Efficacy and Safety of Intranasal MSP-2017 (Etripamil) for the Conversion of PSVT to Sinus Rhythm: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Intranasal MSP-2017 (Etripamil) for the Conversion of PSVT to Sinus Rhythm (NCT02296190), a randomized phase 2 study. The primary outcome is The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration.

2. Clinical Question

3. Trial Design

This was a Phase 2, randomized, double-blind, parallel-group study with placebo control. Its official title describes a multicenter, dose-ranging electrophysiological study of intranasal MSP-2017 for conversion of induced PSVT to sinus rhythm. The intervention is also named etripamil in the registry. The trial status is completed; the registry lists a start date of 2015-03-27 and primary completion in 2016-12. Enrollment is recorded as 199.

Participants were assigned to one of four single-dose etripamil groups—140 mg, 105 mg, 70 mg, or 35 mg—or to placebo. Each assigned dose was delivered through 4 intranasal applications at time 0. The endpoint data list 21 participants for 140 mg, 20 for 105 mg, 23 for 70 mg, 20 for 35 mg, and 20 for placebo. These are the denominators posted for the efficacy outcome, not a reconciliation of all enrolled participants.

The registry describes the efficacy analysis population as randomized participants who had induced and sustained supraventricular tachycardia for 5 minutes, received study drug, and completed conversion assessment. Thus, the outcome denominators reflect an evaluable population defined by these conditions. Details about the number of randomized participants excluded from this endpoint population, and the reasons for any exclusions, are not reported in the registry record.

The stated objective was to demonstrate superiority of at least 1 intranasal etripamil dose over placebo for terminating PSVT induced in an electrophysiology laboratory. The original sample-size justification, allocation ratio details beyond the posted group counts, and other protocol-level design assumptions are not reported in the registry record. The registry identifies one primary outcome measure and one reported analysis.

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: The efficacy analysis was based on the Evaluable Population which included all randomized subjects who were induced and sustained Supraventricular tachycardia (SVT) for 5 minutes, received the study drug, and completed the assessment of conversion to sinus rhythm. The "Open- Label Etripamil 70 mg" group was not part of the Evaluable Population, as the subjects did not meet the criteria of having sustained Supraventricular tachycardia (SVT) for 5 minutes.

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: Full analysis set (all randomized participants who received at least 1 dose of study drug)

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as The Percentage of Subjects Successfully Converted From PSVT to Sinus Rhythm Within 15 Minutes of Study Drug Administration, measured over Within 15 minutes of study drug administration.

The primary endpoint is the percentage of participants who successfully converted from PSVT to sinus rhythm within 15 minutes after study drug administration. The description defines success as sinus rhythm lasting at least 30 seconds, after participants had been in sustained PSVT for a minimum of 5 minutes. The posted outcome is expressed as counts of participants with conversion, alongside the assessed group denominators.

This kind of binary endpoint records whether each assessed participant met the specified success criterion within a defined time window. It provides a direct way to compare the frequency of conversion across randomized dose groups and placebo. The short window and minimum duration of sinus rhythm make the event definition more specific than simply recording any brief change in rhythm.

As a general statistical point, a binary endpoint can be clinically interpretable while still leaving important questions unanswered. It does not describe the time to conversion within the 15-minute window, the duration of sinus rhythm beyond the required minimum, subsequent recurrence, or outcomes beyond the electrophysiology-laboratory assessment. Those outcomes are not reported in the registry record. The endpoint therefore addresses the stated immediate conversion question, not every aspect of PSVT treatment or longer-term response.

