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 A 7-Day Cross-over Study of QD (Once Daily) and BID (Twice Daily) TD-4208 in Chronic Obstructive Pulmonary Disease (COPD) (NCT02109172), a randomized phase 2 study. The primary outcome is Weighted Mean (0-24hr) Change From Baseline FEV1 (Forced Expiratory Volume in 1 Second).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02109172 |
| Phase | Phase 2 |
| Condition | Chronic Obstructive Pulmonary Disease, COPD |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Triple |
| Enrollment | 64 |
| Arms in the primary outcome | 3 |
| Lead sponsor | Mylan Inc. |
| Results posted | Yes |
2. Clinical Question
The clinical question was whether lung function, measured as change from baseline in FEV1, differed during treatment periods with nebulized TD-4208 and placebo. The study compared two TD-4208 schedules: 44 mcg twice daily and 175 mcg once daily. The primary outcome was the weighted mean change in FEV1 across the 0-24hr period following the Day 7 morning dose, with the recorded timeframe also specifying -12 hours post-dose and 24 hours post-dose.
Population
People with moderate to severe chronic obstructive pulmonary disease (COPD) were described as the intended study population. The registry record lists 64 participants enrolled. Further eligibility details and the analysis population are not reported in the registry record.
Intervention
TD-4208 inhalation solution was given through a jet nebulizer. One schedule was 44 mcg twice daily for 7 days; the other was 175 mcg once daily for 7 days, with placebo once daily also specified for that schedule.
Comparator
The comparator was placebo inhalation solution twice daily for 7 days. In a crossover study, treatment conditions are evaluated across periods, but the treatment sequence, period details, and any washout are not reported in the registry record.
Primary question
What was the weighted mean change from baseline in FEV1 during the stated 0-24hr window after the Day 7 morning dose for each TD-4208 schedule, and how did the posted estimates compare with placebo?
The posted results show least-squares mean changes of -14.4 mL for placebo, 90.2 mL for TD-4208 44 mcg twice daily, and 98.5 mL for TD-4208 175 mcg once daily. The registry also lists unadjusted recalculated contrasts against placebo. These are descriptive statistical comparisons of the posted outcome, not a complete account of the trial’s original analysis. The registry record does not report a separate direct comparison between the two TD-4208 schedules.
3. Trial Design
This was a Phase 2, randomized, placebo-controlled crossover study of nebulized TD-4208 in people with COPD. The official title describes the study as double-blind, while the registry masking field says triple. Those descriptions differ; the masking arrangements are not explained further in the registry record. The study is listed as completed, with 64 participants enrolled.
The three treatment conditions reported were placebo inhalation solution twice daily for 7 days, TD-4208 44 mcg twice daily for 7 days, and TD-4208 175 mcg once daily for 7 days with placebo once daily. The brief description says the treatments were administered using a jet nebulizer. The crossover model means participants were intended to receive treatment conditions in different periods, rather than being assigned permanently to one parallel group. However, the registry record does not give the treatment sequence, period duration beyond the listed 7-day regimens, any washout procedure, or details of how period effects were handled.
The primary outcome was the weighted mean change from baseline in FEV1, in mL. The listed timeframe is following the Day 7 AM dose, including -12 hours post-dose and 24 hours post-dose. The outcome entries give 64 participants for each of the three conditions. In a crossover design, those entries should not be read as three separate groups of 64 people: participants may contribute measurements under more than one condition. Participant flow and the number completing each period are not reported in the registry record.
