Efficacy and Safety Trial of 12 Weeks of Treatment With Nebulized SUN-101 in Patients With COPD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety Trial of 12 Weeks of Treatment With Nebulized SUN-101 in Patients With COPD (NCT02347761), a randomized phase 3 study. The primary outcome is Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12.

2. Clinical Question

FEV1 is the volume of air exhaled during the first second of a forced expiration. Trough measurement is intended to assess lung function at the specified time near the end of the dosing interval. In this study, Week 12 trough FEV1 was the mean of measurements taken at two time points 30 minutes apart, approximately 24 hours after the previous morning dose. Change was calculated relative to the baseline morning trough, itself the mean of two pre-dose measurements.

The registry lists a randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 3 trial. It reports 653 enrolled participants and three treatment groups. The key statistical comparison is not simply whether each group’s mean changed from baseline; it is how much the mean change in each SUN-101 group differed from the placebo group, with uncertainty considered alongside the estimate.

3. Trial Design

GOLDEN-3 is registered as a Phase 3, randomized, quadruple-masked, parallel-group trial. Its official title describes a double-blind, placebo-controlled, multicenter study of 12 weeks of nebulized SUN-101 treatment in patients with COPD. The registry status is completed. The record lists 653 enrolled participants and three groups: SUN-101 50 mcg twice daily, SUN-101 25 mcg twice daily, and placebo twice daily, each using the eFlow Closed System nebulizer.

The primary outcome was change from baseline in trough FEV1 at Week 12. The listed analysis population included randomized participants who received at least one dose of study medication, with participants analyzed according to their randomized assignment. The primary endpoint description says all collected spirometry values were used, whether or not a participant remained on randomized treatment and whether or not other therapies might affect the values. It says missing values were assumed missing at random.

The treatment groups’ reported least-squares mean changes were 0.096 liters for 50 mcg, 0.089 liters for 25 mcg, and -0.007 liters for placebo. The reported between-group estimates came from a mixed model for repeated measurements. For the 50 mcg comparison, the registry reports a least-squares mean difference of 0.104 liters, with a 95% confidence interval from 0.066 to 0.141 and p < 0.001. For the 25 mcg comparison, the reported difference was 0.096 liters, with a 95% confidence interval from 0.059 to 0.133 and p < 0.001.

The registry record does not report the original sample-size justification, the detailed statistical analysis plan, or whether interim analyses were planned or conducted. Those details should not be inferred from the completed enrollment or the planning illustrations based on observed effects.

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.

All Collected

Reasons for not completing this period:

On Study Treatment

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent to Treat (ITT) Population: all subjects who were randomized to treatment and received at least one dose of study medication. Subjects were analyzed based on the treatment they were randomized to.

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 Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12, measured over Baseline and Week 12.

The primary endpoint is change from baseline in trough forced expiratory volume in 1 second (FEV1) at Week 12, measured in liters. FEV1 records the amount of air exhaled during the first second of a forced expiration and is used as a continuous measure of lung function. A change score places the follow-up value in relation to the participant’s own baseline measurement.

In this trial, trough FEV1 at Week 12 was defined as the mean of two measurements taken 30 minutes apart, approximately 24 hours after the previous morning dose. Baseline morning trough FEV1 was the mean of values collected 45 and 15 minutes before the first dose. The endpoint is the Week 12 trough value minus that baseline value. The reported group values are least-squares means, which are model-based averages rather than simple arithmetic averages.

General: a trough assessment can characterize a measurement at a specified point near the end of a dosing interval, rather than at an unspecified time after treatment. Comparing change between randomized groups helps distinguish the observed treatment-group pattern from change also seen under placebo. The endpoint does not by itself describe every aspect of COPD, symptoms, daily functioning, or longer-term outcomes. The registry record lists several secondary outcomes addressing other measures, but the primary endpoint remains the specific lung-function measure defined above.

The primary outcome description states that all collected spirometry values were included, even if participants stopped randomized treatment or values might have been affected by other therapies. Missing values were assumed missing at random. That assumption is part of how the analysis handles unavailable measurements; the registry record does not establish whether it is fully realistic for every participant.

