Dose Ranging Study of ALX-0171 in Infants Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose Ranging Study of ALX-0171 in Infants Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection (NCT02979431), a randomized phase 2 study. The primary outcome is Time for Viral Load to Drop Below Assay Quantification Limit (BQL) (Plaque Assay Analysis).

2. Clinical Question

The study also set out to assess safety and other clinical, virologic, pharmacokinetic, pharmacodynamic, and immunogenicity outcomes. The registry record describes a dose-ranging comparison, so the question was not limited to whether a single dose differed from placebo. The primary endpoint was virologic: it measured the timing of a specified assay result rather than a direct measure of symptom relief or another clinical outcome.

3. Trial Design

This was a phase 2, randomized, quadruple-masked, parallel-group, placebo-controlled dose-ranging study. The registry lists an enrollment of 180 and describes the setting as infants and young children hospitalized for RSV lower respiratory tract infection. The study status is completed. The record lists the sponsor as Ablynx, a Sanofi company.

Participants were assigned to one of three inhaled ALX-0171 dose groups or placebo. The listed regimens were once daily for 3 consecutive days. The primary outcome used a modified intent-to-treat population consisting of randomized participants who received at least 1 study drug administration. Participants remained classified according to randomized assignment for this analysis. The arm-level primary outcome counts are 42 for placebo, 45 for ALX-0171 3.0 mg/kg, 43 for ALX-0171 6.0 mg/kg, and 45 for ALX-0171 9.0mg/kg.

Quadruple masking indicates that the registry labels the study as masked at four levels, but which roles were masked and how masking was maintained are not reported in the registry record. Details about the randomization procedure, allocation concealment, site count, eligibility criteria beyond the stated population, and handling of treatment adherence are not reported in the registry record. The record gives a primary completion date of 2018-05-25 and a study start date of 2017-01-11; those dates describe the registry timeline, not the duration of follow-up for each participant.

The primary comparison order was specified as ALX-0171 9 mg/kg versus placebo, then 6mg/kg versus placebo, then 3mg/kg versus placebo. The record states that these logrank tests were conducted sequentially to preserve the family-wise error rate at 0.05. This ordered testing procedure is distinct from the parallel-group treatment assignment: it describes how the primary statistical comparisons were handled.

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: A total of 301 subjects were screened.180 subjects were randomized to receive ALX-0171 3.0 mg/kg, ALX-0171 6.0 mg/kg, ALX-0171 9.0 mg/kg or placebo, yielding an overall allocation ratio of 3:1 active to placebo.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: modified Intent-to-Treat Population (mITT): All randomized subjects who received at least 1 study drug administration. In this population, the subjects were classified as randomized (i.e.,using the treatment to which the subject was randomized).

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: modified Intent-to-Treat Population (mITT): All randomized subjects who received at least 1 study drug administration. In this population, the subjects were classified as randomized (i.e.,using the treatment to which the subject was randomized).

6. Primary Endpoint

The registry lists the primary outcome as Time for Viral Load to Drop Below Assay Quantification Limit (BQL) (Plaque Assay Analysis), measured over Overall Study Period (i.e., approximately 28 days).

The primary endpoint was time from the first study drug administration until the first occurrence of a plaque-assay viral-load result below the assay quantification limit in nasal mid-turbinate swab specimens. To count as reaching the endpoint, the next measured value also had to remain below the limit. The registry describes the overall study period as approximately 28 days.

This endpoint is a time-to-event measure. The event is not a particular symptom improving; it is the qualifying below-limit assay result. Participants whose data were missing or who did not reach the endpoint during the trial were censored at their last non-missing viral-load assessment. Censoring retains information about the period during which an event was not observed, without treating a participant who has no observed event as if the event occurred at the last visit.

Time-to-event methods are used when the outcome is the time until an event and some participants do not have an observed event during follow-up. The endpoint can therefore incorporate both the timing of observed events and the incomplete observation of participants who were censored. The registry reports group medians with 95% confidence intervals and specifies logrank tests for comparing each dose group with placebo. A median describes the time by which the estimated event distribution has reached its midpoint; the confidence interval conveys uncertainty around that estimate. The endpoint was selected to assess antiviral activity, but by itself it does not establish the size or importance of any clinical benefit.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary analysis used a logrank test to compare time-to-BQL between each ALX-0171 group and the combined placebo group. The test is designed for time-to-event data, including settings where some participants are censored rather than observed to experience the event. The registry defines the event and censoring rule, and reports medians with 95% confidence intervals for each group.