The registry lists one outcome measure and no posted analysis entries. It does not report the trial’s original statistical analysis plan, sample-size justification, analysis populations, or the model used for the crossover data. The estimates and comparisons discussed in the results therefore need to be distinguished from an account of the trial’s full prespecified analysis, which is not available in the registry record.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Overall Study
| Stage | Placebo First, Then 44mcg, Then 175mcg | Placebo First, Then 175mcg, Then 44mcg | 44mcg First, Then 175mcg, Then Placebo | 44mcg First, Then Placebo, Then 175mcg | 175mcg First, Then 44mcg, Then Placebo | 175mcg First, Then Placebo, Then 44mcg |
|---|---|---|---|---|---|---|
| STARTED | 11 | 11 | 10 | 11 | 10 | 11 |
| COMPLETED | 10 | 11 | 9 | 10 | 9 | 10 |
| NOT COMPLETED | 1 | 0 | 1 | 1 | 1 | 1 |
Reasons for not completing this period:
| Reason | Placebo First, Then 44mcg, Then 175mcg | Placebo First, Then 175mcg, Then 44mcg | 44mcg First, Then 175mcg, Then Placebo | 44mcg First, Then Placebo, Then 175mcg | 175mcg First, Then 44mcg, Then Placebo | 175mcg First, Then Placebo, Then 44mcg |
|---|---|---|---|---|---|---|
| Withdrawal by Subject | 1 | 0 | 0 | 1 | 0 | 0 |
| Adverse Event | 0 | 0 | 1 | 0 | 0 | 1 |
| Death | 0 | 0 | 0 | 0 | 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 | Entire Study Population |
|---|---|---|
| Participants analysed | 64 | |
| Age, Categorical: <=18 years | Participants | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 39 |
| Age, Categorical: >=65 years | Participants | 25 |
| Sex: Female, Male: Female | Participants | 27 |
| Sex: Female, Male: Male | Participants | 37 |
6. Primary Endpoint
The registry lists the primary outcome as Weighted Mean (0-24hr) Change From Baseline FEV1 (Forced Expiratory Volume in 1 Second), measured over Following the Day 7 AM dose -12 hours post-dose and 24 hours post-dose.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | Standard Error |
| Unit | mL |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is the weighted mean change from baseline in FEV1, measured in mL. FEV1, or forced expiratory volume in 1 second, is the amount of air forcibly exhaled in the first second of a breathing test. The registry describes the outcome as a change from baseline rather than an absolute follow-up measurement.
The result is a least-squares mean, a model-based average that can account for factors included in an analysis model. Which factors or model terms were used for the original trial analysis is not reported in the registry record. The endpoint’s timeframe is listed as following the Day 7 AM dose, with measurements described across the 0-24hr period and the recorded wording also noting -12 hours post-dose and 24 hours post-dose. The precise weighting procedure is not reported in the registry record.
Repeated lung-function measurements across a dosing interval can describe the average change over that interval, rather than relying on a single measurement at one moment. That is a general rationale for a weighted mean endpoint. It does not, by itself, indicate how the measurements were weighted or how missing measurements were treated in this study.
The posted endpoint values are -14.4 mL for placebo, 90.2 mL for TD-4208 44 mcg twice daily, and 98.5 mL for TD-4208 175 mcg once daily. These are the reported treatment-condition means. They are not, on their own, estimates of the difference between schedules; the registry’s comparison entries separately give estimates against placebo.
7. Results Posted in the Registry
- TD-4208 44 mcg Twice Daily: mean 90.20 versus -14.40 on control; difference 104.60 (95% CI 62.62 to 146.58), standardized effect d = 0.86; z-test p = <0.001.
- TD-4208 175 mcg Once Daily: mean 98.50 versus -14.40 on control; difference 112.90 (95% CI 70.88 to 154.92), standardized effect d = 0.93; z-test p = <0.001.
Mean difference: TD-4208 44 mcg Twice Daily
95% CI: 62.62 to 146.58
Recalculated from the posted summary statistics
8. Statistical Interpretation
The posted least-squares mean change from baseline in FEV1 was -14.4 mL for placebo, 90.2 mL for TD-4208 44 mcg twice daily, and 98.5 mL for TD-4208 175 mcg once daily. The registry’s unadjusted recalculated mean difference against placebo was 104.6 mL for the twice-daily schedule, with a 95% confidence interval from 62.62 to 146.6 mL and p < 0.001. For the once-daily schedule, the unadjusted recalculated mean difference against placebo was 112.9 mL, with a 95% confidence interval from 70.88 to 154.9 mL and p < 0.001.
These comparisons describe the posted summary statistics. They are simple, unadjusted recalculations and do not reproduce a crossover-specific analysis using individual participant data. In particular, the comparison calculations use approximate standard deviations derived from the posted standard errors; they do not incorporate the within-participant correlation that can be important when the same participants receive multiple conditions. The registry record does not include an original analysis estimate or model output against which to check these recalculations. The sponsor’s own analysis takes precedence if a discrepancy is recorded; no discrepancy is flagged in this record.
