Study of Buprenorphine Sublingual Spray for the Treatment of Moderate to Severe Pain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Buprenorphine Sublingual Spray for the Treatment of Moderate to Severe Pain (NCT02634788), a randomized phase 3 study. The primary outcome is Numeric Rating Scale (NRS) Summed Pain Intensity Difference (SPID) Over 0 to 48 Hours After Time 0 (NRS SPID-48).

2. Clinical Question

3. Trial Design

This was a randomized, double-blind, parallel-group, placebo-controlled Phase 3 study sponsored by INSYS Therapeutics Inc. Its stated objective was to evaluate the analgesic efficacy of buprenorphine sublingual spray compared with placebo among participants with postoperative pain after bunionectomy. The registry record lists 322 participants enrolled and a completed study. It lists the start date as 2016-01-29 and primary completion as 2016-06-24.

Four groups are described: placebo and buprenorphine at 0.5 mg, 0.25 mg, or 0.125 mg TID. Each group’s treatment description specifies sublingual spray administered three times daily for two days. Double masking means the study was recorded as double-blind; further details about who was masked or how masking was maintained are not reported in the registry record.

The primary outcome was a continuous measure of pain intensity accumulated across 0 to 48 hours. The registry record reports least-squares means with standard errors by group and ANCOVA comparisons against placebo. It specifies treatment and site as main effects and baseline pain intensity as a covariate. The analysis population was randomized participants in the Intent-to-Treat population without missing SPID-48 values; missing values were not imputed.

The registry record does not report the trial’s original sample-size justification, the planned analysis population beyond the stated endpoint definition, or whether interim analyses were conducted. It also does not report allocation concealment or further protocol details. These omissions limit what can be inferred about the planning and conduct of the analysis from the registry record alone.

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: All randomized participants from the Intent-to-Treat (ITT) Population who did not have missing SPID-48 values. Missing SPID-48 data were not imputed.

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: Safety Population included all participants who were treated with the study drug.

6. Primary Endpoint

The registry lists the primary outcome as Numeric Rating Scale (NRS) Summed Pain Intensity Difference (SPID) Over 0 to 48 Hours After Time 0 (NRS SPID-48), measured over Baseline and 0 to 48 hours after Time 0.

The primary endpoint, NRS SPID-48, combines pain-intensity differences across the period from 0 to 48 hours after the first dose. Participants rated pain on an 11-point Numeric Rating Scale (NRS), from 0=no pain to 10=worst possible pain. A pain-intensity difference is the Time 0 pain score minus the score at a later assessment. Those differences are multiplied by the time elapsed since the prior assessment and summed across the measurement period.

Under this definition, a positive SPID indicates reduction in pain intensity relative to Time 0, while a negative score indicates an increase. The stated range for SPID-48 is -480 to 480. Because the measure accumulates differences over time, it reflects both the direction and duration of changes rather than a single pain rating. This can be useful when the question concerns pain experience across a defined observation period.

In general, an accumulated endpoint can retain information from multiple assessments, but its interpretation depends on the assessment schedule and the calculation rule. The registry record describes assessments at multiple time points up to 48 hours but does not enumerate the full schedule in the endpoint description. The primary endpoint analysis used ANCOVA, including treatment and site as main effects and baseline pain intensity as a covariate. The analysis excluded randomized participants with missing SPID-48 values, and those values were not imputed.

7. Results Posted in the Registry

• Buprenorphine 0.5 mg TID: mean 171.33 versus 89.40 on control; difference 81.93 (95% CI 53.62 to 110.24), standardized effect d = 0.94; z-test p = <0.001.
• Buprenorphine 0.25 mg TID: mean 125.58 versus 89.40 on control; difference 36.18 (95% CI 8.17 to 64.19), standardized effect d = 0.41; z-test p = 0.011.
• Buprenorphine 0.125 mg TID: mean 124.85 versus 89.40 on control; difference 35.45 (95% CI 7.66 to 63.24), standardized effect d = 0.41; z-test p = 0.012.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percentage of Participants Using Rescue Medication for Pain

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Buprenorphine 0.5 mg TID: 55.6% (45/81) versus 97.5% (77/79) on control; risk difference -41.9 percentage points (95% CI -53.3 to -30.6), risk ratio 0.57 (0.47–0.69); unadjusted two-proportion z-test p = <0.001.
  • Buprenorphine 0.25 mg TID: 87.5% (70/80) versus 97.5% (77/79) on control; risk difference -10.0 percentage points (95% CI -18.0 to -1.9), risk ratio 0.90 (0.82–0.98); unadjusted two-proportion z-test p = 0.017.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Buprenorphine 0.5 mg TID than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Buprenorphine 0.25 mg TID than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry lists a broad set of secondary outcomes, including pain intensity and pain-intensity difference at selected follow-up times, summed pain-intensity differences, total pain relief, onset and peak timing, pain-relief categories, and rescue-medication use. Taken together, these measures examine pain from different angles: point-in-time ratings, accumulated changes, reported relief, timing, and use of additional pain medication. Their overall role is to add context to the primary 0-to-48-hour accumulated pain measure, rather than to replace it.

