Study to Evaluate Efficacy of LAI When Added to Multi-drug Regimen Compared to Multi-drug Regimen Alone: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate Efficacy of LAI When Added to Multi-drug Regimen Compared to Multi-drug Regimen Alone (NCT02344004), a randomized phase 3 study. The primary outcome is Number of Participants Achieving Culture Conversion by Month 6 in the Liposomal Amikacin for Inhalation (LAI) + Multi-drug Regimen (MDR) Arm Compared to the MDR Alone Arm.

2. Clinical Question

This question concerns a microbiological outcome, not a direct measure of symptoms, daily functioning, or long-term disease course. The registry also lists secondary outcomes involving the six-minute walk test, time to culture conversion, sustained culture conversion, and respiratory health-related quality of life. Those outcomes are distinct from the primary comparison and should not be substituted for it.

3. Trial Design

This was a Phase 3, randomized, open-label, multicenter, parallel-group study. The registry lists an enrollment of 336 and reports that participants were randomized in a 2:1 ratio to LAI 590 mg once daily plus MDR or MDR alone. The primary population was the intent-to-treat population, defined in the registry as all randomized participants; it lists 224 assigned to LAI plus MDR and 112 assigned to MDR alone.

The comparator was not described as a single standardized drug combination. Participants continued their already prescribed anti-mycobacterial regimen, based on the 2007 ATS/IDSA guidelines. In the intervention arm, LAI was added to that regimen. The record says inhaled LAI was aerosolized in an eFlow nebulizer over approximately 14 minutes.

Open-label means that masking was not used, as stated in the registry. Participants and study staff could therefore know the assigned treatment. Randomization helps make assigned groups comparable on average, but does not itself prevent biases in care, reporting, or assessment that can arise when treatment assignment is known. The primary outcome was based on sputum culture results, although the record does not report details about laboratory masking or central assessment.

The study started on 2015-05-27, reached primary completion on 2018-07-03, and is listed as completed. The registry identifies Insmed Incorporated as the sponsor. It does not report the protocol’s allocation-generation details, the rationale for the allocation ratio, or the specific statistical analysis plan.

4. Participant Flow and Accounting

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

Before assignment: Participant flow table reflects the disposition through end of the study (Month 28). The deaths under Reasons for Discontinuation reflect the primary reason (according to investigator's judgment) that the participant discontinued and does not represent all deaths in the trial.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The ITT population was the set of all randomized participants. Participants were classified according to their assigned treatment. There was a total of 336 participants in the ITT population, including 224 participants in the LAI + MDR arm and 112 participants in the MDR alone arm.

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 Number of Participants Achieving Culture Conversion by Month 6 in the Liposomal Amikacin for Inhalation (LAI) + Multi-drug Regimen (MDR) Arm Compared to the MDR Alone Arm, measured over by Month 6.

The primary endpoint was the number of participants achieving MAC culture conversion by Month 6. Sputum specimens were collected at screening, baseline, and monthly visits through Month 6. A visit was considered culture-negative only when all sputum samples collected at that visit had negative culture results.

To meet the endpoint, a participant needed three consecutive monthly MAC-negative sputum cultures during the first six months. The first of those three consecutive negative cultures had to occur by Month 4 for the participant to qualify as converted by Month 6. Each participant in the intent-to-treat population was classified as a converter or non-converter by Month 6.

This type of endpoint turns repeated microbiological measurements into a participant-level binary outcome. It can make the comparison straightforward to describe: each randomized participant either met the registry’s conversion definition or did not. Requiring consecutive negative cultures also distinguishes a sustained sequence of negative results from an isolated negative result. That is the endpoint’s operational definition; it does not by itself establish how a participant feels or functions.