The confidence intervals quantify uncertainty around each recalculated mean difference under the assumptions used for those comparisons. They exclude zero, and the associated unadjusted p-values are both reported as p < 0.001. This is evidence of a difference in the posted summaries under that calculation, not a complete test of the trial’s original statistical hypotheses. The p-values are unadjusted, and the record does not report how multiplicity across treatment comparisons was addressed.
The estimates do not answer whether the two TD-4208 schedules differ from each other. No direct comparison between the active schedules is posted. The fact that their mean changes and placebo contrasts are both listed does not establish equivalence, non-inferiority, or superiority of one schedule over the other. Such conclusions require an appropriate direct analysis, including its estimand and uncertainty, which is not reported in the registry record.
Interpretation also depends on the trial design and available reporting. A crossover comparison can use the same participants across conditions, but its valid analysis ordinarily needs to account for repeated measurements and potentially relevant period or sequence effects. The registry record does not describe those methods. It also does not give participant flow by period, missing outcome handling, or an analysis population. Thus, the displayed summary supports a cautious reading of the reported FEV1 values and recalculated contrasts, but it cannot establish how the original trial analysis treated these design features.
These are statistical findings about one lung-function endpoint over the stated treatment period. They do not establish effects beyond that endpoint or timeframe, and the registry record does not provide a basis for medical advice or broader conclusions about treatment. Safety information is reported separately and should not be inferred from the FEV1 comparisons.
9. Statistical Methods Explained
The registry lists a continuous primary outcome: weighted mean change from baseline in FEV1, measured in mL. For continuous outcomes, a mean expresses the central value of measurements on the outcome scale. Here, the treatment-condition values are least-squares means, and the associated spread is reported as a standard error. A standard error describes the uncertainty of an estimated mean; it is not the spread of individual participant measurements. The record does not state the model used to produce the original least-squares means.
What does the mean difference describe?
A mean difference compares average outcome values between two conditions on the same measurement scale. The posted recalculated contrast for TD-4208 44 mcg twice daily versus placebo is 104.6 mL; for TD-4208 175 mcg once daily versus placebo it is 112.9 mL. These are unadjusted recalculations from the posted summary statistics. The corresponding treatment-condition estimates are 90.2 mL and 98.5 mL, while the placebo estimate is -14.4 mL. The registry record does not post a separate direct contrast between the two active schedules.
A positive difference in this reporting means the posted mean for the named TD-4208 condition is higher than the placebo mean on the outcome scale. That description is statistical, not a medical recommendation. The recalculated differences rely on the posted arm-level summaries and should not be mistaken for output from a fitted crossover model. The record does not supply participant-level data or the covariance between measurements from the same participant, both of which can matter in crossover comparisons.
How should the p-values be read?
Both recalculated comparisons have p < 0.001. A p-value describes how incompatible the observed data are with a specified null model, under the assumptions of the analysis. It is not the probability that the null hypothesis is true, nor a measure of the size or clinical importance of an effect. These values are explicitly unadjusted. The registry record does not describe the original hypothesis-testing plan or any adjustment for testing multiple treatment comparisons.
Because these are unadjusted recalculations, their inferential interpretation is conditional on the simplifying calculation and its assumptions. The record reports approximate pooled standard deviations for the contrasts. In a crossover trial, treating observations as if they came from independent groups can fail to use the pairing within participants and can yield uncertainty estimates that do not match a crossover model. The posted recalculations should therefore be distinguished from the intended trial analysis, which is not reported.
Why does the crossover structure matter?
In general, a crossover design exposes participants to more than one treatment condition. Comparing conditions within the same person can reduce the influence of stable differences between people, because each participant can contribute information to more than one condition. That advantage depends on suitable design and analysis. Outcomes may also vary by period, treatment sequence, or lingering effects from an earlier condition. A suitable analysis may need to account for repeated measurements and relevant design terms. These are general considerations, not confirmed features of the analysis used in this trial.
The registry identifies the study as crossover but does not report sequence allocation, period-specific results, washout details, or a model accounting for repeated observations. Consequently, it is not possible to tell from the registry record whether or how the analysis handled these issues. The listed count of 64 for each condition does not mean there were 64 distinct participants in each of three independent groups; the study enrolled 64 participants and used a crossover design.
