Safety and Efficacy of Sufentanil NanoTab for Management of Acute Pain Following Bunionectomy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Sufentanil NanoTab for Management of Acute Pain Following Bunionectomy (NCT01710345), a randomized phase 2 study. The primary outcome is SPID-12.

2. Clinical Question

3. Trial Design

This was a randomized, phase 2, parallel-group study sponsored by Talphera, Inc. The registry lists the status as completed, enrollment as 101, and masking as quadruple. It identifies acute pain as the condition and describes the study as dose-finding for sublingual Sufentanil NanoTab after surgery. The registry record lists a start date of 2012-10 and primary completion in 2013-02.

Three groups are listed: Sufentanil NanoTab 20 mcg, Sufentanil NanoTab 30 mcg, and Placebo NanoTab. Each intervention description says the tablet could be used as needed every 60 minutes for 12 hours. These are the recorded treatment instructions; the registry record does not report how often participants used the tablets or how adherence was assessed.

The registry identifies randomization and a parallel design, but the method used to generate or conceal the allocation is not reported in the registry record. The record labels masking as quadruple without specifying which groups of people were masked. Further details of the study setting, eligibility criteria, participant characteristics, and treatment implementation are not reported in the registry record.

The primary outcome was SPID-12, measured over 12 hours. Outcome records list least-squares means and standard errors for the three groups. The registry also lists two analyses, each comparing one active-dose group with placebo. Enrollment is recorded as 101, whereas the group sizes attached to the primary outcome are 40, 40, and 20. The record does not explain the relationship between the enrollment figure and the group sizes shown for this outcome, so they should be read as distinct registry entries rather than reconciled by assumption.

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:

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as SPID-12, measured over 12 hours.

The primary endpoint, SPID-12, combines pain intensity changes over the 12-hour study period. The description says pain intensity was scored from 0, meaning no pain, to 10, meaning the worst possible pain, at baseline and throughout the study period. At each assessment, the baseline score is compared with the score at that time; those differences are then summed to form SPID-12.

The stated scale ranges from -120, indicating an increase in pain, to 120, indicating a decrease in pain. A higher SPID-12 score is better according to the registry’s endpoint description. This direction matters when interpreting group means: a higher value represents a more favorable direction on this measure, but the score alone does not describe each participant’s experience or the timing of changes during the 12 hours.

A summed measure can capture the pattern of pain change across multiple assessments rather than relying on a single time point. It can therefore serve as a summary of the measured experience over the defined interval. At the same time, the registry record does not report the assessment schedule, how missing assessments were handled, or a threshold for a clinically important difference. The reported means and standard errors should be interpreted as summaries of the endpoint, not as a complete account of individual responses.

7. Results Posted in the Registry

• Sufentanil NanoTab 20 mcg: mean -5.65 versus -7.12 on control; difference 1.47 (95% CI -7.24 to 10.18), standardized effect d = 0.09; z-test p = 0.741.
• Sufentanil NanoTab 30 mcg: mean 6.53 versus -7.12 on control; difference 13.65 (95% CI 4.93 to 22.37), standardized effect d = 0.84; z-test p = 0.002.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean difference represent?

A mean difference compares the average endpoint value in one group with the average in another. For the reported comparisons, placebo is the reference group, and each active dose is considered separately. The registry reports least-squares means for the arm summaries and identifies the sponsor’s analysis as ANCOVA of mean differences in final values. An ANCOVA is a model-based comparison that can account for specified covariates. Which covariates were included, how they were selected, and how the model was implemented are not reported in the registry record.

The recalculated differences use the posted arm summaries and are described as simple, unadjusted recalculations. They do not reproduce the sponsor’s ANCOVA model. For the 20 mcg comparison, the recalculated estimate is 1.47 and the sponsor reports 1.47. For the 30 mcg comparison, the recalculated estimate is 13.65 and the sponsor reports 13.66. Small differences between recalculation and sponsor analysis can arise because they are not the same analysis; the exact reason for the differences is not reported in the registry record. The sponsor’s own analysis takes precedence.

What does a standard error describe?

A standard error describes the estimated uncertainty in a group mean, rather than the spread of individual participant values. The registry lists standard errors of 2.55 for 20 mcg, 2.56 for 30 mcg, and 3.64 for placebo. A smaller standard error generally indicates a more precise estimate of the mean, while a larger one indicates more sampling uncertainty. Standard errors are not ranges containing all or most participant outcomes. The registry does not provide the raw outcome values or standard deviations for these groups.

