A Study Of ¹²⁹XE MRI To Assess Disease Progression In Patients With COPD Treated With Or Without Azithromycin And Standard-of-Care Medications: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Of ¹²⁹XE MRI To Assess Disease Progression In Patients With COPD Treated With Or Without Azithromycin And Standard-of-Care Medications (NCT04353661), a randomized phase 2 study. The primary outcome is Change in 129Xenon (129Xe) Magnetic Resonance Imaging (MRI) Ventilation Defect Percentage (VDP) From Baseline to Week 24.

2. Clinical Question

3. Trial Design

This was a phase 2, randomized, parallel study with no masking, according to the registry record. It concerned chronic obstructive pulmonary disease and was sponsored by Genentech, Inc. The listed enrollment was 12. The record gives a start date of 2021-11-16, a primary completion date of 2023-06-29, and a status of terminated.

The intervention list names azithromycin and hyperpolarized ¹²⁹Xe. The arm descriptions include open-label azithromycin plus SOC therapy, open-label SOC therapy, and an observational SOC therapy group. The descriptions state that the groups received their listed therapy for 52 weeks. Although the record labels the study randomized, it also labels one group observational. The relationship between those descriptions, including how assignment to each group occurred, is not reported in the registry record.

The stated study aim was to test whether daily azithromycin would reduce exacerbations and improve lung ventilation and perfusion measured with XE-MRI. It also proposed comparing the sensitivity of XE-MRI for COPD progression with standard clinical assessment measures, including lung function tests, the 6 minute walk test, and patient-reported quality of life. The registry record does not report the detailed randomization procedure, concealment of allocation, or protocol-level descriptions of these assessments.

The primary endpoint was change in ¹²⁹Xe MRI VDP from baseline to Week 24. The posted outcome values are for three groups, with analyzed counts of 3, 4, and 2. These are outcome-specific counts of participants with available data, not a reconciliation of enrollment. The registry record does not report why the study was terminated.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT population. Overall number of participants analyzed is the number of participants with data available for analyses.

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 in 129Xenon (129Xe) Magnetic Resonance Imaging (MRI) Ventilation Defect Percentage (VDP) From Baseline to Week 24, measured over Baseline up to Week 24.

The primary endpoint is change in ventilation defect percentage (VDP) measured using hyperpolarized ¹²⁹Xe MRI, from baseline to Week 24. The description says that administered ¹²⁹Xe gas was used for MRI mapping of ventilation and gas distribution in the alveolar space, uptake in interstitial barrier tissues, and transfer to red blood cells. VDP is the MRI measure named for the primary outcome; the registry record does not provide its detailed calculation or interpretation thresholds.

The direction of change matters: the record specifies that a positive change from baseline indicated worse outcomes. Thus, the reported mean changes should be read with that stated direction in mind, not as though an increase necessarily represented improvement. A mean summarizes the observed changes in a group, while the standard deviation describes the spread of participant values around that mean. Neither quantity alone establishes a treatment effect.

This endpoint was used to assess whether an imaging measure could capture changes in lung ventilation over the study period. The study description also frames MRI as a measure to compare with standard clinical assessments. That aim is distinct from demonstrating that a change in the imaging measure corresponds to a meaningful change in symptoms or other clinical outcomes. The registry record does not report a threshold for clinically important VDP change or a validated relationship between VDP and clinical benefit.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary outcome is a continuous measure summarized by its mean and standard deviation. This is a common way to describe a measurement such as change in VDP: the mean gives the group’s average observed change, and the standard deviation conveys how dispersed participant-level changes were around that average. The mean is not a statement about every participant, and the standard deviation is not a confidence interval for the mean.

What does a confidence interval add?

In general, a confidence interval expresses uncertainty around an estimated quantity, such as a group mean or a difference between groups. Its width reflects both the variability in the data and the amount of information available. A narrow interval indicates more precision than a wide interval, under the model used to construct it. The primary results reported in the registry record do not include confidence intervals, so the precision of the group means and any comparative effect cannot be read from interval estimates.

Why is the comparison not available?

The registry record states that values are missing or not estimable for a two-arm comparison of this continuous endpoint. That means the posted results do not support an inferential two-arm comparison in the form expected for the endpoint. It is not appropriate to reconstruct one from the group summaries: the record supplies no comparison estimate, standard error, confidence interval, or p-value. A valid comparison can depend on the analysis population, participant-level data, model specification, and assumptions about missing observations. Those details are not reported in the registry record.

The outcome values are presented for three groups, rather than as a single two-arm estimate. The labels distinguish open-label azithromycin plus SOC, open-label SOC, and observational SOC. Because the record does not explain the assignment process linking those groups to randomization, the labels alone do not establish that every contrast would have the properties of a randomized comparison. In general, random allocation can support a causal comparison by balancing measured and unmeasured characteristics on average, but that benefit depends on the actual assignment process and analysis. The relationship between the randomized designation and the observational group is not reported in the registry record.

How should the standard deviations be read?