7. Results Posted in the Registry

• SUN-101 50 mcg BID eFlow (CS) Nebulizer: mean 0.10 versus -0.01 on control; difference 0.10 (95% CI 0.07 to 0.14), standardized effect d = 0.51; z-test p = <0.001.
• SUN-101 25 mcg BID eFlow (CS) Nebulizer: mean 0.09 versus -0.01 on control; difference 0.10 (95% CI 0.06 to 0.13), standardized effect d = 0.47; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in the Substudy Population

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • SUN-101 50 mcg BID eFlow (CS) Nebulizer: mean 0.07 versus -0.05 on control; difference 0.12 (95% CI 0.04 to 0.20), standardized effect d = 0.59; z-test p = 0.003.
  • SUN-101 25 mcg BID eFlow (CS) Nebulizer: mean 0.06 versus -0.05 on control; difference 0.11 (95% CI -0.49 to 0.70), standardized effect d = 0.07; z-test p = 0.728.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for SUN-101 50 mcg BID eFlow (CS) Nebulizer than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SUN-101 25 mcg BID eFlow (CS) Nebulizer and the control. The interval gives the range of effects that remain compatible with the data.

Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in Substudy Population

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • SUN-101 50 mcg BID eFlow (CS) Nebulizer: mean 0.07 versus -0.05 on control; difference 0.12 (95% CI 0.04 to 0.21), standardized effect d = 0.56; z-test p = 0.005.
  • SUN-101 25 mcg BID eFlow (CS) Nebulizer: mean 0.05 versus -0.05 on control; difference 0.10 (95% CI 0.01 to 0.20), standardized effect d = 0.45; z-test p = 0.032.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for SUN-101 50 mcg BID eFlow (CS) Nebulizer than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for SUN-101 25 mcg BID eFlow (CS) Nebulizer than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • SUN-101 50 mcg BID eFlow (CS) Nebulizer: mean 0.15 versus 0.01 on control; difference 0.13 (95% CI -0.31 to 0.58), standardized effect d = 0.06; z-test p = 0.559.
  • SUN-101 25 mcg BID eFlow (CS) Nebulizer: mean 0.15 versus 0.01 on control; difference 0.14 (95% CI -0.31 to 0.58), standardized effect d = 0.06; z-test p = 0.548.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SUN-101 50 mcg BID eFlow (CS) Nebulizer and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between SUN-101 25 mcg BID eFlow (CS) Nebulizer and the control. The interval gives the range of effects that remain compatible with the data.

Across the posted secondary outcomes, the overall pattern is mixed rather than uniformly precise. The two listed FEV1 area-under-the-curve outcomes in the substudy have positive estimated treatment-versus-placebo differences for both doses, but the estimates and uncertainty vary. One of the 25 mcg substudy recalculations is especially imprecise, with a confidence interval extending from -0.488 to 0.699 and p = 0.728. The other listed 25 mcg substudy recalculation has a positive interval from 0.009 to 0.196 and p = 0.032. These are unadjusted recalculations, not sponsor-reported analyses in the registry.

For trough FVC, the recalculated estimates are positive for both doses, but both confidence intervals include zero: -0.313 to 0.579 for 50 mcg and -0.309 to 0.583 for 25 mcg. The corresponding unadjusted p-values are 0.559 and 0.548. The posted summaries also contain comparatively large standard errors for the placebo FVC value, which contribute to the broad calculated intervals. The registry does not provide sponsor-reported analyses for these secondary outcomes in the listed results.

These outcomes address related but different measures from the primary trough FEV1 endpoint. They may add context, but do not replace the primary analysis. General: when many outcomes or comparisons are examined, some apparently notable results can arise by chance even if no underlying effect exists. The registry record does not report a multiplicity adjustment for the listed secondary results. Their unadjusted p-values should therefore carry less confirmatory weight than the primary analysis, especially where estimates are imprecise or results vary across related measures.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in the Substudy Population
• Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in Substudy Population
• Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12
• Change From Baseline in Trough Forced Vital Capacity (FVC) Week 12
• Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) at Week 12/End of Study
• Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) Week 12/End of Study
• Change in Number of Rescue Medication Puffs Per Day Over the 12-week Double-blind Treatment Period
• Number of Subjects With Major Adverse Cardiac Events (MACE)

9. Statistical Interpretation

10. Statistical Methods Explained

What does a least-squares mean represent?