The registry record does not report how many participants met the definition in either arm, the treatment contrast, a confidence interval, or a p-value. Consequently, the endpoint definition can be described, but the comparative efficacy result cannot be reconstructed from the registry information in this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a randomized, open-label, parallel-group study and a binary primary endpoint. It does not report the detailed statistical analysis plan, the test used for the primary comparison, a confidence interval, or a p-value. The concepts below explain how such information is generally interpreted; they are not claims about the analyses used in this trial.

What does randomization contribute?

In general, randomization assigns participants to treatment groups using a chance-based process. It aims to reduce systematic differences between groups at the time of assignment, including differences in measured and unmeasured characteristics. It does not guarantee that groups will be identical, and it does not address every source of bias after assignment. The registry says participants were randomized, but it does not report the sequence-generation method, concealment procedures, or any stratification factors.

What does a binary endpoint mean?

A binary endpoint places each participant into one of two outcome categories. In this trial, the categories were converter and non-converter by Month 6, using the specified sequence of negative monthly MAC sputum cultures. The count of participants in each category can be described within each assigned arm. Common comparisons for binary outcomes include a difference in proportions, a ratio of proportions, or an odds ratio. These are general statistical options; the registry record does not identify which measure was used for the primary analysis.

Whatever measure is chosen, its interpretation depends on the endpoint definition and the population analyzed. The endpoint requires consecutive monthly negative cultures, and the record defines the intent-to-treat population as all randomized participants. The registry does not supply the arm-specific outcome counts needed to calculate or interpret an effect estimate.

How should uncertainty be read?

In general, a confidence interval describes a range of values compatible with the observed data under the assumptions of the analysis. A narrower interval indicates greater precision than a wider interval, while the interval’s location indicates which effect sizes are consistent with the data. A p-value addresses how unusual data at least as discrepant as those observed would be under a specified null hypothesis and model. It is not the probability that the null hypothesis is true, and it does not express the clinical importance of an effect. No interval or p-value for the primary endpoint is reported in the registry record, so neither precision nor statistical evidence for a between-group contrast can be assessed from these entries.

Why does the analysis population matter?

The intent-to-treat principle generally analyzes participants according to the groups to which they were randomized, regardless of subsequent treatment changes. It preserves the comparison created by randomization and estimates an effect of assignment under the analysis’s handling of outcomes. The record identifies the intent-to-treat population but does not provide the primary analysis results or say how missing culture results were classified. The precise operational analysis therefore cannot be inferred from the population label alone.

What does open-label design imply?

In an open-label trial, masking is not used. Knowledge of assignment can influence behavior, co-interventions, decisions to stop or change treatment, and reporting of subjective outcomes. The primary endpoint is based on cultures, which are not themselves a participant’s subjective report, but handling and assessment procedures can still matter. The registry does not report whether laboratory personnel or endpoint assessors were masked to assignment.

What is the role of sample-size planning?

In general, sample-size planning uses assumptions about the effect to detect, variability or event frequency, significance level, power, allocation, and analysis method. A planning illustration based on an observed effect is not an observed trial result and is not observed power. It describes a hypothetical design under stated assumptions. The registry record does not report the trial’s sample-size justification or enough primary outcome results to assess a planning illustration based on an observed effect. Its planning assumptions describe a two-sided significance level of 0.05, equal allocation, a normal approximation, and effect fractions, but those assumptions alone do not establish the trial’s own design rationale or yield a trial result.

For binary outcomes, event frequencies and the planned contrast influence the required group size. If the true effect differs from the assumed effect, the precision and power of a study may differ from the planning expectation. These are general design principles, not a description of an unreported analysis in this trial. The registry record does not state whether interim analyses were planned or conducted, nor does it report an adjustment strategy for multiple comparisons.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary culture-conversion outcome and several secondary outcomes, including six-minute walk distance, time to culture conversion, sustained culture conversion, and St. George’s Respiratory Questionnaire total score. Evaluating multiple outcomes can increase the chance of a false-positive finding if each is tested without an appropriate strategy. The registry record does not report a multiplicity-control procedure, a hierarchy among secondary outcomes, or which comparisons were confirmatory versus exploratory. The presence of several listed outcomes does not establish that every outcome was tested or that any particular adjustment was used.