In general, the standard deviation measures spread among observations, not uncertainty about a treatment effect. The reported primary-endpoint standard deviations are 12.7, 5.12, and 7.07 across the three groups. With the small outcome-specific analyzed counts reported for these groups, individual observations can have substantial influence on a group mean. The registry record does not provide participant-level data, distribution plots, or an analysis checking the assumptions of a particular statistical model.

For continuous outcomes, methods often model the mean change or compare changes between groups. Such methods may require assumptions about the distribution of residuals, variance patterns, and missing data. The exact primary statistical model, any adjustment variables, and the planned contrast are not reported in the registry record. There is therefore no basis for attributing a particular modeling choice to the investigators.

What do the planning illustrations represent?

General sample-size calculations estimate the amount of information a future study would need to detect a specified effect under stated assumptions. The planning assumptions described for the illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. For non-time-to-event outcomes, such illustrations are expressed as participants per arm. They are planning illustrations based on the observed effect, not observed power and not the trial’s own design justification. The registry record does not report a sample-size justification for this study, and a planning calculation cannot repair the absence of an estimable comparison.

General statistical interpretation also distinguishes statistical uncertainty from clinical importance. Even a precisely estimated difference would require context to decide whether its size matters clinically; conversely, an imprecise result does not establish that there is no effect. Here, a comparative estimate and its uncertainty are not posted, and the registry record does not give a clinically important VDP threshold. The safest statistical reading is therefore to describe the observed group summaries and their limitations without converting them into a treatment conclusion.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Arm A Open-label: Azithromycin + SOC Therapy", "Arm A Open-label: SOC Therapy", "Arm B Observational : SOC Therapy")
n   <- c(3, 4, 2)
m   <- c(6.33, -1.75, -1)
sp  <- c(12.7, 5.12, 7.07)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Arm A Open-label: Azithromycin + SOC Therapy  3  6.330  12.700  -25.219  37.879
CARM  Arm A Open-label: SOC Therapy  4  -1.750  5.120  -9.897  6.397
CARM  Arm B Observational : SOC Therapy  2  -1.000  7.070  -64.521  62.521

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists five outcome measures and names three secondary outcomes: adverse events with severity determined according to the WHO Toxicity Scale, change in ¹²⁹Xe MRI VDP from baseline to Week 48, and change in pre-bronchodilator FEV1 from baseline to Week 24 and Week 48. The record reports zero analyses. A complete account of all outcomes and their analysis results is therefore not present in the registry record.

When a study tests multiple outcomes or multiple time points, the chance of at least one apparently notable result can increase if each is assessed separately. General approaches to multiplicity include defining a primary outcome in advance, adjusting the testing threshold, or treating secondary analyses as exploratory. The multiplicity strategy for this study is not reported in the registry record. The presence of a named primary endpoint does not, by itself, establish how other outcomes or time points were handled statistically.

The primary endpoint description defines the ITT population as participants with data available for analysis. That wording identifies the stated analysis population but does not explain how missing data were handled, whether any imputation was used, or whether sensitivity analyses were performed. The reason for unavailable measurements and the number missing at each assessment are not reported in the registry record. The analyzed counts differ by listed group, and the record does not explain the relationship between those endpoint-specific counts and overall enrollment.

In general, complete-case summaries describe participants with observed data and can be affected if the availability of measurements is related to participant characteristics or outcomes. Whether such a concern applied in this study cannot be determined from the registry record. The protocol’s missing-data assumptions and any prespecified analysis plan are not reported, so the posted means should be understood as summaries among those with available endpoint data rather than evidence about an unobserved full-data analysis.

12. Safety Results

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

Deaths

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 (33.3%), respiratory syncytial virus infection (25.0%), accident (25.0%), limb injury (25.0%), subcutaneous emphysema (20.0%).

The serious adverse-event summaries are reported by registry safety group. In Cohort A - SOC + Azithromycin, 1 participant was affected among 3 at risk; in Cohort A - SOC, 2 were affected among 5 at risk; and in Cohort B - SOC, 2 were affected among 4 at risk. The deaths field is 0 for each listed group. These are the reported group counts, not a comparative safety analysis.

The record also reports other adverse-event counts separately: 3 affected among 3 at risk in Cohort A - SOC + Azithromycin, 5 among 5 in Cohort A - SOC, and 2 among 4 in Cohort B - SOC. The registry lists the leading serious-event terms with percentages: chronic obstructive pulmonary disease, 33.3%; respiratory syncytial virus infection, 25.0%; accident, 25.0%; limb injury, 25.0%; and subcutaneous emphysema, 20.0%. The record does not give further context for interpreting those percentages or linking each term to a particular group.

Adverse-event counts do not alone establish whether an event was caused by a study treatment. The safety-group labels also differ from some of the primary-outcome arm labels, and the registry record does not explain that mapping. The summaries should therefore be read as reported safety counts, not as evidence of comparative risk.

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

The posted primary results show the mean change in VDP within each listed group among participants with endpoint data. The endpoint definition says that positive change indicated worse outcomes. The mean changes were 6.33 for open-label azithromycin plus SOC, -1.75 for open-label SOC, and -1.0 for observational SOC. The associated standard deviations were 12.7, 5.12, and 7.07, respectively. These summaries describe the observed data; they do not establish what would have happened to the same participants under another treatment.