The primary outcome is reported as a least-squares mean (LS mean), with a standard error. General: a least-squares mean is an estimate from a statistical model, rather than necessarily the raw average of all observed values. It is useful when the analysis models repeated measurements or accounts for features of the data structure. The registry’s reported comparisons use a mixed model for repeated measurements. The full model specification, including all covariates and covariance choices, is not reported in the registry record.

The treatment-group LS mean changes were 0.096 liters for SUN-101 50 mcg, 0.089 liters for SUN-101 25 mcg, and -0.007 liters for placebo. A between-group mean difference expresses the estimated contrast between a treatment group and placebo. In the formal analyses, the differences were 0.104 liters and 0.096 liters, respectively. These are model-based contrasts; they are not the treatment groups’ individual changes and should not be read as direct comparisons between the two doses.

Why use a mixed model for repeated measurements?

General: repeated-measures models are designed for outcomes collected at multiple visits from the same participant. Measurements from one person are generally related to one another, so treating them as entirely independent observations can misrepresent uncertainty. A mixed model can account for this within-participant structure and use available repeated observations under its assumptions. The registry identifies the method as a mixed model for repeated measurements but does not report enough detail to reconstruct its exact specification.

The endpoint description states that all collected values were used, including values collected after a participant stopped randomized treatment if the participant remained in the study. It also says values not collected remained missing and were assumed missing at random. General: a missing-at-random assumption means that, conditional on the information represented in the analysis, the probability of a value being missing does not depend on its unobserved value. This assumption cannot be verified from the short registry description alone, and the record does not report sensitivity analyses for departures from it.

What do the p-values and confidence intervals convey?

The registry’s mixed-model analyses report a 95% confidence interval and p-value for each comparison. The 50 mcg difference is 0.104 liters, with a 95% confidence interval from 0.066 to 0.141 and p < 0.001. The 25 mcg difference is 0.096 liters, with a 95% confidence interval from 0.059 to 0.133 and p < 0.001. General: a confidence interval describes a range of values compatible with the data and model at its stated confidence level. A p-value describes evidence against a null hypothesis of no difference, conditional on the analysis assumptions. Neither statistic independently establishes clinical importance.

The separately calculated unadjusted comparisons are based on posted group summaries. They reproduce the point estimates but use an approximate standard deviation and do not implement the sponsor’s repeated-measures model. As a result, their intervals and p-values are not identical to the model-based results. Such recalculations can serve as a transparent check on the reported summaries, but they should not be treated as a replacement for the sponsor’s stated analysis.

Why can over-dispersion matter?

General: dispersion describes how variable individual measurements are around a group estimate. If variability is larger than a simple model assumes, standard errors can be too small, leading to confidence intervals that are too narrow and p-values that overstate precision. Conversely, a large standard error signals uncertainty even when the estimated mean difference is not small. The registry gives standard errors for the primary LS means, but the unadjusted recalculation uses an approximate standard deviation derived from the posted summaries. It is therefore important not to mistake the recalculated interval for the trial’s full model-based uncertainty.

The secondary results illustrate why data quality and dispersion deserve attention: some posted standard errors differ substantially between groups, including the 25 mcg substudy LS mean standard error of 0.301 liters and the placebo FVC standard error of 0.227 liters. Those entries are reported as recorded; the registry does not explain their pattern. The associated simple recalculations can consequently be highly imprecise and should not be treated as definitive confirmatory analyses.

What does the analysis population mean?

The primary endpoint description defines the Intent to Treat population as subjects randomized and given at least one dose of study medication, analyzed according to randomized treatment. General: retaining randomized assignment in analysis aims to preserve the comparability created by randomization. Here, the stated population is not every person enrolled regardless of treatment exposure; the registry definition requires at least one dose. The record does not provide further participant-flow detail in the primary-outcome description.

The registry does not report the original power calculation or the details needed to reproduce every element of the analysis plan. The sample-size illustrations associated with the observed effects are separate planning calculations and are not evidence about the trial’s original design choices or observed power.