For the primary endpoint, the registry defines the intent-to-treat population as all randomized participants and says participants were classified as converter or non-converter by Month 6. However, it does not report the number with unavailable cultures, missing-data rules, imputation methods, sensitivity analyses, or handling of treatment discontinuation. The endpoint requires a sequence of negative cultures, so the availability and timing of cultures are relevant to classification. The record does not explain what happened when one or more required cultures were missing or unevaluable.

The record also does not report a per-protocol population, a modified intent-to-treat definition, or a comparison of results across analysis populations. It is therefore not possible to assess whether conclusions were robust to alternative missing-data assumptions or population definitions. The assigned-arm counts are reported, but they are not a substitute for outcome availability or an explanation of missingness.

Finally, the registry does not report interim analyses, stopping rules, or whether any adjustments were made to account for repeated looks at accumulating data. Their presence or absence cannot be inferred from the study’s completion status. The statistical plan for multiplicity, missing data, and analysis populations is not reported in the registry record.

11. 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: haemoptysis (4.5%), pneumonia (3.6%), chronic obstructive pulmonary disease (3.1%), infective exacerbation of bronchiectasis (2.7%), respiratory failure (1.8%).

The registry lists serious adverse events for 45 of 223 participants at risk in the LAI plus MDR group and 23 of 112 participants at risk in the MDR group. It lists other adverse events for 199 of 223 at risk in the LAI plus MDR group and 72 of 112 at risk in the MDR group. These are participant counts, not counts of every event episode; the registry information does not provide event-level detail or explain how recurrent events were counted.

The serious adverse event terms listed most often include haemoptysis (4.5%), pneumonia (3.6%), chronic obstructive pulmonary disease (3.1%), infective exacerbation of bronchiectasis (2.7%), respiratory failure (1.8%), and pulmonary cavitation (1.8%). The denominator and method used for these term percentages are not reported in the registry record. The record also lists 11 deaths in the LAI plus MDR group and 8 in the MDR group. It does not provide further details about timing, cause, relatedness to treatment, or adjudication.

The at-risk counts are not identical to the assigned-arm counts reported for the intent-to-treat population; the record does not explain why. These safety entries are descriptive and should not be treated as adjusted comparisons or as proof that treatment caused or prevented an event. Differences in follow-up, exposure, participant characteristics, or event ascertainment cannot be assessed from these counts alone.

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

The record describes a clinically focused question: whether adding inhaled LAI to an existing multi-drug regimen was associated with more MAC culture conversion by Month 6 than the regimen alone. It clearly defines conversion as a sequence of consecutive monthly negative cultures and identifies all randomized participants as the intent-to-treat population. These features make the intended primary comparison understandable.

However, the registry record does not report the number of converters in either arm, the comparative effect estimate, or its uncertainty. Therefore, it does not establish the direction or size of the primary result, nor how precisely that result was estimated. The trial’s completion status and its planned enrollment do not substitute for reported outcome results. No claim that LAI improved, worsened, or had no effect on culture conversion can be supported from the efficacy information in this record.

Even if a statistical comparison were available, a result on culture conversion would address that defined microbiological endpoint. It would not by itself answer every question about symptoms, function, quality of life, durability of response, or longer-term outcomes. The registry lists some secondary outcomes, but their results are not reported in the record.

The safety counts offer a separate descriptive view of recorded adverse events and deaths. Without further information about event timing, relatedness, exposure, and comparative analysis, they cannot establish causation or provide a complete account of benefit and risk. The open-label design is also relevant: knowledge of assignment may affect aspects of care and assessment, although the registry does not describe the safeguards used for culture assessment.

Accordingly, the appropriate reading is limited. The study design and endpoint definition are documented, as are selected safety counts, but the comparative primary efficacy result and important analysis details are not reported in the registry record. The absence of a result in this record is not evidence of no effect; it is a limit on what can be concluded from these entries.

