcome, and it does not report a p-value, confidence interval, or adjusted treatment estimate. It also does not specify the statistical model, handling of missing outcome data, or a multiplicity procedure. General statistical explanation: a statistical model makes assumptions about how observations are distributed and how treatment groups are compared. For binary outcomes, analysis may use different methods, and those methods can yield different estimates or uncertainty measures. The choice and details matter, particularly when event counts are small or when multiple categories are considered.

Over-dispersion is a general concern when observed variability is greater than a model expects. In count outcomes, it can make model-based uncertainty estimates too small if the model does not accommodate the extra variability. The registry’s primary endpoint is a participant count with an event, rather than an event-rate model, and no model choice is reported. Thus, there is no basis for attributing a particular over-dispersion adjustment to this trial. Similarly, no analysis can be reconstructed from the posted summary counts alone without choosing assumptions that the registry record does not specify.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome is described as having several categories or time points, and the registry record does not reduce it to one comparison. The outcome title focuses on participants with adverse experiences during Weeks 0-12, but the available description also distinguishes event categories and severity. Multiple outcomes or comparisons can create a multiplicity issue: when many statistical tests are considered, the chance of at least one apparently unusual result can increase. General statistical explanation: a prespecified analysis plan can define which comparisons are primary and whether any adjustment or hierarchical testing approach is used. Such a plan is not reported in the registry record, so it is not possible to determine how multiplicity was handled.

Missing-data methods are also not reported in the registry record. The posted risk counts identify the denominators used for the listed adverse-event summaries, but they do not explain how participants with incomplete follow-up were handled, whether follow-up was complete for all participants, or how exposure time was treated. The registry record does not report a missingness analysis or sensitivity analysis. These details matter because the interpretation of a participant-level safety count can depend on whether participants had comparable opportunities for events to be observed.

The primary outcome identifies the safety population. The registry record does not report the detailed definition of that population, the number excluded from it, or how it relates to the randomized population. It also does not report a statistical analysis population, an intention-to-treat analysis, or an approach to protocol deviations. These omissions do not alter the posted counts, but they limit assessment of how those counts relate to random assignment and whether the analysis followed a prespecified population definition.

For these reasons, the results can be read descriptively, but the record does not support a full audit of the inferential plan, missing-data handling, or population-level analysis choices. Absence of these details is not evidence that a particular method was or was not used; the methods are simply not reported in the registry record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: atrial fibrillation (0.6%), cellulitis (0.6%), gastrointestinal carcinoma (0.6%), pancreatic carcinoma (0.6%), flank pain (0.6%).

Serious adverse events and other adverse events are separate categories in the registry results. In the double-blind period, the serious-event count was 0 of 168 for Albuterol MDPI and 1 of 170 for placebo MDPI. The other-adverse-event counts were 51 of 168 and 80 of 170, respectively. In the open-label period, serious events were 3 of 169 and 4 of 168 in the former-placebo and former-albuterol groups; other events were 64 of 169 and 67 of 168. The denominators are the participants at risk for each listed group and period.

The protocol definition of a serious adverse event includes death, a life-threatening event, inpatient hospitalization or prolongation of hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event requiring intervention to prevent such outcomes. Seriousness is not the same as severity rating: the record describes investigator ratings of mild, moderate, and severe, and defines severe as an event that prevents normal daily activities.

The counts do not establish that an event was caused by study treatment. The registry states that treatment relation was determined by the investigator, but the counts alone do not show those judgments. Death counts are not reported in the registry record. The serious-event terms listed at 0.6% each are not tied to a specific group or period in the available record, so they should be treated as descriptive terms without further attribution.

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

The posted results establish that adverse events were recorded among participants during both the blinded and open-label periods. In the first 12 weeks, the registry reports participant counts for serious adverse events and other adverse events in each randomized group. In the later period, it reports counts among participants from the original groups while both groups were receiving open-label Albuterol MDPI. These are observations from the study, not by themselves conclusions about the causal effect of treatment.

The counts do not show whether a difference between groups is statistically distinguishable from chance variation. The registry record does not report confidence intervals, p-values, adjusted estimates, or a formal primary comparison. A numerical contrast between the groups should not be constructed from the counts for this narrative, and no statement about the size or certainty of a treatment effect can be supported without a reported analysis. The absence of inferential results also does not show that the groups are equivalent or that a difference is absent.