What does a time-to-event analysis compare?

General explanation: A time-to-event analysis uses the timing of events across follow-up, rather than reducing every participant’s outcome to a simple event/no-event count. It can use information from participants whose event is not observed by the end of their available follow-up, provided the censoring assumptions are appropriate. In this study, a participant was censored at the last non-missing viral-load assessment if the data were missing or the participant did not reach BQL during the trial. The registry does not report further details about the amount or pattern of missing data.

The logrank test compares the event-time experience of groups across the follow-up period. It is not a direct test of the difference between the reported medians. The endpoint definition also requires confirmation by the next measured value below the assay limit, so a single below-limit measurement does not alone count as an event. These details define what is being compared and affect how the event times are determined.

How should the median and interval be read?

General explanation: A median time is a summary of the estimated distribution of event times. It is not the average time, and it does not mean that every participant experienced the event at that time. A confidence interval expresses uncertainty around an estimate under the statistical method used. It is not a range that contains every participant’s event time. The registry reports 95% confidence intervals for the group medians, but the specific method used to calculate those intervals is not reported in the registry record.

The group sizes for the primary endpoint are reported as 42 for placebo, 45 for ALX-0171 3.0 mg/kg, 43 for ALX-0171 6.0 mg/kg, and 45 for ALX-0171 9.0mg/kg. Group sizes and precision are not interchangeable: a group estimate can remain uncertain even when its sample is similar in size to another group, particularly when event timing and censoring differ. The posted confidence intervals communicate the estimated precision more directly than the group counts alone.

Why were comparisons tested in a sequence?

General explanation: When several treatment comparisons are tested, the probability of at least one false-positive finding can rise if each test is considered independently at the same significance level. A sequential testing strategy can control this family-wise error rate by specifying an order for the tests and evaluating them according to that order. The registry states that the primary comparisons were performed sequentially to preserve the family-wise error rate at 0.05, beginning with ALX-0171 9 mg/kg versus placebo, followed by 6mg/kg and then 3mg/kg versus placebo.

The registry reports p-values for all three primary comparisons, but does not report further details about the sequential procedure, such as the exact decision rule beyond the stated order and error-rate objective. The p-values should be understood in the context of this stated procedure, not as three unrelated tests selected after observing the results.

What do the secondary analyses add?

The registry lists secondary outcomes involving global severity score, clinical response timing, time to BQL by RT-qPCR, time to undetectable viral load by plaque assay, and viral-load changes and time-weighted averages using plaque assay or RT-qPCR. A secondary global severity score outcome is summarized using least-squares means and standard errors, with mixed models analyses reported for some comparisons. General explanation: Mixed models can account for a structure in repeated or otherwise related measurements, depending on the model specification. The registry does not report the full model specification, covariance structure, or all analysis details, so those features cannot be assessed from the record.

Some displayed secondary comparison calculations are explicitly recalculated as simple unadjusted comparisons from posted summary statistics. Such calculations are not the sponsor’s full model and do not reproduce any adjustment or model structure not captured by those summaries. The planning illustrations use the observed effect as a basis for hypothetical future sample-size calculations; they are not observed power, evidence that a future study would achieve its planned effect, or a description of the original trial’s design justification. The registry does not report the original sample-size justification.

10. Analyses Reported by the Sponsor

The registry reports sponsor analyses for the secondary global severity score outcome using mixed models. For ALX-0171 6.0 mg/kg versus placebo, the reported difference in least-squares means is -0.490, with p =0.404. The simple recalculation from posted summary statistics gives a mean difference of -0.490 and an unadjusted p-value of 0.403. The point estimates match as reported, while the p-values differ slightly. The recalculation does not reproduce the sponsor’s full mixed-model analysis.

For ALX-0171 9.0mg/kg versus placebo, the sponsor analysis reports a net mean difference of -0.645 and p =0.271. A corresponding recalculated comparison is not reported. The recalculation includes a comparison for ALX-0171 3.0 mg/kg, but a sponsor analysis for that comparison is not reported in the registry results. Those gaps should not be filled by assuming that an unreported sponsor result agrees or disagrees with the recalculation.