The recalculated comparisons use approximate pooled standard deviations derived from the posted standard errors and group sizes. That approximation is identified as such in the recalculation. It enables a summary-statistic comparison, but it cannot recover the details of the original participant-level model, covariate adjustment, or data handling. The resulting unadjusted p-values and confidence intervals should therefore be kept distinct from the sponsor’s ANCOVA outputs.

How should the p-values be read?

A p-value measures how unusual data at least as incompatible with a specified null hypothesis would be under the assumptions of a particular statistical model. It is not the probability that the null hypothesis is true, nor the probability that the observed result occurred by chance in an everyday sense. The sponsor reports p = 0.742 for 20 mcg versus placebo and p = 0.003 for 30 mcg versus placebo. Those values belong to the sponsor’s analyses. The recalculated unadjusted p-values are 0.741 and 0.002, respectively, and use a different approach.

Statistical evidence from a p-value does not by itself convey effect size, precision, clinical importance, or the reliability of assumptions. The estimated mean difference and confidence interval provide complementary information about magnitude and uncertainty. The registry does not report a threshold defining an important SPID-12 difference, so the size of an estimate cannot be classified as clinically important from this record alone.

Why can an ANCOVA result differ from a summary-statistic recalculation?

The sponsor’s analysis is identified as ANCOVA, whereas the recalculation is unadjusted and based on posted summary values. Model adjustment can affect an estimated comparison and its uncertainty. However, the covariates and analytical details are not reported in the registry record, so the specific source of the small differences cannot be established from the posted information. The reported discrepancy is a reason to keep the two sets of results clearly labeled, not to choose the result with the more favorable p-value.

The sponsor’s mean differences are 1.47 and 13.66, and its p-values are 0.742 and 0.003. The recalculated differences are 1.47 and 13.65, and the recalculated p-values are 0.741 and 0.002. The sponsor’s analysis remains the primary account of its reported statistical results. The recalculations offer a transparent, limited check based on group summaries; they cannot substitute for a model fitted to the underlying participant-level data.

What information would be needed to assess the analysis more fully?

Further assessment would require details such as the prespecified analysis plan, covariates in the ANCOVA, analysis population, missing-outcome handling, and any sensitivity analyses. Those details are not reported in the registry record. The record also does not report an original sample-size justification, interim analyses, or a multiplicity procedure. Their absence from the registry entry does not establish whether these procedures were or were not used; it means their use cannot be assessed from the posted record.

10. Confidence Intervals and Precision

The sponsor reports point estimates and p-values but no confidence limits for either comparison. The recalculated intervals use the posted summary statistics and an approximate pooled standard deviation. They are unadjusted and should not be presented as intervals from the sponsor’s ANCOVA.

For Sufentanil NanoTab 20 mcg compared with placebo, the recalculated mean difference is 1.47, with a 95% interval from -7.241 to 10.18. This span includes zero and values on either side of zero, so the summary-statistic recalculation is compatible with a range of possible differences, including little or no difference as well as differences in either direction. Its width signals limited precision for this comparison.

For Sufentanil NanoTab 30 mcg compared with placebo, the recalculated mean difference is 13.65, with a 95% interval from 4.928 to 22.37. This interval is entirely above zero under the recalculation. It still spans a range of possible magnitudes, and the registry does not report a clinical-importance threshold for SPID-12. The interval therefore conveys statistical uncertainty, not whether all values within it would matter to participants.

Confidence intervals describe uncertainty in an estimated effect under the statistical method and its assumptions. They are not a guarantee that the true value lies within a particular interval, and they do not account for design or analysis limitations that are not represented in the calculation. Because the sponsor’s ANCOVA confidence limits are not reported in the registry record, the recalculated intervals should be interpreted cautiously and alongside the sponsor’s own estimates and p-values.

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 planning figures are participants per arm, not total events. They are illustrative calculations based on the observed effect, not a report of the study’s original design assumptions. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The original trial’s own sample-size assumptions and justification are not reported in the registry record.

The 80% power column describes the planned number of participants per arm under which the calculation would have an 80% chance of detecting the specified effect if that effect and the calculation assumptions were correct. The 90% power column uses a higher target chance of detection, and therefore generally calls for more participants per arm for the same assumed effect. These are planning concepts, not guarantees about the results of a future study.

Rows describing planning for 100%, 75%, or 50% of the observed effect use progressively smaller effects as the target. Smaller effects are harder to distinguish from random variation, so the planning calculation requires more participants per arm. The figures differ substantially between the two active-dose comparisons because their observed effects differ. They should not be treated as a recommended design without independent decisions about the target effect, outcome variability, analysis, and other design features.

These values are not observed power. They are planning illustrations based on the observed effect and the stated assumptions. They do not describe the probability that the completed study was capable of detecting its result, and they do not resolve uncertainty about the original design or analysis.