The posted rescue-medication results generally follow the pattern of the primary endpoint: the 0.5 mg TID group has a lower reported proportion using rescue medication than placebo, while the two lower-dose groups are closer to placebo. This provides a related but distinct outcome, since rescue-medication use is not the same measure as pain intensity. The registry record lists 14 secondary outcomes, but detailed results for all listed outcomes are not included in the available record. Unreported results should not be inferred from the primary endpoint.

Some secondary comparisons have unadjusted statistical results. When many outcomes or comparisons are assessed, the chance of obtaining at least one apparently notable result by chance can increase. In general, multiplicity procedures can address that issue, but the registry record does not report whether the secondary analyses used a multiplicity adjustment or a prespecified hierarchy. For that reason, unadjusted secondary findings carry less weight than the designated primary endpoint and should be viewed as supportive or exploratory rather than conclusive.

The secondary outcomes can help characterize whether different measurements point in a broadly similar direction, but they do not independently establish a treatment effect. They may also differ in populations, assessment times, missing-data patterns, and statistical properties. Further details about those analysis choices are not reported in the registry record. Their interpretation therefore depends on the endpoint definitions and analysis methods as well as the primary result.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• NRS Mean Pain Intensity Difference (PID) at 4, 8, 24 and 48 Hours After Time 0
• NRS Mean Pain Intensity Score at 4, 8, 24 and 48 Hours After Time 0
• NRS SPID Over 4 Hours (SPID-4), 8 Hours (SPID-8) and 24 Hours (SPID-24) After Time 0
• Total Pain Relief (TOTPAR) Over 4, 8, 24 and 48 Hours After Time 0
• Time to Onset of Analgesia
• Percentage of Participants With Scores in Each Pain Relief Category at 4, 8, 24 and 48 Hours After Time 0
• Percentage of Participants With Peak Scores in Each Pain Relief Category
• Time to Peak Pain Relief

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: each participant’s SPID-48 is a numerical score, and the group summaries are least-squares means. A least-squares mean is a model-based group estimate that accounts for the covariates and factors included in the analysis. It is not simply the raw arithmetic mean unless the model and data make those quantities coincide. The registry record reports standard errors for the group estimates: 10.11 for placebo, 10.32 for buprenorphine 0.5 mg TID, 10.1 for 0.25 mg TID, and 9.944 for 0.125 mg TID.

The primary analysis used analysis of covariance (ANCOVA). In general, ANCOVA estimates group differences while adjusting for specified covariates. Here, the record says treatment and site were included as main effects and baseline pain intensity was included as the covariate. Baseline adjustment can account for initial differences in the measured outcome, while including site allows the model to account for site-related variation. The registry record does not give further details of the model specification, such as whether interactions or additional covariates were considered.

The comparisons are reported as least-squares mean differences between each buprenorphine dose and placebo. A positive difference in this endpoint means the estimated SPID-48 is higher in the buprenorphine group than in placebo; the endpoint definition associates positive scores with reduced pain relative to Time 0. The differences are model-based estimates, and their uncertainty is described with 95% confidence intervals. A confidence interval gives a range of values compatible with the data and the statistical model at the stated confidence level. It does not represent the range of individual participant outcomes.

The reported p-values quantify how incompatible the observed contrast is with a null hypothesis of no difference under the analysis assumptions. They do not measure the probability that the null hypothesis is true, nor do they describe the size or clinical importance of an effect. The registry reports p-values from the ANCOVA comparisons, while a separate simple recalculation uses posted summary statistics and is explicitly unadjusted. For understanding the trial’s stated analysis, the ANCOVA results are the relevant posted results.

In general, variance describes how widely individual outcomes vary, while a standard error describes uncertainty in an estimated mean or contrast. The registry provides standard errors for the arm estimates. The simple recalculation estimates a pooled standard deviation from those standard errors and sample sizes, and marks that estimate as approximate. Standard deviations and standard errors are not interchangeable: the former describe outcome variability among participants, while the latter describe precision of an estimate. Any standardized effect based on the approximate pooled standard deviation is therefore an additional summary, not the sponsor’s primary analysis.

