This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Effect of Gefapixant (MK-7264/AF-219) on Cough Reflex Sensitivity in Healthy and Chronic Cough Participants (MK-7264-014) (NCT02476890), a randomized phase 2 study. The primary outcome is Cough Reflex Sensitivity to Capsaicin in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02476890 |
| Phase | Phase 2 |
| Condition | Refractory Chronic Cough |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Triple |
| Enrollment | 36 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) |
| Results posted | Yes |
2. Clinical Question
Population
The study included healthy participants and participants with chronic cough. The registry record identifies refractory chronic cough as a condition studied. The analyzed population for the primary endpoint was treated participants with at least one post-dose assessment of cough reflex sensitivity during capsaicin challenge. Participant eligibility details and the numbers analyzed for the primary endpoint are not reported in the registry record.
Intervention
The intervention was a single dose of gefapixant 100 mg. Participants received the medicine in one treatment period of a crossover sequence. The primary objective was to assess its effect on cough reflex sensitivity after challenges using capsaicin, citric acid, adenosine triphosphate (ATP), and distilled water. The primary endpoint described in the record focuses on capsaicin.
Comparator
The comparator was a single dose of placebo. Participants received gefapixant and placebo in different orders: placebo followed by gefapixant, or gefapixant followed by placebo. A minimum 48-hour washout separated the two treatment periods. The registry record does not report further details about the washout rationale or how period and sequence effects were handled in the analysis.
Primary question
The primary question was whether cough reflex sensitivity to capsaicin differed between gefapixant 100 mg and placebo, using the average of assessments at 1, 3, and 5 hours after dosing. Sensitivity was assessed by the capsaicin concentration associated with at least 2 coughs (C2) and at least 5 coughs (C5). The primary outcome results are not reported in the registry record, so the size and precision of any treatment contrast cannot be described.
3. Trial Design
This was a phase 2, randomized, triple-masked crossover study. The registry record lists an enrollment of 36 and describes two participant groups: healthy participants and participants with chronic cough. In a crossover design, participants receive more than one treatment in separate periods; in this study, the listed sequences were placebo followed by gefapixant 100 mg, or gefapixant 100 mg followed by placebo. A minimum 48-hour washout separated Period 1 and Period 2.
The crossover structure makes the treatment comparison different from a parallel-group trial. Each participant can contribute observations under both gefapixant and placebo, so the contrast may use within-participant information as well as information about variation between participants. The registry record does not state the exact model terms used to account for participant, period, sequence, or potential carryover effects. It records a mixed effects model for the primary endpoint, but further model specification is not reported in the registry record.
The study evaluated a single dose rather than a course of repeated treatment. Its primary objective concerned cough reflex sensitivity after challenge testing with capsaicin, citric acid, ATP, and distilled water. The specified primary endpoint was capsaicin sensitivity; the record also lists secondary outcomes involving cough severity, urge to cough, cough frequency, and adverse events. Secondary cough symptom outcomes were limited to chronic cough participants.
The registry lists a study start date of 2015-10-28, primary completion on 2016-10-20, and status as completed. The sponsor is Afferent Pharmaceuticals, Inc., a subsidiary of Merck & Co., Inc. The specific identities of the masked parties, the allocation method, eligibility criteria, and the reasoning behind the sample size are not reported in the registry record. The total enrollment alone does not show how many participants completed both periods or contributed data to each endpoint.
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 6-day Screening period (Day -6 to Day -1) ensured that each participant met all the specified eligibility criteria. In addition, cough reflex sensitivity was measured at Screening by standard clinical methodology using cough challenge in response to four agents (capsaicin, citric acid, adenosine triphosphate (ATP), and distilled water).