7. Results Posted in the Registry

• Etripamil_140 mg: 95.2% (20/21) versus 35.0% (7/20) on control; risk difference 60.2 percentage points (95% CI 37.4 to 83.0), risk ratio 2.72 (1.49–4.98); unadjusted two-proportion z-test p = <0.001.
• Etripamil_ 105 mg: 75.0% (15/20) versus 35.0% (7/20) on control; risk difference 40.0 percentage points (95% CI 11.8 to 68.2), risk ratio 2.14 (1.12–4.10); unadjusted two-proportion z-test p = 0.011.
• Etripamil_70 mg: 87.0% (20/23) versus 35.0% (7/20) on control; risk difference 52.0 percentage points (95% CI 26.9 to 77.0), risk ratio 2.48 (1.34–4.61); unadjusted two-proportion z-test p = <0.001.
• Etripamil_35 mg: 65.0% (13/20) versus 35.0% (7/20) on control; risk difference 30.0 percentage points (95% CI 0.4 to 59.6), risk ratio 1.86 (0.94–3.66); unadjusted two-proportion z-test p = 0.058.

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is binary: a participant either met the conversion definition within the specified time window or did not. The posted counts give the number meeting the definition and the denominator assessed in each group. For example, the 140 mg group has 20 conversions among 21 assessed participants, while placebo has 7 among 20. These counts are the basis for the simple recalculations; they do not supply participant-level data or details of the original analysis dataset.

What does a risk difference describe?

A risk difference subtracts the observed event proportion in one group from the event proportion in another. Here, the recalculated comparisons use each etripamil group and placebo. A positive difference means that the observed conversion proportion was higher in the etripamil group in that comparison. The risk difference is an absolute contrast on the event-proportion scale. It does not state how many additional conversions would occur in another population, and its estimate can vary with the study population and setting.

The reported recalculated risk differences are 0.602 for 140 mg, 0.4 for 105 mg, 0.520 for 70 mg, and 0.3 for 35 mg. These are unadjusted recalculations from the posted summary statistics. They are not the sponsor’s own estimates. The registry reports a Fisher Exact test across the five groups, but does not provide the corresponding sponsor effect estimate or confidence interval. Since a discrepancy is flagged, the sponsor’s own analysis takes precedence over these recalculations.

What does a confidence interval communicate?

A confidence interval expresses uncertainty around an estimated effect under the method used to construct it. It gives a range of effect values compatible with the data and assumptions of that method; it is not a guarantee that the true effect lies within the particular interval. Here, the recalculated intervals are comparatively wide, reflecting that the outcome groups contain limited numbers of assessed participants. Their breadth also shows that the precise size of the dose-versus-placebo differences is not established by the point estimates alone.

For example, the 140 mg risk-difference interval runs from 0.374 to 0.830, and the 35 mg interval runs from 0.004 to 0.596. The latter spans from a small positive difference to a much larger one. These intervals describe the simple recalculations, not sponsor-reported intervals. The method used for the registry’s own overall test is identified as Fisher Exact, but a sponsor confidence interval is not reported in the registry record.

Why are there several p-values?

The registry’s sponsor analysis reports one Fisher Exact test covering the five groups, with p < 0.05. The dose-specific p-values printed with the recalculations are unadjusted pairwise results, not the same analysis. When several dose groups are compared with a control, multiple testing can increase the chance of at least one apparently unusual result under a null model. Whether the sponsor used a multiplicity adjustment, and what comparisons were prespecified, are not reported in the registry record. The overall test and the recalculated pairwise results therefore answer different statistical questions.

A p-value is a measure of how incompatible the observed data are with a specified null hypothesis under the test’s assumptions. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. A value such as p = 0.011 does not replace the estimated risk difference or its interval. Likewise, p = 0.058 for the 35 mg recalculation should not be interpreted as proof of no difference; the estimated difference and its uncertainty remain relevant.

What does Fisher Exact testing do?

Fisher Exact is a test for categorical count data. It evaluates whether the pattern of observed counts across the groups is compatible with a null hypothesis of no association between group and outcome, using an exact probability calculation under its stated framework. It is suitable for sparse count settings, but the registry does not report the full test specification, any follow-up comparisons, or adjustments. The posted result is an overall superiority test across five groups, not a separately reported test for each dose.

The recalculated risk differences, relative risks, odds ratios, confidence intervals, and p-values are summary-statistic calculations, not a reanalysis of individual participant records. The recalculation does not recover covariate-adjusted estimates, account for unreported exclusions, or establish the protocol’s intended model. No covariate adjustment is described in the registry record.