11. Confidence Intervals and Precision

The sponsor-reported 95% confidence interval for the 50 mcg comparison runs from 0.066 to 0.141 liters around an estimated difference of 0.104 liters. For the 25 mcg comparison, the interval runs from 0.059 to 0.133 liters around an estimated difference of 0.096 liters. Both intervals lie above zero. These intervals convey the uncertainty in the model-based estimates under the analysis assumptions; they are not guarantees that the true difference lies within a fixed range.

The unadjusted recalculations give a 0.065 to 0.142 interval for 50 mcg and a 0.058 to 0.134 interval for 25 mcg. The point estimates match the reported model-based differences, but the bounds differ because the recalculations use posted summaries and approximate unadjusted methods rather than the repeated-measures model. The registry reports no discrepancy flag, but the two methods should still be distinguished by what they estimate and how they handle the data.

General: the width of a confidence interval reflects both the amount of information and the variability represented by the analysis. A narrower interval indicates greater statistical precision under the model; it does not establish that an effect is important in practice. A confidence interval that excludes zero is evidence against a zero difference in the corresponding analysis, but does not resolve questions about missing-data assumptions, multiplicity, or clinical relevance.

The registry reports standard errors for the LS means, but does not give a clinical threshold for interpreting the size of a trough FEV1 difference. Thus statistical precision can be described from the estimates and intervals, while the clinical importance of these particular differences cannot be determined from the registry record alone.

12. 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.

The sample-size illustrations are planning examples based on the observed effect, not the trial’s original design calculation. For these continuous outcomes, the figures are participants per arm, not total events. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each row changes the effect targeted: 100% of the observed effect, 75% of the observed effect, or 50% of the observed effect.

The 80% power column gives the illustrated number of participants per arm for a design with an 80% chance of detecting the stated effect under those assumptions, if that effect and model assumptions were true. The 90% power column gives the corresponding planning figure for a 90% chance. Higher target power generally calls for more participants. For a fixed power target, smaller effects require more participants because they are harder to distinguish from variability.

For the primary comparison against placebo, the illustrations use the observed comparisons and show the planning figures for each dose separately. The rows are scenarios, not a recommendation about an appropriate future trial, and they do not document the design choices made for GOLDEN-3. The registry record does not report the trial’s own original sample-size assumptions or justification. These calculations are not observed power: observed effects from a completed trial cannot establish the probability that the trial had to detect its true effect.

13. 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 z_1−α/2 = 1.960) and the desired power (z_1−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

1. Observed difference Δ = 0.104; pooled standard deviation σ = 0.204.
2. n = 2 × (1.96 + 0.842)² × 0.204² / 0.104² = 61.1, rounded up to 62 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 <- 0.1036                      # observed difference in means
sigma <- 0.204354165604717                     # 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(2347761)
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 = 62 (80% power), 82 (90% power)
 75% of observed effect: n per arm = 109 (80% power), 146 (90% power)
 50% of observed effect: n per arm = 245 (80% power), 328 (90% power)
power.t.test: 62.1 
Simulated power at n = 62 per arm: 0.795 (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.

14. Analyses Reported by the Sponsor

The registry’s reported primary analyses use a mixed model for repeated measurements and give least-squares mean differences with 95% confidence intervals and p-values. For SUN-101 50 mcg, the reported difference is 0.104 liters, the interval is 0.066 to 0.141, and p < 0.001. For SUN-101 25 mcg, the reported difference is 0.096 liters, the interval is 0.059 to 0.133, and p < 0.001.

The unadjusted recalculations from the posted group summaries yield the same point estimates, but somewhat different intervals and p-values. Their method uses approximate variability from the summaries and does not recreate the sponsor’s repeated-measures model. For example, the recalculated p-values are < 0.001 for both comparisons, while the reported model-based p-values are < 0.001. The different precision reflects the different calculations, not a different point estimate.