The blinded period and the open-label period should be interpreted separately. The first offers a randomized placebo-controlled comparison under masking. The later period provides longer safety follow-up but lacks a concurrent placebo group, and the treatment assignment is no longer a contrast between albuterol and placebo. The open-label counts therefore cannot confirm or extend the initial randomized contrast.

The record also does not report details needed to judge event duration, recurrence, timing, exposure-adjusted rates, attribution to treatment, or handling of missing information. The study’s stated goal included assessment of device performance through the life of the device, but specific device-performance findings are not reported in the registry record. Overall, the posted information supports a descriptive account of observed safety events over the stated periods. It does not establish efficacy, prove causation for an adverse event, or quantify the precision of a treatment comparison.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of why study design and outcome interpretation must be kept together. The first period combines randomization, masking, a placebo comparator, and a defined 12-week safety window. Those features make the initial period the relevant setting for a randomized comparison of adverse-event counts. The second period extends follow-up, but its open-label treatment arrangement changes the question: it describes events during longer-term treatment rather than preserving a placebo-controlled contrast.

The outcome is clinically recognizable but statistically broad. “Adverse experiences” can include different event types and severities, and the registry description indicates multiple categories or time points. A single participant count can be useful for summarizing whether an event occurred, but it does not convey the number of episodes, their timing, or their recurrence. Without a reported analysis plan, it is also difficult to assess how the different categories were prioritized or compared.

The record illustrates the distinction between observed counts and inferential evidence. Counts document what occurred among enrolled participants, while an estimate with an uncertainty measure would be needed to characterize the precision of a comparison. Reporting both is important in safety studies, where uncommon serious events may be especially difficult to interpret from sparse counts alone. The posted record contains serious-event counts, but it does not report inferential results or confidence intervals for the primary comparison.

Finally, the study’s longer follow-up and device-performance objective underscore that a trial can address more than one question. The registry describes the purpose of assessing safety and device performance, but the available outcome results do not include specific device-performance findings. Clear separation of randomized comparisons, open-label follow-up, and distinct outcome aims helps prevent descriptive safety data from being interpreted as a broader conclusion than the recorded analyses support.

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 provides limited information for evaluating the statistical analysis. It does not report an inferential analysis for the primary outcome, a confidence interval, a p-value, or an adjusted comparison. The record also does not report the statistical analysis plan, the method used to handle multiplicity, or the trial’s sample-size justification. This prevents assessment of whether the posted outcomes were analyzed according to a prespecified inferential strategy.

The outcome is described as having several categories or time points and is not reduced to one comparison. The available adverse-event summaries do not include event-level detail, timing, recurrence, duration, exposure-adjusted rates, or group-specific attribution for the listed serious adverse event terms. Death counts are not reported in the registry record. The registry record also does not describe missing-data handling, completeness of follow-up, or sensitivity analyses.

There is a design limitation in interpreting the full 52-week period as a treatment comparison. Only the first 12 weeks were double-blind and placebo-controlled. The later 40 weeks were open-label, with participants from both original groups receiving Albuterol MDPI. Those later counts can inform descriptive follow-up but do not provide a randomized comparison against placebo for that period.

The total enrollment is listed as 364, while the outcome summaries use period-specific denominators. The registry record does not explain all differences between those counts and enrollment, define the safety population in detail, or report how participants with differing follow-up were handled. These gaps constrain interpretation of the relation between the randomized population and the reported safety population. Device-performance findings, despite being part of the study purpose, are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety Study of Albuterol Spiromax® in Subjects With Asthma — NCT01698320.
• Registry record last updated 2015-08-19; status last verified 2015-08.
• Results first posted 2015-08-19.
• 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

NCT01698320 is a completed Phase 3 randomized, quadruple-masked, parallel-group study of Albuterol Spiromax® in subjects with asthma. The registry record lists enrollment of 364 and a sponsor of Teva Branded Pharmaceutical Products R&D, Inc. The study began in 2012-10, with primary completion in 2013-12.

The study included a 12-week double-blind placebo-controlled QID period followed by a 40-week open-label PRN period. Its primary safety outcome was participants with adverse experiences during Weeks 0-12 in the safety population. The registry reports serious and other adverse-event counts for both periods. The open-label period followed both original groups while they received Albuterol MDPI.

The registry record does not report inferential analyses for the primary comparison, confidence intervals, p-values, multiplicity handling, missing-data methods, or the trial’s sample-size justification. It also does not report device-performance findings. The adverse-event counts therefore support descriptive reading, while the precision and inferential meaning of a treatment comparison remain unreported.