The registry record does not report an estimable two-arm comparison for the continuous primary endpoint. Consequently, the results do not establish a statistically supported difference between azithromycin plus SOC and SOC alone, nor do they establish equivalence or absence of an effect. No comparative estimate or confidence interval is posted to show the direction and precision of a treatment contrast. The group means should not be treated as a substitute for that comparison.

The record identifies the study as randomized but includes an observational SOC group and does not report how that group was formed or how assignment worked across the listed arms. This ambiguity limits interpretation of the group summaries as evidence of treatment effects. The analyzed group counts are small, and the record does not report the reasons for missing primary-endpoint data or the methods used to address them.

The stated rationale was to assess exacerbations and lung ventilation and perfusion with XE-MRI, and to compare MRI sensitivity with standard clinical measures. The posted primary endpoint is an imaging measure at Week 24. The record does not report a clinically important threshold for VDP change or establish that VDP changes correspond to changes in patient-reported quality of life, walking performance, lung function, or exacerbation outcomes.

These results therefore support a limited descriptive account of the recorded VDP summaries and safety counts. They do not establish that azithromycin improved or worsened COPD outcomes, and they do not establish that the imaging measure is a validated substitute for clinical outcomes. The terminated status is recorded, but the reason for termination and its implications for data collection are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial raises a useful statistical distinction between a descriptive result and a comparative result. Group means and standard deviations can show the observed pattern in each arm, but a treatment question generally requires an estimate of the difference between groups and a measure of uncertainty around that estimate. The registry record reports the former for VDP but says a two-arm comparison is not estimable. Readers should not mistake several group summaries for a direct test of the primary question.

The endpoint also illustrates how an imaging measure can serve as a candidate marker of disease progression. The study intended to assess ¹²⁹Xe MRI alongside lung function, walking, exacerbation, and quality-of-life measures. A statistical association between imaging change and other measures, if assessed, would be a different question from whether treatment changes the imaging measure. The registry record does not report results establishing such a relationship.

The combination of a randomized designation and an observational arm label is another design issue with analytical consequences. A registry description should make clear how each group arose, because randomization and observational allocation support different interpretations. That relationship is not reported in the registry record, so the arm summaries cannot be read as a straightforward randomized treatment contrast.

Finally, the study highlights the importance of outcome availability and analysis transparency. The primary population is defined by having data available, while the endpoint-specific analyzed counts are small and the record does not describe missing-data methods. Without a reported comparison, uncertainty estimate, analysis plan, or explanation of missingness, the posted numbers are best treated as descriptive evidence. This distinction matters when evaluating early-stage imaging research and deciding what further evidence would be needed to support a comparative conclusion.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several trial-specific limitations constrain interpretation. The study status is terminated, but the reason for termination is not reported in the registry record. The record gives an enrollment of 12, while the primary endpoint summaries have analyzed counts of 3, 4, and 2 across the listed groups. The relationship between enrollment and the endpoint-specific data availability is not explained, and reasons for missing measurements are not reported.

The design description presents a further ambiguity: allocation is labeled randomized, while one SOC group is labeled observational. The registry record does not explain how participants entered that group, how assignment occurred across all listed groups, or whether the analysis preserved randomized comparisons. This limits causal interpretation of differences among the displayed group summaries.

The primary endpoint is a continuous imaging measure, but no two-arm comparison is estimable from the posted results. The record supplies no comparative estimate, confidence interval, or p-value, and it does not report the primary statistical model or adjustment strategy. It also does not report a threshold for a clinically important change in VDP. The means and standard deviations therefore offer limited information about treatment effects or clinical relevance.

Although the record lists secondary outcomes and safety summaries, it reports zero analyses. The multiplicity plan, missing-data assumptions, and any sensitivity analyses are not reported in the registry record. The available material also does not establish how the safety groups correspond to the primary endpoint arms. These reporting gaps make it difficult to assess completeness and consistency across outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study Of ¹²⁹XE MRI To Assess Disease Progression In Patients With COPD Treated With Or Without Azithromycin And Standard-of-Care Medications — NCT04353661.
• Registry record last updated 2024-12-24; status last verified 2024-11.
• Results first posted 2024-12-24.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes NCT04353661 as a terminated phase 2 randomized, parallel study with no masking in patients with COPD. It lists enrollment of 12 and compares descriptions involving azithromycin plus SOC with SOC therapy, including an observational SOC group. The study was sponsored by Genentech, Inc.; the recorded start date is 2021-11-16 and the primary completion date is 2023-06-29.

The primary endpoint was change in ¹²⁹Xe MRI VDP from baseline to Week 24, with positive change defined as worse outcomes. The posted group means and standard deviations are descriptive, and the registry record states that values are missing or not estimable for a two-arm continuous-endpoint comparison. The record lists secondary outcomes and safety counts, but reports zero analyses. It does not report the reason for termination, the detailed analysis plan, or the handling of missing data.