The recalculations are best read as ancillary checks, while the registry’s formal reported analyses describe the sponsor’s stated primary method. The record does not provide sufficient model details to independently reproduce the mixed-model analyses. No discrepancy is flagged in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and multiple secondary outcomes, including lung-function measures, health status measured by the St. George’s Respiratory Questionnaire, rescue medication use, and major adverse cardiac events. It does not report a multiplicity adjustment for the secondary outcome analyses. Without information on the full testing strategy, a reader cannot determine whether the reported secondary comparisons were treated as confirmatory, exploratory, or part of a prespecified hierarchy.

General: testing many outcomes raises the chance of obtaining at least one apparently unusual result by chance. Multiplicity procedures control that risk by adjusting how evidence is evaluated across a family of tests. In the absence of a reported adjustment or testing hierarchy, individual unadjusted secondary p-values should not be interpreted as if they were the sole planned test. The registry record also does not report a detailed statistical analysis plan that would clarify the prespecification of the secondary tests.

Missing data are addressed in the primary endpoint description: values not collected remained missing and were assumed missing at random. All collected values were used, including measurements after discontinuation of randomized treatment when participants remained in the study. The description says that “ALL COLLECTED” and “ON TREATMENT” data are the same, with the difference being the visits included for participants who discontinued treatment but continued study participation. The registry does not report sensitivity analyses examining other missing-data assumptions.

The primary analysis population is defined as randomized subjects who received at least one dose of study medication, analyzed according to assigned group. The registry record does not provide additional detail about exclusions, missing-outcome counts, or participant flow by analysis population. The original sample-size justification, interim analyses, and complete statistical plan are also not reported in the registry record. Those absences limit assessment of how the reported analyses relate to the trial’s original design and decision rules.

16. 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: chronic obstructive pulmonary disease (1.8%), pneumonia (0.9%), angina pectoris (0.5%), coronary artery stenosis (0.5%), small intestinal obstruction (0.5%).

The registry reports serious adverse event figures by group. Serious adverse events affected 10 participants among 218 at risk in the SUN-101 50 mcg group, 8 among 217 at risk in the SUN-101 25 mcg group, and 11 among 218 at risk in the placebo group. The figures for other adverse events are 37 among 218 at risk, 23 among 217 at risk, and 38 among 218 at risk, respectively. These counts describe the posted group-level safety data and are not calculations of comparative risk.

The most frequently listed serious-event terms include chronic obstructive pulmonary disease (1.8%), pneumonia (0.9%), angina pectoris (0.5%), coronary artery stenosis (0.5%), small intestinal obstruction (0.5%), and pyelonephritis (0.5%). The registry record does not report death counts in the available safety fields. It also does not provide a comparative statistical analysis of serious adverse events in the information.

General: safety counts should be considered alongside the period of observation, definitions, severity, and participant characteristics. These figures alone do not establish that a treatment caused or prevented an event, and they should not be interpreted as a complete assessment of safety.

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

The primary registry analyses show positive model-based differences in change from baseline in trough FEV1 at Week 12 for each SUN-101 dose compared with placebo. The reported estimates are 0.104 liters for 50 mcg and 0.096 liters for 25 mcg, with both 95% confidence intervals above zero and both p-values < 0.001. The result is a comparison of group-level changes for this defined endpoint and follow-up time.

This does not show that one SUN-101 dose is superior to the other: the reported primary comparisons are each against placebo, and the registry record does not report a direct test between doses. Nor do these results by themselves establish the size of any benefit that patients would notice. The registry does not give a clinical-importance threshold for the endpoint, and statistical significance is not a substitute for one.

The outcome is trough FEV1, not every dimension of COPD. Secondary outcomes include FEV1 area under the curve, trough FVC, health status, rescue medication use, and cardiac events, but the listed results do not provide uniform evidence across all measures. Several secondary recalculations are imprecise, and the registry does not report a multiplicity adjustment for them. The primary finding should not be extended to unreported outcomes, different populations, or longer-term follow-up.

Interpretation also depends on the model and missing-data assumptions. The registry states that the primary analysis used all collected values and assumed missingness at random, but does not report sensitivity analyses or enough detail to reconstruct the mixed model. The endpoint results describe what the posted analysis estimated under its methods; they do not remove uncertainty related to missing data or establish that the same pattern would occur in other settings.