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

Worked calculation for this trial

1. Observed difference Δ = 1.470; pooled standard deviation σ = 16.177.
2. n = 2 × (1.96 + 0.842)² × 16.177² / 1.470² = 1,901.1, rounded up to 1,902 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 <- 1.47                      # observed difference in means
sigma <- 16.1772232389906                     # 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(1710345)
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 = 1,902 (80% power), 2,546 (90% power)
 75% of observed effect: n per arm = 3,380 (80% power), 4,525 (90% power)
 50% of observed effect: n per arm = 7,605 (80% power), 10,181 (90% power)
power.t.test: 1902.1 
Simulated power at n = 1,902 per arm: 0.802 (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.

13. Analyses Reported by the Sponsor

The sponsor’s registry analyses are ANCOVA comparisons of final values. They report a mean difference of 1.47 and p = 0.742 for Sufentanil NanoTab 20 mcg versus placebo, and a mean difference of 13.66 and p = 0.003 for Sufentanil NanoTab 30 mcg versus placebo. Confidence limits for these sponsor analyses are not reported in the registry record.

The recalculations use posted group summaries rather than the sponsor’s ANCOVA model. They give mean differences of 1.47 and 13.65, with unadjusted p-values of 0.741 and 0.002, respectively. The small discrepancies are noted, but the sponsor’s own analysis takes precedence. The difference in analytical approach means that recalculated uncertainty measures should not be substituted for missing sponsor-reported confidence limits.

The registry record does not report which covariates were included in the ANCOVA or provide enough detail to reproduce it. The recalculations are therefore best read as checks based on available summaries, not as a competing analysis of the participant-level data. Both sets of estimates point in the same direction for each comparison, but interpretation should follow the sponsor’s reported estimates and p-values while retaining the limitations of the record.

14. Multiplicity, Missing Data and Analysis Populations

The registry reports two primary-outcome comparisons: 20 mcg versus placebo and 30 mcg versus placebo. It does not report whether the two comparisons were treated as a single family for statistical testing, whether any adjustment was made for multiple comparisons, or whether a testing hierarchy was prespecified. The reported p-values should therefore be read as the individual values in the registry, without assuming that they control the overall chance of a false-positive finding across comparisons.

No secondary outcomes are posted in the record. The registry lists one outcome measure and two analyses. This does not establish that no other measurements were collected; it describes what is posted in the registry record. The primary endpoint is identified as SPID-12 over 12 hours, but a detailed protocol for assessment timing is not reported.

Handling of missing outcome data is not reported in the registry record. The record does not state whether all randomized participants contributed to the primary analysis, how incomplete assessments were handled, or whether sensitivity analyses addressed missingness. The analysis population is also not specified. Consequently, the reported group means cannot be connected to a clearly described intention-to-treat or other analysis population from this record alone.

The sponsor identifies ANCOVA as the analysis method, but its covariates and implementation details are not reported. The registry record also does not report the original sample-size rationale or interim analyses. These omissions limit assessment of whether the analysis followed a prespecified plan and how robust the estimates might be to alternative assumptions. They should not be interpreted as proof that such procedures were absent; their status is not reported in the registry record.

15. 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: osteomyeolitis (2.5%), cellulitis (2.5%).

The registry lists serious adverse events for each group as counts affected among those at risk. For Sufentanil NanoTab 20 mcg, 2 of 40 participants were affected; for Sufentanil NanoTab 30 mcg, 0 of 40 were affected; and for Placebo NanoTab, 0 of 20 were affected. These are descriptive figures for the recorded groups and do not by themselves establish a causal relationship to an intervention.

The registry lists Osteomyeolitis and Cellulitis as the top serious-event terms, each at 2.5%. The record does not provide further detail about event timing, severity, relatedness assessments, or participant-level overlap between terms. The deaths fields are not populated, so deaths are not reported in the registry record; that should not be interpreted as confirmation that none occurred.

Serious adverse event counts are distinct from the broader other-adverse-event counts, which the registry also records. This reading focuses on serious events and does not infer comparative safety from small group counts. A complete safety interpretation would require definitions, follow-up, event descriptions, and an assessment of exposure and relatedness, which are not reported in the registry record.

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

The posted results describe a randomized study comparing two Sufentanil NanoTab doses with placebo on SPID-12 over 12 hours after bunionectomy. The sponsor’s ANCOVA reports a mean difference of 1.47 for 20 mcg versus placebo and 13.66 for 30 mcg versus placebo. The corresponding reported p-values are 0.742 and 0.003. The estimates are in the direction of higher SPID-12 for the active groups relative to placebo, with a much larger posted estimate for the 30 mcg comparison.