What does a confidence interval add?
A confidence interval gives a range of values compatible with the data and calculation under repeated use of the same method. Its width conveys precision: a narrower interval indicates less statistical uncertainty about the estimate, while a wider interval indicates more. The intervals for the recalculated contrasts are 62.62 to 146.6 mL for twice-daily TD-4208 versus placebo and 70.88 to 154.9 mL for once-daily TD-4208 versus placebo. Their limits should be interpreted in light of the approximate, unadjusted calculation rather than as verified output from the trial’s original model.
Neither interval is a range containing a specified proportion of individual participant responses. Nor does an interval settle questions about clinical importance, validity of the analysis assumptions, or generalizability. The registry record does not report a threshold for a clinically meaningful difference.
What is the role of the standard error?
The treatment-condition standard errors are 15.29 for placebo, 15.0 for TD-4208 44 mcg twice daily, and 15.03 for TD-4208 175 mcg once daily. They characterize the uncertainty around the listed least-squares means, not the variability between participants. A standard deviation instead describes spread among observations. The recalculated comparisons estimate pooled standard deviations of 121.2 and 121.3, respectively, and mark these as approximate. A large difference between the scale of a standard error and a standard deviation is not inherently inconsistent: they describe different quantities.
General statistical caution applies when inferring variability from standard errors. The conversion relies on sample-size and independence assumptions; in a crossover design, within-participant dependence complicates that relationship. The registry record does not include sufficient detail to verify the approximations or reconstruct the original model-based uncertainty.
10. Confidence Intervals and Precision
The recalculated mean difference for TD-4208 44 mcg twice daily versus placebo is 104.6 mL, with a 95% confidence interval from 62.62 to 146.6 mL. For TD-4208 175 mcg once daily versus placebo, the recalculated mean difference is 112.9 mL, with a 95% confidence interval from 70.88 to 154.9 mL. Both intervals are wholly above zero, and both associated unadjusted p-values are p < 0.001.
A confidence interval describes uncertainty in an estimated difference under the assumptions of the calculation. In general, a narrower interval indicates greater precision, while a wider interval indicates less precision. The reported intervals allow readers to see a range of estimates compatible with these recalculations, rather than relying only on the point estimates. They do not show the range of individual participant changes, and they do not state the probability that the true difference lies within the interval.
The precision claims are limited by the method used to produce these contrasts. The values are unadjusted recalculations from posted summary statistics, with approximate pooled standard deviations. They are not identified as results from the original trial model. Because the design is crossover, accounting for the same participants contributing measurements under different conditions may affect standard errors and intervals. The registry record does not report the within-participant covariance or the original crossover model, so the intervals cannot be checked against a participant-level analysis.
The two intervals are for separate comparisons with placebo. Their overlap does not establish that the active schedules are similar, and the intervals cannot substitute for a direct comparison between those schedules. No direct estimate or confidence interval for that question is reported in the registry record. Nor is a clinical-importance threshold reported, so statistical precision alone does not determine whether a difference is meaningful to patients or clinicians.
11. Planning a Similar Trial: Sample Size
This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.
| Effect to detect | Participants per arm, 80% power | Participants per arm, 90% power |
|---|---|---|
| 100% of the observed effect | 22 | 29 |
| 75% of the observed effect | 38 | 51 |
| 50% of the observed effect | 85 | 113 |
The planning illustrations give participants per arm for 80% power and participants per arm for 90% power. These are arm-level planning counts for a two-arm comparison; they are not total event counts. The assumptions stated for the illustrations are a two-sided significance level 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as the stated fraction of the observed effect. The trial’s original design assumptions and sample-size justification are not reported in the registry record.
For the comparison of TD-4208 44 mcg twice daily with placebo, the entries are 22 participants per arm for 80% power and 29 for 90% power when planning for 100% of the observed effect. Planning for 75% of the observed effect gives 38 participants per arm for 80% power and 51 for 90% power. Planning for 50% of the observed effect gives 85 participants per arm for 80% power and 113 for 90% power.
For the comparison of TD-4208 175 mcg once daily with placebo, the corresponding entries are 19 participants per arm for 80% power and 25 for 90% power when planning for 100% of the observed effect; 33 and 44 when planning for 75%; and 73 and 98 when planning for 50%.