Overall Study
| Stage | Placebo Then Gefapixant 100 mg/Healthy (Sequence A) | Gefapixant 100 mg Then Placebo/Healthy (Sequence B) | Placebo Then Gefapixant 100 mg/Chronic Cough (Sequence A) | Gefapixant 100 mg Then Placebo/Chronic Cough (Sequence B) |
|---|---|---|---|---|
| STARTED | 6 | 6 | 12 | 12 |
| Washout | 6 | 6 | 12 | 12 |
| COMPLETED | 6 | 6 | 12 | 12 |
| NOT COMPLETED | 0 | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: The analyzed population was all treated participants who had at least 1 post-dose primary endpoint assessment of cough reflex sensitivity in response to capsaicin challenge.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | Placebo Then Gefapixant 100 mg/Healthy (Sequence A) | Gefapixant 100 mg Then Placebo/Healthy (Sequence B) | Placebo Then Gefapixant 100 mg/Chronic Cough (Sequence A) | Gefapixant 100 mg Then Placebo/Chronic Cough (Sequence B) | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 6 | 6 | 12 | 12 | 36 | |
| Age, Continuous | years | 40.0 (SD 10.79) | 35.7 (SD 6.09) | 61.6 (SD 9.15) | 60.6 (SD 8.58) | 53.3 (SD 14.0) |
| Sex: Female, Male: Female | Participants | 6 | 5 | 11 | 10 | 32 |
| Sex: Female, Male: Male | Participants | 0 | 1 | 1 | 2 | 4 |
6. Primary Endpoint
The registry lists the primary outcome as Cough Reflex Sensitivity to Capsaicin in Participants Who Received Gefapixant 100 mg and Placebo (Period 1 & Period 2 Combined), measured over Average of 1, 3, and 5 hours post-dose.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | natural log (µM) |
| Endpoint classification | Continuous Endpoint |
The primary endpoint measured cough reflex sensitivity to capsaicin. C2 was the concentration associated with at least 2 coughs, and C5 was the concentration associated with at least 5 coughs. The challenge used inhaled capsaicin diluted with saline. Concentrations used in the challenge ranged from 0.3 micromoles (µM) to 1000 µM. The endpoint was expressed on the natural log scale, and the registry describes least-squares means and 95% confidence intervals.
Assessments were made at 1, 3, and 5 hours after dosing, with the primary measure defined as the average across those time points. Cough reflex sensitivity is a response to a controlled cough challenge, rather than a direct measure of everyday cough frequency or how a participant feels over a longer period. The registry also lists secondary measures of cough severity, urge to cough, and cough frequency after challenge testing in chronic cough participants, but these are separate outcomes.
In general, a challenge endpoint can offer a standardized way to measure the sensitivity of a reflex under specified test conditions. It can be useful for characterizing a short-term physiological response. It does not, by itself, establish how a treatment affects symptoms outside the testing setting. The primary endpoint results are not reported in the registry record, so neither the observed treatment contrast nor its precision can be assessed from the record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry describes a clear intended comparison: cough reflex sensitivity after a single dose of gefapixant 100 mg versus placebo, averaged across assessments at 1, 3, and 5 hours after dosing. C2 and C5 represent two thresholds within the capsaicin challenge: the concentration associated with at least 2 coughs and the concentration associated with at least 5 coughs. Results were planned for expression as least-squares means on a natural log scale, with 95% confidence intervals.
However, the primary outcome results are not reported in the registry record. There are no posted treatment estimates, confidence intervals, p-values, or participant counts for the primary endpoint in the record used for this description. Consequently, the direction, magnitude, and precision of the gefapixant-placebo comparison cannot be characterized. The record does not support a conclusion about whether the observed cough reflex sensitivity differed between treatments.
The registry identifies multiple challenge agents in the study objective, but the detailed primary outcome description concerns capsaicin. It also lists secondary outcomes for cough severity, urge to cough, cough frequency, and adverse events. The secondary symptom measures are specified for chronic cough participants. Their numerical results are not reported in the registry record used here, so they cannot be used to fill the gap in the primary endpoint evidence.
The crossover design means that participants received both treatments in separate periods, with a minimum 48-hour washout. This design can make paired comparisons informative because each participant serves as a comparator to themselves. It also makes the interpretation dependent on the analysis accounting appropriately for the repeated observations and treatment periods. The registry describes a mixed effects model, but does not report enough detail to determine which period, sequence, or carryover terms were included.
Safety information is available by group. The registry lists zero serious adverse events among those at risk in each of the four healthy and chronic cough treatment groups. It also reports counts for participants with other adverse events, which varied across the listed treatment groups. Those counts are descriptive; the record does not provide a comparative safety analysis or enough detail to infer why the counts differ. No deaths are listed in the groups.
Any planning illustration based on an observed effect should be distinguished from the original study design and from evidence of efficacy. A sample-size illustration is a calculation about planning under stated assumptions, not observed power and not a substitute for treatment estimates with uncertainty. The registry record does not report the original sample-size justification. Without the primary endpoint results, there is no observed effect available in this account for readers to interpret directly.
9. Statistical Methods Explained
The primary endpoint analysis used a mixed effects model on natural log-transformed concentrations. The model was intended to estimate average C2 or C5 across the three post-dose assessment times for each treatment group and compare treatment with placebo. The registry describes the resulting measure as a least-squares mean. It does not give the full model specification, the covariance structure, the degrees-of-freedom method, or the exact terms included for treatment period and sequence.