The recalculated values are unadjusted approximations based on the posted summary statistics; they are not replacements for the sponsor’s model-based analysis. For interpretation of the trial’s own analysis, the sponsor’s reported method and result take precedence. The registry does not report enough model detail to independently reproduce the mixed-model results.

11. Multiplicity, Missing Data and Analysis Populations

The primary analysis addressed multiple dose-versus-placebo comparisons using a stated sequential order: 9 mg/kg, then 6mg/kg, then 3mg/kg. The registry says this sequence was used to preserve the family-wise error rate at 0.05. That stated control applies to the primary comparisons as described. The exact operational details of the procedure are not reported in the registry record.

The record lists numerous secondary outcomes and reports some secondary analyses, but does not report whether multiplicity was controlled across those outcomes or comparisons. Without that information, secondary p-values should be interpreted cautiously, particularly if they are unadjusted. The registry also does not report a full statistical analysis plan, interim analyses, or a sample-size justification. Those elements should not be inferred from the fact that the study was randomized or that it had a stated enrollment.

For the primary endpoint, participants with missing data and participants who did not reach BQL during the trial were censored at their last non-missing viral-load assessment. The registry does not report the amount of missing endpoint data, reasons for missingness, sensitivity analyses, or whether censoring differed across groups. Those details matter because time-to-event methods rely on assumptions about censoring; the posted definition alone does not establish whether those assumptions were appropriate in practice.

The primary analysis population was modified intent-to-treat: randomized subjects who received at least 1 study drug administration, analyzed according to randomized group. This differs from an analysis of every randomized participant regardless of whether treatment was received. The record does not report the number excluded from this population or a detailed account of exclusions. The population definition should therefore be kept in view when considering how broadly the results apply to all randomized participants.

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: pneumonia bacterial (2.5%), bronchiolitis (2.5%), bronchitis (2.5%), influenza (2.5%), pneumonia viral (2.5%).

The registry reports serious adverse events among participants at risk: 5 in the placebo group, 4 in the ALX-0171 3.0 mg/kg group, 3 in the ALX-0171 6.0 mg/kg group, and 3 in the ALX-0171 9.0mg/kg group. The corresponding numbers at risk are 40, 45, 44, and 46. Deaths are reported as 0 in each group. These are descriptive counts; they do not by themselves establish whether an event was caused by study treatment.

The registry also reports other adverse events among participants at risk: 17 for placebo, 16 for ALX-0171 3.0 mg/kg, 16 for ALX-0171 6.0 mg/kg, and 10 for ALX-0171 9.0mg/kg. The record lists serious-event terms including bacterial pneumonia, bronchiolitis, bronchitis, influenza, viral pneumonia, and respiratory failure, with reported percentages of 2.5% for the first five listed terms and 2.3% for respiratory failure. The posted summaries do not identify these percentages by treatment group, so they should not be assigned to a particular arm.

Safety counts are not a substitute for a comparative safety analysis. The registry record does not report event-level timing, severity grading beyond serious status, relatedness assessments, exposure-adjusted rates, or statistical comparisons for these figures. Small descriptive counts and the reported absence of deaths do not establish that an intervention is safe or unsafe.

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

The primary result describes a difference in the reported time-to-BQL summaries between the ALX-0171 dose groups and placebo. The medians are lower in the active-treatment groups than in the placebo group, and the registry reports logrank p-values for each comparison under the stated sequential testing procedure. These findings concern a defined virologic event measured in nasal swab specimens during the study period.

They do not show that every participant reached BQL, nor do they state how each participant’s viral load changed over time. Censoring was used for participants with missing data or without an observed BQL event during the trial. The confidence intervals convey uncertainty about the median estimates, but do not describe the full range of participant outcomes or eliminate uncertainty about how the endpoint would behave in other populations or settings.

The primary endpoint is not itself a measure of symptom improvement, duration of hospitalization, or another patient-important clinical outcome. The registry lists secondary clinical outcomes, but the primary virologic result should not be translated directly into a clinical effect. Nor does a statistically significant comparison establish the clinical importance of the observed difference. The registry record does not report a threshold for a clinically meaningful change in this endpoint.