Why does the analysis population matter?

The endpoint description defines an evaluable population based on randomization, induction and sustained SVT, receipt of study drug, and completion of conversion assessment. Conditioning the endpoint analysis on these post-randomization criteria can make the analyzed group differ from the full randomized population. The registry does not report a full participant flow or explain how missing or incomplete endpoint assessments were handled. Consequently, the posted endpoint counts should be interpreted as results for the stated evaluable population rather than assumed to represent every randomized participant.

General statistical considerations also include whether the event definition, time window, comparison strategy, and handling of missing data were set before results were known. The registry record does not report enough detail to evaluate those choices fully. The reported analysis and the simple recalculations should be kept distinct: the former is the sponsor’s overall test; the latter are unadjusted comparisons derived from the posted group counts.

10. Confidence Intervals and Precision

The recalculated confidence intervals show uncertainty in the estimated risk differences. For 140 mg, the estimate is 0.602 and the interval is 0.374 to 0.830. For 105 mg, the estimate is 0.4 and the interval is 0.118 to 0.682. For 70 mg, the estimate is 0.520 and the interval is 0.269 to 0.770. For 35 mg, the estimate is 0.3 and the interval is 0.004 to 0.596. These intervals belong to the unadjusted recalculations, not to the sponsor’s reported Fisher Exact analysis.

Each interval covers a range of plausible risk-difference values under the calculation method. Their widths indicate that the exact magnitude of the difference is not estimated with high precision. The interval for 35 mg is especially broad relative to its point estimate, and includes values ranging from a small difference to a considerably larger one. The intervals should be read alongside the underlying counts, which are modest in each group.

Confidence intervals do not address every source of uncertainty. They do not account for questions about the evaluable population, unreported missing-data handling, multiplicity, or differences between the sponsor analysis and the recalculations. The registry record does not report a sponsor confidence interval for the overall test. These recalculated intervals therefore describe statistical uncertainty conditional on the posted counts and the simple unadjusted calculation, rather than resolving the analysis discrepancy or establishing how results would generalize beyond the study setting.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size illustrations give participants per arm for the two-group planning comparisons; they are not total event counts. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to a stated fraction of the observed effect. The 80% power column describes the planned group size under those assumptions for a design intended to have an 80% chance of detecting the specified effect if that effect is true. The 90% column uses the corresponding higher power target. These are planning calculations, not observed power.

Rows for 100% of the observed effect use the full recalculated effect as the planning target; rows for 75% and 50% use progressively smaller target effects. Smaller effects generally require more participants to detect under otherwise fixed assumptions. For 140 mg, planning for 75% of the observed effect gives 18 participants per arm for 80% power and 23 for 90% power. For 105 mg, the corresponding figures are 43 and 57; for 70 mg, 25 and 33; and for 35 mg, 76 and 102. The figures depend on the stated assumptions and are not the trial’s original design requirements.

The original sample-size assumptions and justification are not reported in the registry record. These illustrations are computed from the observed effect, so they should not be interpreted as evidence that the completed trial had a particular probability of finding a result. The curve is a visual rendering of planning behavior across effect assumptions; it does not add a separate observed outcome or alter the underlying assumptions.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.350; treatment proportion p₁ = 0.952; average p̄ = 0.651.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6740 = 1.3210.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5224 = 0.4396.
4. n = (1.3210 + 0.4396)² / (0.6024)² = 8.5, rounded up to 9 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.35                          # control proportion
p1 <- 0.952380952380952                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(2296190)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 9 (80% power), 11 (90% power)
 75% of observed effect: n per arm = 18 (80% power), 23 (90% power)
 50% of observed effect: n per arm = 43 (80% power), 56 (90% power)
power.prop.test: 8.5 
Simulated power at n = 9 per arm: 0.869 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry reports the sponsor’s own analysis as a Fisher Exact superiority test across the 140 mg, 105 mg, 70 mg, 35 mg, and placebo groups, with p < 0.05. It does not report a sponsor effect estimate, confidence interval, or dose-specific p-values for this test. The posted group counts also allow simple recalculations of risk differences and unadjusted pairwise p-values for each dose against placebo.