For the simple recalculations, the estimated differences and confidence intervals are close to the sponsor’s posted ANCOVA comparisons, but they are not identical in every detail. These recalculations do not adjust for treatment, site, and baseline pain intensity as the ANCOVA does. They should be treated as a secondary check using posted summary statistics, not as a replacement for the sponsor’s model-based analysis. The registry record does not report a discrepancy flag for these results.

The sample-size illustrations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. They consider effects that are stated fractions of the observed effect. In general, power is the probability of detecting an effect of a specified size under the assumptions of a statistical model and study design, if that effect is present. The illustrations are planning calculations based on observed effects, not evidence about the power the completed trial actually had. The trial’s own original sample-size justification and design assumptions are not reported in the registry record.

For continuous outcomes, a mean difference is directly expressed in the outcome’s units. For the secondary rescue-medication outcome, the data are binary at the participant level: a participant either used rescue medication during the stated window or did not. In general, a risk difference expresses the difference between proportions in two groups, while a confidence interval describes uncertainty in that difference. The posted secondary calculations are unadjusted; no adjusted model or multiplicity correction for those comparisons is reported.

Over-dispersion is a general concern when observed variability exceeds what a statistical model assumes. In binary or count settings, ignoring over-dispersion can make standard errors too small and confidence intervals too narrow. The registry record does not identify over-dispersion as a feature of the primary continuous endpoint analysis, so it should not be assumed to have affected these results. More broadly, model assumptions matter because uncertainty estimates depend on whether the statistical model reasonably describes the data.

11. Confidence Intervals and Precision

The sponsor’s 95% confidence intervals for the primary mean differences are 53.82 to 110.04 for buprenorphine 0.5 mg TID versus placebo, 8.43 to 63.93 for 0.25 mg TID versus placebo, and 7.86 to 63.05 for 0.125 mg TID versus placebo. Each interval is entirely above zero, which is consistent with a positive estimated difference under the reported ANCOVA model. The intervals nevertheless span a range of possible contrast values; the point estimates should not be treated as exact population effects.

In general, a narrower confidence interval indicates greater precision, while a wider interval indicates more uncertainty about the size of the estimate. Precision is influenced by factors including sample size and outcome variability. The posted interval for the 0.5 mg TID contrast is centered around a larger estimated difference than the intervals for the lower-dose contrasts. The intervals for the two lower-dose comparisons overlap substantially, but overlap alone is not a formal test of whether those doses differ. No direct active-dose contrast is reported.

The confidence intervals are conditional on the statistical model and analysis population used. The primary endpoint analysis included randomized participants without missing SPID-48 values, and missing values were not imputed. The number of participants excluded from that analysis for missing endpoint data is not reported in the registry record. That absence prevents assessment of how missing endpoint values might affect precision or the representativeness of the analyzed population.

Confidence intervals address sampling uncertainty under the analysis assumptions, not every source of uncertainty. They do not address unreported choices in study design, possible bias, generalizability beyond the study setting, or the clinical importance of a difference. The reported intervals are a useful guide to statistical precision, but interpretation should also consider the outcome definition, analysis population, and the registry’s incomplete reporting of some design and analysis details.

12. 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 planning illustrations report participants per arm for the two-arm comparisons, not total participants across the trial. They are based on 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 the stated fraction of the observed effect. The original design assumptions and sample-size justification for the completed trial are not reported in the registry record.

The 80% power column gives the number of participants per arm estimated to provide an 80% chance of detecting the selected effect under those planning assumptions. The 90% power column gives the corresponding number per arm for a 90% chance. These are planning illustrations rather than descriptions of the completed trial’s design. This is not observed power.

Each planning row uses a different portion of the observed effect as the target effect. The illustrations show that smaller effects need more participants to detect under the same assumptions. For example, the figures for planning for 50% of the observed effect are larger than the figures for planning for 100% of the observed effect. This follows the general statistical relationship between effect size and sample requirements: when the target difference is smaller, more information is needed to distinguish it from random variation.

The calculations are not guarantees that a future study will achieve the stated power. They rely on assumptions about allocation, significance level, effect size, and the normal approximation, and do not include design features that are not listed in the planning assumptions. They should be read as illustrative scenarios tied to the observed estimates, not as evidence about the original rationale for enrollment.