The 80% power column represents the planned chance of detecting the assumed effect under the stated statistical assumptions if that effect is present; the 90% column targets a higher chance of detection. Smaller effects require more participants under these assumptions, as illustrated by the increasing counts when the planned effect is reduced. These figures are planning illustrations based on the observed effect, not observed power and not evidence about the trial’s original design. Because the underlying comparisons are unadjusted recalculations and the study is crossover, the illustrations should not be read as a design calculation that accounts for the trial’s original paired-data structure.
12. How the Sample Size Is Derived
Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z1−α/2 = 1.960) and the desired power (z1−β = 0.842 for 80% and 1.282 for 90%).
Formula
n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.
Worked calculation for this trial
- Observed difference Δ = 104.600; pooled standard deviation σ = 121.166.
- n = 2 × (1.96 + 0.842)2 × 121.1662 / 104.6002 = 21.1, rounded up to 22 participants per arm for 80% power.
The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).
R code
alpha <- 0.05
z_a <- qnorm(1 - alpha / 2) # two-sided
delta <- 104.6 # observed difference in means
sigma <- 121.165552860539 # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))
# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")
# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2109172)
n <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n)) # difference in sample means
s2 <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1)) # pooled sample variance
tstat <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))
Output from running the code
100% of observed effect: n per arm = 22 (80% power), 29 (90% power)
75% of observed effect: n per arm = 38 (80% power), 51 (90% power)
50% of observed effect: n per arm = 85 (80% power), 113 (90% power)
power.t.test: 22.1
Simulated power at n = 22 per arm: 0.796 (20000 replicates)The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.
13. Multiplicity, Missing Data and Analysis Populations
The registry record lists one primary outcome measure and no secondary outcomes. It also lists no posted analysis entries. That limited outcome listing does not establish that the trial measured no other outcomes; it describes what is reported in the record. The original statistical analysis plan, including the intended hypothesis hierarchy and analysis populations, is not reported in the registry record.
Multiplicity arises when more than one hypothesis or comparison is tested. Repeated testing can increase the chance of observing at least one apparently notable result by chance if each test is interpreted without regard to the others. General approaches include prespecifying a primary comparison, controlling a family-wise error rate, or using other planned procedures. Which approach, if any, was used for this trial is not reported in the registry record.
The two reported comparisons are against placebo: each TD-4208 schedule versus placebo. Their displayed p-values are unadjusted, both p < 0.001. They should not be described as multiplicity-adjusted results. The record does not report whether these were the only comparisons planned, whether one was designated primary, or whether adjustment was applied in an analysis not posted in the record. No direct comparison between the active schedules is reported.
Missing-data methods and analysis populations also matter. The registry does not state whether the outcome analysis used all randomized participants, participants who completed all periods, or another defined set. It does not report missing FEV1 measurements, exclusions, withdrawals by treatment period, imputation procedures, or sensitivity analyses. In a crossover design, incomplete participation can affect which within-person comparisons are available; the handling of such cases is not described.
The posted outcome entries list 64 participants for each condition, while the enrollment count is 64 and the design is crossover. These counts do not reveal participant flow or guarantee that every enrolled person contributed a usable measurement to every period. Without analysis-population definitions and missing-data details, the completeness and representativeness of the analyzed measurements cannot be assessed from the registry record.
