Abuse Potential of Intranasal VYCAVERT Tablets (Hydrocodone Bitartrate/Acetaminophen) in Recreational Opioid Users: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Abuse Potential of Intranasal VYCAVERT Tablets (Hydrocodone Bitartrate/Acetaminophen) in Recreational Opioid Users (NCT01759446), a randomized phase 2 study. The primary outcome is Emax - Maximum Drug Liking.

2. Clinical Question

3. Trial Design

The registry describes a Phase 2, randomized, double-blind, active- and placebo-controlled, five-way crossover study conducted at a single center. Participants were non-dependent recreational opioid users. In a crossover design, a participant receives more than one study condition, allowing responses under different conditions to be collected from the same person. The record’s arm descriptions say that each listed condition was taken first and that the other arms were then taken in crossover sequence. The precise sequence allocation and its implementation are not reported in the registry record.

The five conditions were placebo powder; pulverized generic hydrocodone/acetaminophen 10/325 mg; pulverized Vycavert hydrocodone/acetaminophen 10/325 mg; generic hydrocodone/acetaminophen with additional inactive ingredients; and generic hydrocodone/acetaminophen with one placebo tablet. All were described as administered intranasally. The registry lists enrollment of 44. For the primary outcome, each condition has 40 participants in the posted results, and the outcome population is described as completers of all doses per protocol.

Maximum drug liking was assessed over an 8-hour timeframe. The record lists assessments at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 8 hours post-dosing. The primary endpoint is the maximum score, rather than a single rating at one assessment time. The record does not report the washout interval between conditions, the detailed randomization procedure, or the analysis model used for the crossover structure.

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: Each subject had to pass a blinded snorted drug discrimination phase to meet enrollment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Completers of all doses per protocol

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: Adult Recreational Snorting Drug Users who completed the study design per protocol

6. Primary Endpoint

The registry lists the primary outcome as Emax - Maximum Drug Liking, measured over 8 hours.

The primary endpoint, Emax—Maximum Drug Liking, is the highest reported drug-liking score during the 8 hours after dosing. Participants answered whether they disliked or liked the drug effect they were feeling at the time. Ratings used a 100-point bipolar visual analog scale: 50 was anchored as neither like nor dislike, 0 as strong disliking, and 100 as strong liking. Assessments were scheduled at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 8 hours post-dosing.

This endpoint summarizes the strongest subjective liking response across the assessment period. In general, maximum scores can capture a peak response that might not be represented by a single rating time. The measure is relevant to the trial’s stated aim of assessing relative abuse potential in recreational opioid users, but it is a subjective rating and is not a direct measure of later drug use, dependence, or behavior outside the study. The posted values are means and standard deviations for participants who completed all doses per protocol. The registry record does not report the individual response profiles or the analysis used to account for repeated observations within participants.

7. Results Posted in the Registry

• Generic H/A: mean 75.00 versus 54.50 on control; difference 20.50 (95% CI 15.99 to 25.01), standardized effect d = 1.99; z-test p = <0.001.
• Vycavert: mean 72.10 versus 54.50 on control; difference 17.60 (95% CI 12.79 to 22.41), standardized effect d = 1.60; z-test p = <0.001.
• Generic H/A Plus i: mean 75.60 versus 54.50 on control; difference 21.10 (95% CI 16.42 to 25.78), standardized effect d = 1.97; z-test p = <0.001.
• Generic H/A Plus p: mean 73.00 versus 54.50 on control; difference 18.50 (95% CI 13.65 to 23.35), standardized effect d = 1.67; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

In general, a mean is the arithmetic average of the observed scores in a group. For this continuous endpoint, the registry reports a mean and standard deviation for each condition. A mean gives a summary of the group’s score level, while the standard deviation describes how dispersed scores are around that mean. The means are 54.5 for placebo, 75.0 for generic hydrocodone/acetaminophen, 72.1 for Vycavert, 75.6 for generic hydrocodone/acetaminophen plus additional inactive ingredients, and 73.0 for generic hydrocodone/acetaminophen plus one placebo tablet. The associated standard deviations are 8.52, 11.81, 12.98, 12.48, and 13.13. These are descriptive summaries, not individual participant outcomes.