13. 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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 81.930; pooled standard deviation σ = 87.540.
2. n = 2 × (1.96 + 0.842)² × 87.540² / 81.930² = 17.9, rounded up to 18 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
delta <- 81.93                      # observed difference in means
sigma <- 87.5404632912985                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2634788)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 18 (80% power), 24 (90% power)
 75% of observed effect: n per arm = 32 (80% power), 43 (90% power)
 50% of observed effect: n per arm = 72 (80% power), 96 (90% power)
power.t.test: 18.9 
Simulated power at n = 18 per arm: 0.779 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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.

14. Analyses Reported by the Sponsor

The registry’s own reported primary analyses use ANCOVA and present least-squares mean differences against placebo. The sponsor reports 81.93 for buprenorphine 0.5 mg TID, 36.18 for 0.25 mg TID, and 35.46 for 0.125 mg TID, with the confidence intervals and p-values stated in the primary-endpoint results. Those model-based comparisons account for treatment and site and adjust for baseline pain intensity, as described in the record.

A separate simple recalculation from posted arm summaries gives estimates of 81.93, 36.18, and 35.45 for the same comparisons. Its intervals and p-values are unadjusted and are not exactly the same as the sponsor’s ANCOVA intervals and p-values. The recalculation is useful as a check on the scale and direction of the reported contrasts, but it does not reproduce the adjusted analysis. The sponsor’s analysis is the trial’s reported analysis; the simple recalculation should not be mistaken for an alternative primary result.

The registry record does not flag a discrepancy between the recalculation and the sponsor’s analysis. Small differences in displayed values do not establish a substantive contradiction, especially when methods differ. Interpretation should therefore be anchored in the reported ANCOVA estimates and their intervals, while recognizing that no additional analysis details beyond those in the record are available.

15. Multiplicity, Missing Data and Analysis Populations

The registry record identifies one primary endpoint, NRS SPID-48, and lists numerous secondary outcomes. It reports ANCOVA comparisons for the primary endpoint and a collection of secondary outcomes, including repeated pain assessments and measures of pain relief and medication use. The record does not report a multiplicity adjustment, a testing hierarchy, or a strategy for controlling the overall type I error across the primary and secondary analyses. Consequently, the primary result has a clearer designated role, while individual unadjusted secondary findings require caution.

In general, multiplicity arises when several hypotheses are tested. The more comparisons made, the greater the chance that one or more results may appear statistically notable even if there is no corresponding effect. Methods such as prespecified hierarchies or adjusted significance thresholds can address this concern, but the use of any such method in this trial is not reported in the registry record. It is not appropriate to assume that the posted secondary p-values were adjusted.

The primary endpoint population included all randomized participants from the Intent-to-Treat population who did not have missing SPID-48 values. The record explicitly states that missing SPID-48 data were not imputed. It does not report the number of randomized participants with missing primary endpoint values or give details about the reasons for missingness. Without those details, the influence of missing data on the estimated contrasts cannot be assessed from the registry record.

In general, a complete-case analysis can be sensitive to how missingness relates to treatment and outcome. If participants with missing data differ systematically from those with observed outcomes, the analyzed group may not fully represent all randomized participants. This is a general methodological consideration, not a claim that such bias occurred in this trial. The registry record also does not report interim analyses or additional sensitivity analyses for missing outcomes.

The record’s description of baseline adjustment and the included treatment and site effects is useful, but further model diagnostics and analysis-plan details are not reported. This limits assessment of whether all modeling and missing-data decisions were prespecified or whether alternative assumptions were examined.

16. Safety Results

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

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: angioedema (1.2%).

The registry reports serious adverse events among participants at risk in each group: 0 of 79 for placebo, 1 of 81 for buprenorphine 0.5 mg TID, 0 of 80 for buprenorphine 0.25 mg TID, and 0 of 82 for buprenorphine 0.125 mg TID. The single serious adverse event is listed under angioedema, with a reported term percentage of 1.2%. These are counts in the registry record, not estimates of comparative risk with uncertainty intervals.

The small number of reported serious events limits the precision of any between-group safety interpretation. Zero reported events in a group does not establish that the risk is zero, and the registry record does not provide a formal comparative safety analysis. The deaths field has no reported value; deaths are therefore not reported in the registry record, rather than established as absent.

These figures do not establish whether an event was caused by study treatment. The registry record gives event counts but does not provide enough detail to assess timing, relatedness, severity beyond the serious-event designation, or clinical course. They should be read as descriptive safety reporting for this trial and its stated treatment period.

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

The primary results show positive model-based differences in NRS SPID-48 for each buprenorphine dose compared with placebo. Under the endpoint definition, positive SPID values indicate reduced pain relative to Time 0, and a positive contrast indicates a higher estimated SPID in the buprenorphine group. The sponsor’s confidence intervals for all three comparisons lie above zero. These are findings about the measured outcome and analysis in this particular trial.