14. 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 |
|---|---|---|---|
| Placebo | 0 | 64 | 0.0% |
| TD-4208 44mcg Twice Daily | 0 | 64 | 0.0% |
| TD-4208 175mcg Once Daily | 1 | 64 | 1.6% |
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 |
|---|---|
| Placebo | 23 of 64 |
| TD-4208 44mcg Twice Daily | 24 of 64 |
| TD-4208 175mcg Once Daily | 14 of 64 |
Most frequent serious adverse event terms
| Event term | Organ system | Placebo | TD-4208 44mcg Twice Daily | TD-4208 175mcg Once Daily |
|---|---|---|---|---|
| Coronary Artery Insufficiency | Cardiac disorders | 0 of 64 | 0 of 64 | 1 of 64 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Placebo | TD-4208 44mcg Twice Daily | TD-4208 175mcg Once Daily |
|---|---|---|---|---|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | 3 of 64 | 1 of 64 | 1 of 64 |
| Contusion | Injury, poisoning and procedural complications | 1 of 64 | 2 of 64 | 1 of 64 |
| Headache | Nervous system disorders | 1 of 64 | 2 of 64 | 1 of 64 |
| Breath sounds abnormal | Respiratory, thoracic and mediastinal disorders | 2 of 64 | 0 of 64 | 0 of 64 |
| Chest Discomfort | Respiratory, thoracic and mediastinal disorders | 0 of 64 | 1 of 64 | 1 of 64 |
| Cough | Respiratory, thoracic and mediastinal disorders | 1 of 64 | 1 of 64 | 0 of 64 |
| Dermatitis contact | Skin and subcutaneous tissue disorders | 0 of 64 | 0 of 64 | 2 of 64 |
| Blood Pressure Increased | Vascular disorders | 0 of 64 | 1 of 64 | 0 of 64 |
| COPD | Respiratory, thoracic and mediastinal disorders | 0 of 64 | 1 of 64 | 0 of 64 |
| Dizziness | Nervous system disorders | 0 of 64 | 1 of 64 | 0 of 64 |
Serious events with the highest arm-level rate: coronary artery insufficiency (1.6%).
The serious adverse event counts are reported among 64 participants for each treatment condition. The registry lists 0 serious adverse events for placebo, 0 for TD-4208 44mcg Twice Daily, and 1 for TD-4208 175mcg Once Daily. These are counts reported for the listed conditions; the registry record does not explain whether the same participant could contribute to more than one condition in the crossover design, nor does it provide event-level timing or a detailed attribution assessment.
The serious event term listed is Coronary Artery Insufficiency, with 1.6% shown as the term’s percentage. The record does not link that term explicitly to a specific treatment condition in the reported term listing, so it should not be assigned to a group on that basis alone. Death counts are not reported in the registry record.
Serious adverse event counts are not the same as counts of all adverse events, and a count does not convey event duration, severity details, or causal assessment. The record also lists other adverse events affecting 23 participants in the placebo condition, 24 in the twice-daily condition, and 14 in the once-daily condition. These counts are separate from the serious-event figures. The registry does not provide enough detail to compare safety across conditions or draw conclusions about causation.
These figures describe what is posted for this study and its reported treatment conditions. They should be interpreted alongside the limited event detail and the crossover structure, not as a complete safety profile or a basis for medical decisions.
15. What the Result Does, and Does Not, Mean
The posted results describe changes in a lung-function measure over the stated Day 7 interval. The placebo least-squares mean change was -14.4 mL; the corresponding estimates were 90.2 mL for TD-4208 44 mcg twice daily and 98.5 mL for TD-4208 175 mcg once daily. The registry’s unadjusted recalculated mean differences versus placebo were 104.6 mL and 112.9 mL, respectively, and each had p < 0.001. Their confidence intervals were 62.62 to 146.6 mL and 70.88 to 154.9 mL.
Those statistics address the posted primary endpoint under the reported treatment conditions. They do not show whether one active schedule is better than the other: a direct active-schedule comparison is not reported in the registry record. Nor do they establish a clinically meaningful threshold, which is also not reported. Statistical evidence of a difference and the clinical importance of that difference are distinct questions.
The registry describes a randomized crossover design, but it does not report treatment sequence, washout, participant flow by period, or the statistical model used for the original analysis. The recalculated contrasts are unadjusted and use approximate standard deviations; they do not incorporate the paired structure of participant-level crossover data. Consequently, they should not be treated as a substitute for a full analysis based on the original design.
The results also concern a 7-day treatment regimen and one weighted mean FEV1 outcome. The registry record does not report evidence about outcomes beyond the specified interval, longer-term effects, or broader clinical outcomes. The safety listing is limited and does not provide enough detail for a full comparison of adverse events. Neither the lung-function results nor the safety counts should be expanded into treatment advice or conclusions beyond what the registry reports.
Overall, the record gives numerical estimates and uncertainty for the posted endpoint, but important analytic details are absent. A careful reading keeps the outcome, time window, treatment contrasts, and limitations together: the displayed recalculations are informative descriptions of the available summary data, while the trial’s original analysis and several elements needed to assess it are not reported in the registry record.