The recalculations are not a replacement for the sponsor’s analysis. They use the posted summary counts and do not reproduce an individual-level analysis or any unreported adjustment. The registry flags a discrepancy between the sponsor result and the recalculated results. In that circumstance, the sponsor’s own analysis takes precedence, while the recalculations remain useful as transparent descriptive contrasts based on the posted counts. The record does not explain the discrepancy, so its source is not reported in the registry record.

14. Multiplicity, Missing Data and Analysis Populations

The registry reports one primary outcome measure and one sponsor analysis. That analysis is a Fisher Exact superiority test across the five posted groups, with p < 0.05. The study objective refers to superiority of at least 1 dose over placebo, a question involving several dose groups. The registry record does not report whether the sponsor’s analysis included a multiplicity adjustment, whether the overall test was followed by planned dose-versus-placebo tests, or how any such tests were controlled.

The risk differences and p-values for individual doses are simple unadjusted recalculations. They should not be treated as multiplicity-adjusted evidence. Repeated testing across multiple comparisons can increase the chance of a false-positive finding if no adjustment or prespecified testing strategy is used. The registry record does not report a hierarchy, gatekeeping procedure, or other approach for handling this issue. Because the sponsor analysis and recalculated comparisons differ in scope, their p-values should not be read as interchangeable.

The efficacy analysis is described as an evaluable population: randomized participants who had induced and sustained SVT for 5 minutes, received study drug, and completed conversion assessment. The endpoint denominators are listed by group. A complete participant flow, reasons for exclusion from the endpoint analysis, and the number or disposition of missing assessments are not reported in the registry record. The handling of missing outcomes, including any imputation or assumptions about incomplete assessments, is also not reported in the registry record.

The registry does not provide a detailed statistical analysis plan, covariate-adjustment strategy, or account of interim analyses. Whether there were interim analyses is not reported in the registry record. These omissions limit assessment of how the analysis population, missing data, and multiple dose comparisons were handled. The posted results can still be described, but the missing information prevents a full appraisal of prespecification and analysis robustness.

15. 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: bundle branch block right (5.0%), catheter site haematoma (5.0%), syncope (5.0%), cough (5.0%).

The posted serious adverse event counts are listed by group, with the number at risk and the number affected. Serious adverse events were recorded for 0 of 21 participants in the 140 mg group, 3 of 20 in the 105 mg group, 0 of 23 in the 70 mg group, 0 of 20 in the 35 mg group, and 1 of 20 in the placebo group. The open-label etripamil 70 mg group lists 0 of 9. Deaths are listed as 0 in every group.

These are counts, not comparative estimates of risk, and they do not establish whether an event was caused by study drug. The registry lists serious-event terms including Bundle Branch Block Right, Catheter site haematoma, Syncope, and Cough, each recorded as 5.0%. The record does not provide enough detail in these figures to determine the timing, duration, clinical course, or causal attribution for individual events. Safety counts should therefore be read descriptively and separately from the efficacy comparison.

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

The posted efficacy counts show that conversion within the defined 15-minute endpoint window was recorded more often in each etripamil dose group than in the placebo group. The simple recalculations quantify the observed differences and their uncertainty. The sponsor’s reported overall Fisher Exact test across the five groups is p < 0.05. Because a discrepancy is flagged, that sponsor analysis takes precedence over the unadjusted recalculations.

The result concerns participants with induced PSVT in an electrophysiology laboratory who met the evaluable-population criteria. The endpoint captures conversion to sinus rhythm lasting at least 30 seconds within the specified window, after sustained PSVT for at least 5 minutes. It does not show how quickly conversion occurred within that window, whether sinus rhythm persisted afterward, or whether episodes recurred. Those outcomes are not reported in the registry record.