The trial findings apply to the studied population, treatment regimens, measurement approach, and analysis population as described in the record. The modified intent-to-treat definition includes randomized participants who received at least 1 administration. Generalization beyond this group, or to other treatment schedules or populations, is not established by these results. The data describe what was observed and analyzed in this study; they do not constitute medical advice or a recommendation about treatment.

14. Why This Trial Matters Statistically

This trial illustrates why the statistical method should match the endpoint. The primary outcome is time until a qualifying assay result, not a single measurement at a fixed visit. Logrank methods and censoring are therefore central to understanding what the primary comparison means. Reading only the group medians would omit the role of participants whose event was not observed during follow-up.

The dose-ranging structure also creates multiple primary comparisons against a shared placebo group. The registry’s prespecified order and stated family-wise error objective are important context for interpreting the reported p-values. Without a plan for multiplicity, repeated comparisons can make apparently strong evidence easier to obtain by chance. The record describes such a procedure for the primary endpoint, while leaving multiplicity handling for secondary outcomes unreported.

The study also demonstrates the distinction between a virologic endpoint and a clinical endpoint. An assay-based measure can address antiviral activity, but statistical evidence on that measure does not automatically establish an effect on symptoms or other clinical outcomes. Similarly, multiple secondary measures can provide useful context but need cautious interpretation when their analysis plans and multiplicity handling are not fully reported.

Finally, the secondary global severity score offers an example of why summary-statistic recalculations and sponsor model results may not be identical in their inferential details. A simple unadjusted calculation is useful as a check on posted summaries, but it is not a reproduction of a mixed model. Keeping the distinction between the sponsor’s analysis and a summary-based recalculation prevents a convenient approximation from being mistaken for the trial’s full analysis.

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.

The registry record does not report the full statistical analysis plan, including the exact details of the sequential primary testing procedure beyond its order and family-wise error objective. It also does not report the original sample-size justification, interim analyses, or a complete account of multiplicity handling for secondary outcomes. As a result, the prespecification and confirmatory status of the secondary analyses cannot be fully assessed from the registry record.

The primary endpoint depends on plaque-assay measurements and a confirmation rule requiring the next value to remain below the quantification limit. The record does not report assay performance details, measurement schedules, the amount of missing data, or sensitivity analyses for the censoring approach. Those omissions limit assessment of how measurement and missingness may have influenced the time-to-event estimates.

Some secondary analyses are reported using mixed models, but the model specifications and assumptions are not reported in the registry record. Summary-based recalculations are therefore not exact replications of those models. The record also does not report sponsor-model results for every comparison described in the recalculations, limiting direct comparison between methods.

The safety summaries are descriptive. The record does not report detailed event-level characteristics, treatment relatedness, or comparative safety analyses in the registry record used. The registry enrollment and the arm-specific analysis counts refer to different reporting contexts, and the record does not explain any differences between them. Eligibility details, masking roles, allocation procedures, and the extent of follow-up by participant are also not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Dose Ranging Study of ALX-0171 in Infants Hospitalized for Respiratory Syncytial Virus Lower Respiratory Tract Infection — NCT02979431.
• Registry record last updated 2019-10-18; status last verified 2019-09.
• Results first posted 2019-10-18.
• 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

NCT02979431 is a completed phase 2 randomized, quadruple-masked, parallel-group, placebo-controlled dose-ranging study in infants and young children hospitalized with RSV lower respiratory tract infection. The registry lists enrollment of 180 and compares inhaled ALX-0171 at 3.0 mg/kg, 6.0 mg/kg, or 9.0 mg/kg with placebo. Each regimen was administered once daily for 3 consecutive days.

The primary endpoint was time from first administration to a confirmed plaque-assay viral-load result below the quantification limit. The registry reports medians and 95% confidence intervals and logrank comparisons conducted sequentially to preserve the family-wise error rate at 0.05. The posted medians were lower in each ALX-0171 group than in placebo, with reported p-values for all three primary comparisons.

The record also lists clinical and virologic secondary outcomes and descriptive adverse-event counts. Details of the complete statistical plan, secondary multiplicity handling, missing-data sensitivity analyses, and original sample-size justification are not reported in the registry record.