16. Why This Trial Matters Statistically
This trial is statistically interesting because a crossover design asks a different analytic question from a parallel-group trial. Participants can contribute observations under multiple treatment conditions, so comparisons may use within-person information. In general, that can reduce the influence of stable differences between individuals. It also creates dependence among observations from the same participant, which an analysis needs to handle appropriately. The registry identifies the design as crossover but does not report the model or covariance structure used for the trial’s own analysis.
The posted summaries make the distinction between treatment-condition means and treatment contrasts visible. The three least-squares means are -14.4 mL for placebo, 90.2 mL for TD-4208 44 mcg twice daily, and 98.5 mL for TD-4208 175 mcg once daily. Separate unadjusted recalculations compare each schedule with placebo. These calculations provide a way to describe the posted summaries, but they cannot recover the original paired analysis from aggregate values alone.
Precision is also central. The confidence intervals convey uncertainty around the recalculated contrasts, while the p-values provide a different summary under the calculation’s assumptions. Neither measure captures whether a difference is clinically important, and neither resolves the absence of the original crossover model or multiplicity plan. Seeing both an estimate and its interval is more informative than focusing only on whether a p-value crosses a threshold.
The registry’s limited analysis reporting demonstrates why results should be read with design details in view. Information about period effects, treatment sequences, missing data, analysis populations, and prespecified comparisons would help readers understand the intended estimand and the validity of the uncertainty estimates. Those details are not reported in the registry record. The posted findings therefore illustrate how the same numerical summary can be useful while still leaving important questions about the analysis unanswered.
17. 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.
Several trial-specific limitations constrain interpretation. The record describes a crossover study, but does not report the treatment sequence, period structure, washout procedure, or whether carryover was considered. These details can matter because outcomes from different periods within a participant are related, and earlier treatment may be relevant to later measurements. The original statistical model and its treatment of participant-level dependence are not reported.
The comparisons against placebo are unadjusted recalculations from posted summary statistics. The record marks the pooled standard deviations as approximate and does not include the within-participant covariance needed to reconstruct a crossover contrast. These recalculations are therefore not equivalent to a trial-specific model analysis. No discrepancy is flagged, but the original analysis itself is not posted.
The registry lists one outcome and no analysis entries, and it does not report a full statistical plan. The original sample-size justification, prespecified primary comparison, multiplicity strategy, and analysis populations are not reported in the registry record. Missing measurement handling, withdrawals, and participant flow by period are also not described. The count of 64 for each treatment condition should be understood alongside the crossover design and enrollment of 64, rather than as evidence of three distinct groups.
The endpoint is limited to weighted mean change from baseline in FEV1 over the stated interval following the Day 7 morning dose. The weighting procedure and any clinically meaningful threshold are not reported. The results cannot establish differences between the two active schedules, because a direct estimate is not reported. Safety reporting is also limited: event detail and attribution are not sufficient to reconstruct a comprehensive safety comparison. These omissions do not negate the posted statistics, but they limit conclusions about the original analysis, other outcomes, and broader interpretation.
18. Related Tutorials
19. Related Statistical Calculators
20. Sources
- ClinicalTrials.gov: A 7-Day Cross-over Study of QD (Once Daily) and BID (Twice Daily) TD-4208 in Chronic Obstructive Pulmonary Disease (COPD) — NCT02109172.
- Registry record last updated 2022-02-24; status last verified 2022-02.
- Results first posted 2016-12-08.
- 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.
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21. Record Summary
The registry describes a completed Phase 2, randomized, placebo-controlled crossover study of nebulized TD-4208 in people with moderate to severe COPD. It lists 64 participants enrolled and three treatment conditions: placebo twice daily, TD-4208 44 mcg twice daily, and TD-4208 175 mcg once daily with placebo once daily. The primary outcome was weighted mean change from baseline in FEV1, measured in mL, over the stated interval following the Day 7 morning dose.
The posted least-squares mean changes were -14.4 mL for placebo, 90.2 mL for twice-daily TD-4208, and 98.5 mL for once-daily TD-4208. Unadjusted recalculated contrasts versus placebo were 104.6 mL and 112.9 mL, with p < 0.001 for each. The registry record does not report the original analysis model, detailed crossover methods, multiplicity handling, or missing-data procedures. Serious adverse events were reported as 0, 0, and 1 across the listed conditions, respectively; further event detail is limited.