The results do not, by themselves, resolve which dose should be preferred, quantify a sponsor-reported dose-specific effect, or establish effects in settings beyond the study population and procedure. The registry’s reported overall test does not supply a sponsor estimate and interval for each dose, while the simple pairwise recalculations are unadjusted. The handling of multiplicity, missing assessments, and other analysis details is not reported in the registry record.

Statistical evidence about this endpoint is not equivalent to a complete assessment of benefit and harm. The safety section provides group-level event counts, but the posted counts alone do not establish causation or fully characterize event profiles. The trial’s findings should be understood as a study-specific assessment of an immediate conversion endpoint, with uncertainty in the effect size and limits on what can be concluded from the registry record.

17. Why This Trial Matters Statistically

This trial illustrates why a dose-ranging randomized study can pose more than one statistical question. The sponsor’s recorded test asks about superiority across five groups, while the recalculated risk differences compare each dose with placebo separately. Those analyses have different scopes, and their p-values cannot be treated as if they answer the same question. The flagged discrepancy makes it particularly important to distinguish the sponsor result from the unadjusted recalculations.

It also illustrates the value of effect estimates and confidence intervals alongside hypothesis tests. A p-value indicates compatibility with a null model under a test’s assumptions, but it does not communicate the size or precision of the difference. The recalculated risk differences offer an absolute scale, while their intervals show uncertainty around that scale. Small group denominators and an evaluable rather than fully described randomized population make careful interpretation important.

Finally, the study makes clear that a precisely defined short-term endpoint is informative but bounded. Conversion within the specified period is not the same question as later rhythm control or outcomes outside the electrophysiology laboratory. Transparent reporting of population flow, missing-data handling, multiplicity strategy, and sponsor effect estimates would help readers connect the posted counts to the intended statistical conclusions. Several of those details are not reported in the registry record.

18. 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 efficacy result is based on an evaluable population defined by induction and sustained SVT, receipt of study drug, and completion of conversion assessment. The registry does not provide a full account of participant flow into that population, explain exclusions, or describe missing endpoint assessments. The group denominators therefore cannot be assumed to represent every randomized participant.

The endpoint is limited to successful conversion within 15 minutes, with sinus rhythm lasting at least 30 seconds. Later recurrence, longer-term outcomes, and time to conversion within the endpoint window are not reported in the registry record. The study setting is induced PSVT in an electrophysiology laboratory, which bounds the context to which the posted endpoint directly applies.

The registry does not report the original sample-size justification, full statistical analysis plan, or multiplicity procedure. It also does not provide sponsor estimates and confidence intervals for the dose-specific comparisons. The simple recalculations are unadjusted and use posted summary counts; they cannot resolve the discrepancy flagged between those calculations and the sponsor’s analysis. The registry record does not explain the source of that discrepancy.

Safety reporting is presented as group counts, without enough detail in the posted figures to evaluate event timing, duration, causal attribution, or comparative risk. These limitations do not negate the recorded outcome, but they restrict how broadly or precisely it can be interpreted.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Efficacy and Safety of Intranasal MSP-2017 (Etripamil) for the Conversion of PSVT to Sinus Rhythm — NCT02296190.
• Registry record last updated 2020-12-30; status last verified 2020-12.
• Results first posted 2020-12-30.
• 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.

22. Record Summary

NCT02296190 is a completed randomized, double-blind, parallel-group, placebo-controlled Phase 2 dose-ranging study of intranasal etripamil for conversion of induced PSVT to sinus rhythm. Enrollment is recorded as 199. The primary endpoint was conversion within 15 minutes, with sinus rhythm lasting at least 30 seconds after sustained PSVT for a minimum of 5 minutes.

The posted evaluable counts show conversion in each etripamil dose group and placebo, and the sponsor reports a Fisher Exact superiority test across the five groups with p < 0.05. Simple unadjusted dose-versus-placebo recalculations provide risk differences and confidence intervals, but the registry flags a discrepancy; the sponsor’s own analysis takes precedence. Original design assumptions, detailed missing-data handling, and multiplicity procedures are not reported in the registry record.