They do not establish how large a difference would matter to participants. The registry record does not state a threshold for clinical importance or a minimal clinically important difference. Statistical evidence about a mean contrast and judgments about practical importance are separate questions. The results also do not describe the experience of every participant; group estimates can conceal substantial variation among individuals.

The study evaluated postoperative pain after bunionectomy and used treatment for two days. The record does not establish whether the estimates apply to other types of pain, other treatment durations, or other populations. Nor do placebo comparisons establish whether the active doses differ from each other; direct active-dose comparisons are not reported.

The findings do not amount to medical advice or a recommendation for an individual. They do not resolve all questions about benefit and harm, and the serious adverse event counts are too limited to provide a complete account of safety. Missing primary endpoint values were not imputed, and the number of missing values is not reported. Multiplicity handling for the secondary outcomes is also not reported. Those limits should be considered alongside the statistical estimates.

18. Why This Trial Matters Statistically

This trial illustrates how an accumulated continuous endpoint can represent repeated measurements across a clinically defined observation window. NRS SPID-48 combines pain-intensity differences and the time between assessments, so its interpretation depends on both the scale and the accumulation rule. The registry provides the definition and the analysis model, allowing readers to distinguish this outcome from a single pain score at one time point.

The report also illustrates the distinction between unadjusted summaries and covariate-adjusted estimates. The sponsor’s primary comparison uses ANCOVA, including treatment and site and adjusting for baseline pain intensity. A simple recalculation from group summaries can check the broad scale of the differences, but it does not replicate the sponsor’s model. Recognizing that distinction is central to reading registry results accurately.

Confidence intervals add information beyond a p-value by showing the range of contrast values compatible with the data and the model. The posted intervals are useful for judging statistical precision, while the absence of a reported clinical-importance threshold prevents a direct conclusion about practical significance. The sample-size illustrations similarly demonstrate how smaller target effects require larger planned groups under stated assumptions, without revealing the rationale for the original enrollment.

Finally, the record makes some important limitations visible: primary endpoint data were not imputed, details about missing observations are absent, and multiplicity handling for secondary outcomes is not reported. These are not reasons to dismiss the posted estimates, but they define what can and cannot be concluded from the registry entry. Careful statistical reading involves both the estimates and the boundaries of the available reporting.

19. 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 original sample-size justification, so the enrollment cannot be linked from this record to a prespecified target effect or power calculation. The planning illustrations based on observed effects do not fill that gap. Interim analysis details are also not reported.

The primary endpoint analysis excluded participants with missing SPID-48 values, and no imputation was performed. The number of missing values and the reasons for missingness are not reported. This leaves uncertainty about the extent to which the analyzed population represents all randomized participants.

The record does not describe multiplicity control for the secondary outcomes, nor does it report detailed results for every listed secondary endpoint. The posted unadjusted secondary comparisons should therefore not be treated as equivalent in evidential weight to the designated primary analysis. Direct comparisons among active doses are not reported, so their relative differences cannot be inferred from comparisons against placebo alone.

The trial addressed postoperative pain after bunionectomy and a two-day treatment course. Generalization beyond that setting or duration is not established by the registry record. More detailed information on masking procedures, allocation concealment, protocol deviations, analysis diagnostics, and adverse-event relatedness is not reported. The serious adverse event counts are sparse and are descriptive rather than a definitive comparative safety assessment.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study of Buprenorphine Sublingual Spray for the Treatment of Moderate to Severe Pain — NCT02634788.
• Registry record last updated 2017-08-14; status last verified 2017-06.
• Results first posted 2017-08-14.
• 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.

23. Record Summary

NCT02634788 is a completed, randomized, double-blind, parallel-group, placebo-controlled Phase 3 trial sponsored by INSYS Therapeutics Inc. The registry record lists 322 participants enrolled and describes buprenorphine sublingual spray at 0.5 mg, 0.25 mg, or 0.125 mg TID for two days, compared with placebo.

The primary endpoint was NRS SPID-48, analyzed using ANCOVA with treatment and site as main effects and baseline pain intensity as a covariate. The sponsor reports positive least-squares mean differences versus placebo for all three dose groups. Primary endpoint data were not imputed for participants with missing values.

Secondary outcomes covered additional pain assessments and related measures, including rescue-medication use. The registry also reports serious adverse event counts, with one event in the 0.5 mg TID group and none in the other listed groups. Important details, including the original sample-size justification, missing-data counts, and multiplicity handling, are not reported in the registry record.