These results are specific to the recorded outcome, study period, groups, and analyses. They do not establish the magnitude of change for an individual participant, the timing of any change, or whether a difference meets a threshold that participants would consider important. No such threshold is reported in the registry record. The p-values are not measures of clinical importance and do not quantify the chance that an intervention is beneficial.

The two comparisons are each against placebo; the registry does not report a direct statistical comparison of 20 mcg with 30 mcg. It would therefore be inappropriate to treat the difference between the two reported estimates as a tested dose-to-dose effect. The record also does not report multiplicity handling, missing-data procedures, or a defined analysis population, all of which constrain interpretation.

The recalculated confidence intervals add a view of uncertainty based on posted summary statistics, but they are not sponsor-reported ANCOVA intervals. The sponsor’s analyses take precedence. Overall, the record supports describing the posted statistical findings and their precision with care, but it does not by itself establish how results would extend to other populations, settings, outcomes, or time periods.

17. Why This Trial Matters Statistically

This study illustrates why a continuous outcome’s definition and direction need to be understood before interpreting a group comparison. SPID-12 combines changes from baseline across assessments, and higher values indicate a greater decrease in pain. The same numerical direction would have a different meaning for an endpoint defined in the opposite way. Careful attention to the outcome’s construction helps prevent misreading an estimate’s sign.

It also demonstrates the value of separating a sponsor’s analysis from a summary-statistic recalculation. The sponsor reports ANCOVA results, while the recalculations are unadjusted and rely on approximate dispersion derived from standard errors. Their estimates and p-values are close but not identical. Clear labeling preserves the distinction between a model-based reported result and a check that cannot reproduce all the original analysis details.

The two active-dose comparisons also raise a general multiplicity question: when several comparisons use the same primary outcome, interpretation depends partly on whether and how the analysis addresses multiple testing. That procedure is not reported in the registry record, so the comparison-specific p-values should not be assumed to represent an adjusted family of tests.

Finally, point estimates, confidence intervals, p-values, and planning calculations answer different questions. An estimate describes the direction and magnitude of a comparison; an interval describes uncertainty under a method; a p-value summarizes evidence relative to a null model; and a sample-size illustration explores planning under stated assumptions. Keeping these roles distinct makes the findings easier to assess without overstating what the registry record establishes.

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 registry entry does not provide enough information to reconstruct the primary analysis. Although it identifies ANCOVA, it does not report the covariates, model specification, analysis population, or missing-data handling. It also does not provide sponsor-reported confidence limits. The unadjusted recalculations are based on summary statistics, include an approximate pooled standard deviation, and cannot recover participant-level analyses.

Enrollment is recorded as 101, while the primary outcome arm records list group sizes of 40, 40, and 20. The registry record does not explain this relationship. No reconciliation or assumption about the reason for the differing entries can be made from the record. Further details about eligibility, baseline characteristics, study setting, and participant flow are not reported.

The outcome is summarized over 12 hours, but the assessment schedule and handling of incomplete assessments are not reported. The record does not state a threshold for a clinically important SPID-12 difference. It also does not report whether multiplicity was addressed, the original sample-size justification, interim analyses, or a prespecified statistical plan. These gaps limit the assessment of clinical meaning, robustness, and design rationale.

For safety, the serious-event counts are descriptive, and the record does not provide event-level detail, relatedness, timing, or follow-up information. Deaths are not reported in the registry record. The available safety entries therefore cannot provide a comprehensive comparative assessment. These are limitations of what is reported in the registry record; they do not establish that unreported procedures, data, or events did not exist.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety and Efficacy of Sufentanil NanoTab for Management of Acute Pain Following Bunionectomy — NCT01710345.
• Registry record last updated 2015-01-26; status last verified 2015-01.
• Results first posted 2015-01-26.
• 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

NCT01710345 is a completed, randomized, phase 2, parallel-group study sponsored by Talphera, Inc. The registry lists enrollment of 101, quadruple masking, a start date of 2012-10, and primary completion in 2013-02. The study concerns acute pain following bunionectomy and is described as dose-finding for sublingual Sufentanil NanoTab.

The interventions were Sufentanil NanoTab 20 mcg, Sufentanil NanoTab 30 mcg, and Placebo NanoTab, each described as available as needed every 60 minutes for 12 hours. The primary outcome was SPID-12 over 12 hours, with higher scores indicating a greater decrease in pain. The sponsor reported ANCOVA comparisons of each active dose with placebo. Further details about analysis populations, missing data, multiplicity, and model specification are not reported in the registry record.