In general, a mixed effects model is useful when measurements are clustered or repeated, because observations from the same participant are usually related rather than independent. A crossover study produces repeated measurements under different treatments within participants. Accounting for this dependence can make the treatment comparison more appropriate than treating every measurement as unrelated. The registry states that a mixed effects model was used, but further choices made in fitting it are not reported in the registry record.
The use of a natural log scale changes how concentration values are represented for analysis. In general, logarithmic transformation can help describe skewed measurements and can make relative patterns easier to model. A least-squares mean is a model-based estimate, rather than simply the arithmetic average of all raw observations. It depends on the fitted model and its assumptions. The record does not provide the estimated least-squares means or treatment contrasts, so their values and implications cannot be discussed.
The registry reports 95% confidence intervals as the dispersion measure. In general, a confidence interval expresses uncertainty around an estimated quantity under the statistical model and its assumptions. Its width reflects both the amount of information available and the variability in the data. It does not show the range of individual participant responses, and it is not a guarantee that the true value lies within that particular interval. No interval limits for the primary endpoint are reported in the registry record.
The challenge concentrations were specified across a range from 0.3 µM to 1000 µM. The endpoint description states that if a concentration value was missing, it was imputed as 1.5 times the maximum concentration, described in the record as 150%. This is a specific handling rule for missing concentration values. The record does not explain how many values were missing, whether missingness differed by treatment or participant group, or what sensitivity analyses were conducted to examine the effect of the imputation.
In general, imputation substitutes an analysis value for a missing observation, and the chosen rule can influence estimates when missingness is substantial or related to the outcome. The rule assigns a value above the maximum concentration for a missing concentration, rather than omitting the observation. This reflects a convention for representing a response beyond the tested range, but it also makes the result dependent on that convention. The registry does not report an alternative analysis or a comparison with other missing-data approaches.
The study's crossover structure also raises familiar design considerations. In general, treatment order, period effects, and carryover can matter when a participant receives treatments sequentially. Randomizing treatment sequence can reduce systematic differences between sequence groups, while a washout is intended to separate treatment periods. The registry records randomized allocation and a minimum 48-hour washout. It does not report a test for carryover, a rationale for the washout duration, or whether the analysis included a period effect. These details should not be inferred from the design label alone.
The primary analysis population was all treated participants who had at least one post-dose primary endpoint assessment of cough reflex sensitivity in response to capsaicin challenge. This is an endpoint-specific analyzed population, not necessarily all enrolled participants. The registry does not report its size, the number excluded from the analysis, or the number with complete observations at every time point. In general, defining an analysis population helps identify which participants contribute to an estimate, but a population definition alone does not reveal how much data were available or how exclusions may affect interpretation.
The record also names a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such calculations are planning illustrations, not observed power. In general, a sample-size calculation depends on assumptions about the effect to detect, outcome variability, allocation, and the chosen statistical framework. It cannot establish that a study was adequately powered after results are known, and it is not evidence that a treatment effect exists. The illustration values and the trial's original sample-size justification are not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The primary outcome description includes both C2 and C5 and uses assessments at 1, 3, and 5 hours after dosing. The registry record also describes multiple challenge agents in the study objective and lists several secondary outcomes. These multiple outcomes and assessment dimensions create the possibility of multiple statistical comparisons. The record does not report a multiplicity adjustment, a hierarchy among the outcomes, or a prespecified strategy for controlling the overall chance of a false-positive finding. The treatment of multiplicity is therefore not reported in the registry record.
Missing concentrations were handled by imputing the value as 1.5 times the maximum concentration, which the record labels as 150%. This provides a stated rule for that particular missing endpoint value. It does not describe all missing-data handling across all outcomes. The number of missing primary endpoint values, reasons for missingness, and any sensitivity analyses are not reported in the registry record. Those details matter because conclusions can depend on how missing values are distributed and handled.
The primary analysis population consisted of treated participants with at least one post-dose capsaicin assessment. The registry does not state how many participants met this definition, how many were enrolled in each group for efficacy analyses, or how many completed both treatment periods. The safety groups list participants at risk, but those safety denominators should not automatically be treated as the primary endpoint analysis counts.