13. Why This Trial Matters Statistically

This trial illustrates why a registry record needs to be read in layers. The design tells readers how assignment was intended to work; the endpoint definition specifies what counted as culture conversion; the analysis population describes whom the primary comparison was meant to include; and the results are needed to estimate the treatment contrast. Here, the first elements are described, while the primary arm-level outcome results and statistical comparison are not reported in the registry record.

The endpoint also illustrates how operational definitions shape interpretation. Requiring three consecutive monthly negative cultures makes the outcome more specific than a single negative test, while the requirement that the first negative culture occur by Month 4 determines who could qualify by Month 6. Readers need that detail before interpreting any reported conversion count. They also need to know how unavailable or unevaluable cultures were handled, which is not reported.

The open-label design and the use of a microbiological primary endpoint raise distinct methodological questions. Randomization supports a fair comparison at assignment, while masking and outcome ascertainment can affect other aspects of bias. The registry identifies the study as open-label but does not report whether laboratory or assessment personnel were masked. The listed secondary measures include functional and patient-reported outcomes, which are conceptually different from culture conversion and may have different susceptibility to open-label influences.

Finally, the record shows why safety counts require context. Counts and selected event terms can describe what was recorded, but denominators, timing, severity, exposure, and relatedness all affect interpretation. Without efficacy estimates and fuller analysis details, readers should distinguish a documented trial question from a documented answer. That distinction is central to sound statistical reading.

14. Limitations

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

The most consequential limitation of the registry record for interpretation is that it does not report the primary endpoint results by arm or the comparative estimate. This prevents assessment of the observed effect and its precision. The registry record also does not report the statistical test or model, confidence interval, p-value, or detailed analysis plan for the primary endpoint.

The culture-conversion definition depends on repeated monthly specimen collection and consecutive negative results. The record explains the required sequence but does not report missing culture frequency, handling of unavailable or unevaluable specimens, or sensitivity analyses for missing outcomes. Those details are important because a participant’s classification depends on the availability and timing of culture results.

The study was open-label. The record does not report whether laboratory staff or outcome assessors were masked, nor how culture results were verified. The comparator allowed participants to continue their already prescribed regimens based on the 2007 ATS/IDSA guidelines; the registry does not describe the range of regimens, adherence, or changes during follow-up. These details limit interpretation of the treatment contrast and the consistency of background care.

The safety at-risk counts differ from the randomized count in the LAI plus MDR group, and the record does not explain the population difference. It gives selected serious-event terms and death counts, but not timing, causes, treatment relatedness, event duration, or a full comparative analysis. The listed term percentages have no reported denominator or calculation details. The registry also does not report protocol deviations, interim analyses, stopping rules, or multiplicity procedures. These omissions restrict evaluation of both the efficacy analysis and the safety summaries.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Evaluate Efficacy of LAI When Added to Multi-drug Regimen Compared to Multi-drug Regimen Alone — NCT02344004.
• Registry record last updated 2020-05-07; status last verified 2020-02.
• Results first posted 2018-11-20.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry describes NCT02344004 as a completed, randomized, open-label, multicenter Phase 3 parallel-group study of LAI added to MDR versus MDR alone for adults with refractory MAC lung infection. Participants were assigned in a 2:1 ratio. The primary endpoint was culture conversion by Month 6, defined by three consecutive monthly MAC-negative sputum cultures, with the first negative culture by Month 4.

The intent-to-treat population included 336 randomized participants: 224 assigned to LAI plus MDR and 112 assigned to MDR alone. The registry record does not report the primary outcome counts or comparative efficacy estimate. It lists serious adverse events, other adverse events, selected serious-event terms, and deaths, but does not provide enough detail to interpret causality or fully compare safety. Missing-data methods, multiplicity procedures, and the detailed statistical plan are not reported in the registry record.