The safety figures provide counts of participants with serious and other adverse events in the trial groups. They do not, on their own, establish causation or provide a complete comparative safety assessment. Overall, the results are specific to the randomized 12-week trial and its posted analyses.

18. Why This Trial Matters Statistically

This trial is a useful statistical example of why the comparison method matters. The primary outcome was measured repeatedly, and the sponsor reported a mixed model for repeated measurements rather than a simple comparison of group summaries. The model-based estimates and unadjusted recalculations have matching point estimates but different confidence limits and p-values. Readers can see why a transparent calculation from summary data is informative as a check, yet cannot replace the analysis that accounts for the trial’s repeated measurements.

The study also illustrates the distinction between an estimate and its precision. The primary differences are accompanied by confidence intervals that quantify uncertainty under the reported model. Secondary outcomes have more variable precision, including broad intervals in some recalculations. A result’s direction alone does not show how precisely it is estimated, while an interval alone does not determine whether the effect matters clinically.

It is also important that the registry’s primary analysis population and missing-data approach are stated. Participants were analyzed according to randomized assignment after receiving at least one dose, and all collected spirometry values were included under the stated missing-at-random assumption. Such details help define what the estimate represents, while the absence of a reported sensitivity analysis or full model specification leaves questions that cannot be resolved from this record.

Finally, the range of secondary outcomes makes multiplicity relevant. Without a reported adjustment or testing hierarchy, secondary p-values should be treated cautiously. The trial is therefore a practical illustration of how study design, analysis populations, repeated-measures methods, missingness, and outcome multiplicity all shape the interpretation of clinical-trial results.

19. 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 are apparent from the registry record. The primary outcome is defined for Week 12, so these results do not describe longer-term change. The registry’s endpoint description specifies that all collected values were analyzed and missing values were assumed missing at random, but it does not report a sensitivity analysis under alternative assumptions. The impact of missing data therefore cannot be assessed from the listed information.

The registry identifies a mixed model for repeated measurements but does not provide its full specification. Details such as the model terms and covariance structure are not reported in the registry record, limiting independent reproduction of the formal analysis. The unadjusted recalculations use approximate dispersion from group summaries and should not be mistaken for the sponsor’s model-based analysis.

Some secondary summary statistics have unusually large reported standard errors relative to other group entries, including 0.301 liters for one substudy estimate and 0.227 liters for the placebo FVC estimate. The registry does not explain these entries. The resulting unadjusted comparisons can be imprecise, and the record does not provide sponsor-reported analyses for the secondary outcomes listed in the calculations.

The registry record does not report a multiplicity adjustment for secondary outcomes, a complete statistical analysis plan, the original sample-size justification, or interim-analysis details. It also does not report a clinical-importance threshold for the primary FEV1 difference. These omissions restrict judgments about confirmatory status, design assumptions, clinical relevance, and robustness beyond the analyses described.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Efficacy and Safety Trial of 12 Weeks of Treatment With Nebulized SUN-101 in Patients With COPD — NCT02347761.
• Registry record last updated 2018-03-22; status last verified 2018-02.
• Results first posted 2018-03-22.
• 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.

23. Record Summary

GOLDEN-3 (NCT02347761) is a completed, randomized, quadruple-masked, parallel-group, placebo-controlled Phase 3 trial of 12 weeks of twice-daily nebulized SUN-101 in COPD. The registry lists 653 enrolled participants and three groups: 50 mcg SUN-101, 25 mcg SUN-101, and placebo, delivered with the eFlow Closed System nebulizer.

The primary endpoint was change from baseline in trough FEV1 at Week 12. The registry reports mixed-model differences versus placebo of 0.104 liters for 50 mcg and 0.096 liters for 25 mcg, with 95% confidence intervals of 0.066 to 0.141 and 0.059 to 0.133, respectively; both p-values are < 0.001. The secondary outcomes show varying precision, and multiplicity handling is not reported in the registry record.

The primary analysis included randomized participants who received at least one dose, analyzed as randomized. The outcome description states that missing values were assumed missing at random. Important details, including the original sample-size justification, full statistical plan, and sensitivity analyses for missing data, are not reported in the registry record.