The registry specifies a mixed effects model but does not give its full model structure. It does not report whether other analysis populations, such as a population requiring data from both periods, were used. An interim analysis plan, protocol deviations, and the rationale for sample size are not reported in the registry record. The absence of those details limits assessment of how the stated endpoint was translated into the final statistical analysis.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Gefapixant 100 mg/Healthy | 0 | 12 | 0.0% |
| Placebo/Healthy | 0 | 12 | 0.0% |
| Gefapixant 100 mg/Chronic Cough | 0 | 24 | 0.0% |
| Placebo/Chronic Cough | 0 | 24 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Gefapixant 100 mg/Healthy | 0 of 12 |
| Placebo/Healthy | 0 of 12 |
| Gefapixant 100 mg/Chronic Cough | 0 of 24 |
| Placebo/Chronic Cough | 0 of 24 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Gefapixant 100 mg/Healthy | 12 of 12 |
| Placebo/Healthy | 6 of 12 |
| Gefapixant 100 mg/Chronic Cough | 21 of 24 |
| Placebo/Chronic Cough | 7 of 24 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Gefapixant 100 mg/Healthy | Placebo/Healthy | Gefapixant 100 mg/Chronic Cough | Placebo/Chronic Cough |
|---|---|---|---|---|---|
| Dysgeusia | Nervous system disorders | 9 of 12 | 1 of 12 | 16 of 24 | 0 of 24 |
| Ageusia | Nervous system disorders | 6 of 12 | 1 of 12 | 7 of 24 | 0 of 24 |
| Dry mouth | Gastrointestinal disorders | 4 of 12 | 0 of 12 | 6 of 24 | 1 of 24 |
| Headache | Nervous system disorders | 0 of 12 | 3 of 12 | 6 of 24 | 2 of 24 |
| Paraesthesia oral | Gastrointestinal disorders | 1 of 12 | 1 of 12 | 4 of 24 | 2 of 24 |
| Hypoaesthesia oral | Gastrointestinal disorders | 3 of 12 | 0 of 12 | 4 of 24 | 0 of 24 |
| Nausea | Gastrointestinal disorders | 0 of 12 | 0 of 12 | 2 of 24 | 1 of 24 |
| Oral disorder | Gastrointestinal disorders | 2 of 12 | 0 of 12 | 1 of 24 | 0 of 24 |
| Dizziness | Nervous system disorders | 0 of 12 | 0 of 12 | 2 of 24 | 1 of 24 |
| Dyspepsia | Gastrointestinal disorders | 1 of 12 | 0 of 12 | 0 of 24 | 1 of 24 |
The serious adverse event figures are reported separately for healthy and chronic cough participants receiving gefapixant 100 mg or placebo. In the healthy gefapixant group, 12 participants were at risk and 0 had a serious adverse event; in the healthy placebo group, 12 were at risk and 0 had a serious adverse event. In the chronic cough gefapixant group, 24 participants were at risk and 0 had a serious adverse event; in the chronic cough placebo group, 24 were at risk and 0 had a serious adverse event. The registry lists 0 deaths in each group.
These figures describe what was recorded in the listed groups. Zero serious adverse events in these groups does not establish that the risk is absent, particularly because the group sizes are limited. The registry does not report a comparative statistical analysis of serious adverse events, nor does it provide further details about the event definitions or observation time for each group.
The record separately lists participants affected by other adverse events: 12 in healthy participants receiving gefapixant, 6 in healthy participants receiving placebo, 21 in chronic cough participants receiving gefapixant, and 7 in chronic cough participants receiving placebo. These are counts, not a statistical comparison. The registry record does not give event-level detail in this safety summary, so the nature, timing, and severity of these other events cannot be characterized from these counts alone.
12. What the Result Does, and Does Not, Mean
The study was designed to examine short-term cough reflex sensitivity after a single dose of gefapixant 100 mg compared with placebo. Its primary measure focused on capsaicin challenge thresholds for C2 and C5, averaged over assessments at 1, 3, and 5 hours after dosing. The crossover design involved both treatments in separate periods, with a minimum 48-hour washout.
The registry record does not report the primary endpoint results. It therefore does not show the estimated treatment contrast, its direction, or its precision. It also does not report the numerical results for the listed secondary symptom outcomes. The study design and outcome definitions explain what the investigators intended to measure, but they are not a substitute for the actual estimates and uncertainty needed to interpret the findings.
Even with numerical results, a change in capsaicin challenge sensitivity would describe a response to a controlled inhaled stimulus under the study conditions. In general, that type of endpoint is not identical to cough burden in daily life, longer-term symptom experience, or outcomes beyond the measured time points. The registry lists secondary measures of cough severity, urge to cough, and cough frequency in chronic cough participants, but their results are not reported.
The safety record reports no serious adverse events and no deaths in the four listed groups, alongside counts for other adverse events. These data are descriptive and do not establish comparative safety. The record does not report a statistical comparison of adverse events or detailed event descriptions in the safety summary.
Accordingly, the registry information supports a description of the question, design, endpoint, and safety counts, but not a conclusion about the treatment effect on cough reflex sensitivity. The missing outcome estimates and analysis details leave both the magnitude of any effect and the uncertainty around it unresolved.
13. Why This Trial Matters Statistically
This trial is statistically notable for combining a crossover design with a laboratory cough challenge endpoint. Because each participant received gefapixant and placebo in separate periods, the study was structured to obtain within-participant comparisons. In general, paired information can reduce the influence of stable differences between people, although the validity of the comparison still depends on appropriate handling of repeated measures and treatment order.
The endpoint also illustrates how a clinical question can be operationalized using thresholds. C2 and C5 define sensitivity by the capsaicin concentration associated with specified cough responses. Measuring these thresholds at multiple post-dose times and then averaging across them creates a clearly defined short-term response measure. The registry describes a natural log scale and a mixed effects model, which are relevant choices for analyzing repeated concentration measurements.
At the same time, the record makes clear why design and methods alone are not enough to assess a result. The primary endpoint estimates and confidence intervals are not reported, and the full model specification and multiplicity strategy are not reported. Without the estimates, a reader cannot assess the magnitude or precision of the comparison; without the additional analysis details, a reader cannot fully evaluate how the model and missing-data rule shaped it.
The study also separates physiological challenge outcomes from symptom measures. Its primary outcome concerns capsaicin sensitivity, while the secondary outcomes include cough severity, urge to cough, and cough frequency for chronic cough participants. Those outcomes address related but distinct aspects of cough. Their numerical results are not reported in the registry record, so the relationship between challenge response and symptom measures cannot be evaluated.
Finally, the record illustrates the distinction between outcome evidence and safety counts. The serious adverse event counts are zero in each listed group, while other adverse event counts are also recorded. These descriptive counts can summarize what was reported but, without detailed event information or comparative analyses, they cannot support strong comparative conclusions. The registry's statistical value is therefore primarily in documenting the design and planned measurement framework, rather than enabling a full evaluation of treatment effects.
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 main limitation for interpreting efficacy is that the primary endpoint results are not reported in the registry record. There are no treatment estimates or confidence intervals to assess for C2 or C5. The numerical results for secondary outcomes are also not reported in the record used for this description. As a result, the direction, size, and precision of the outcome comparisons remain unknown.
The primary endpoint description includes two cough thresholds and multiple post-dose assessments, while the study objective names several challenge agents. The registry does not report how multiplicity across these outcomes was addressed. It also does not provide a full analysis plan or the model's complete specification. Period, sequence, and carryover handling are not described, despite the crossover design.
The record gives a specific imputation rule for missing concentration values but does not report how many values were missing, why they were missing, or whether sensitivity analyses were conducted. It also does not report the number included in the primary endpoint analysis or the number with observations in both periods. Enrollment and safety denominators do not resolve those efficacy analysis details.
The primary measure captures capsaicin-evoked cough reflex sensitivity over a short post-dose interval. It is not itself a measure of longer-term symptom outcomes. Although the registry lists cough severity, urge to cough, and cough frequency as secondary outcomes for chronic cough participants, their results are not reported. The record also does not report the original sample-size justification, eligibility details, or further information about the consequences of deviations from the planned treatment sequences.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Effect of Gefapixant (MK-7264/AF-219) on Cough Reflex Sensitivity in Healthy and Chronic Cough Participants (MK-7264-014) — NCT02476890.
- Registry record last updated 2019-06-18; status last verified 2019-06.
- Results first posted 2018-02-15.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
The registry record describes a completed phase 2 randomized, triple-masked crossover study of gefapixant 100 mg and placebo in healthy and chronic cough participants. Enrollment was 36. Participants received the two treatments in opposite orders across two periods, with a minimum 48-hour washout. The primary endpoint was capsaicin cough reflex sensitivity, measured using C2 and C5 at 1, 3, and 5 hours after dosing and analyzed on a natural log scale with a mixed effects model.
The primary endpoint results, full model specification, multiplicity approach, and original sample-size justification are not reported in the registry record. Safety counts show no serious adverse events or deaths in the listed groups. Counts for other adverse events are also reported by group. These records describe the study's design and available safety information, but do not establish the size or precision of a treatment effect on the primary endpoint.