What does a mean difference represent?

In general, a mean difference expresses the difference in average scores between two conditions, in the original scale’s units. The posted unadjusted recalculations use placebo as the reference. They report differences of 20.5 for generic hydrocodone/acetaminophen, 17.6 for Vycavert, 21.1 for generic hydrocodone/acetaminophen plus additional inactive ingredients, and 18.5 for generic hydrocodone/acetaminophen plus one placebo tablet. These estimates are based on the posted group summaries; they are not identified as results from a model that accounts for the crossover design.

In general, a crossover analysis can use the fact that each participant receives multiple conditions and can account for the relationship between their repeated responses. The registry identifies a five-way crossover, but does not report the analysis model, within-participant covariance, or a paired treatment contrast. The simple summary-statistic comparisons therefore should not be mistaken for a reported crossover-model analysis. The registry record does not report whether period or sequence effects were assessed, or how any such effects were handled.

What does a p-value say?

In general, a p-value measures how compatible data are with a specified null hypothesis under the assumptions of the statistical test. It is not the probability that the null hypothesis is true, and it does not measure the size or practical importance of an effect. The unadjusted p-values for all four posted comparisons are < 0.001. The registry record does not report the test specification or whether these values were adjusted for multiple comparisons. They should therefore be read as unadjusted comparison results, not as evidence about an unreported adjusted analysis.

In general, multiple comparisons increase the opportunity for a chance-positive result across a family of tests if each test is interpreted independently. A prespecified multiplicity strategy can address this issue. The record does not report a multiplicity plan, so the posted unadjusted p-values do not establish how the trial’s original analysis treated the set of comparisons.

Why does the crossover structure matter?

In general, measurements from the same participant are often correlated. An analysis that accounts for this correlation may have different uncertainty from an analysis treating observations as independent. The registry reports 40 participants for each condition, but does not report whether the same 40 participants contributed complete data to every condition or give participant-level paired results. The overall enrollment is 44, while the primary outcome population is specified as completers of all doses per protocol. The reason for the difference between enrollment and the reported condition counts is not reported in the registry record.

The comparison estimates include pooled standard deviations and standard errors, but the record does not describe a formal model behind them. The calculations are simple, unadjusted recalculations from the posted summary statistics. They provide a readable contrast of group means, but cannot reconstruct the within-person covariance or replace an analysis designed for the crossover structure. The discrepancy indicator is false, so no disagreement between a sponsor analysis and these recalculations is identified in the posted record; however, a sponsor analysis and its methods are not reported.

What can the posted analyses support?

The posted data support descriptive statements about the means and spread of scores in the per-protocol completer population, along with the stated unadjusted summary-statistic contrasts against placebo. The registry lists one primary outcome measure and zero posted analyses. The original statistical analysis plan, the trial’s own sample-size justification, any interim analysis plan, and any adjusted crossover analysis are not reported in the registry record. General statistical interpretation cannot fill in those missing protocol details.

10. Confidence Intervals and Precision

Each unadjusted mean-difference recalculation is accompanied by a confidence interval. In general, a confidence interval describes a range of values compatible with the estimate under the assumptions of the method used. Its width conveys precision: a narrower interval indicates less statistical uncertainty under those assumptions. A confidence interval is not a guarantee that the true value lies within the interval, and it does not include uncertainty from unreported design or analysis choices.

For generic hydrocodone/acetaminophen versus placebo, the estimated mean difference is 20.5, with a confidence interval from 15.99 to 25.01. For Vycavert versus placebo, the estimate is 17.6, with an interval from 12.79 to 22.41. For generic hydrocodone/acetaminophen plus additional inactive ingredients versus placebo, the estimate is 21.1, with an interval from 16.42 to 25.78. For generic hydrocodone/acetaminophen plus one placebo tablet versus placebo, the estimate is 18.5, with an interval from 13.65 to 23.35.

All four intervals lie above zero for the reported mean-difference contrasts. This describes the unadjusted recalculations; it does not establish that a crossover-model interval or a multiplicity-adjusted interval would have the same limits. The registry record does not report the confidence level, the analysis method used for an original trial analysis, or whether the intervals reflect within-participant dependence. The posted interval estimates should be interpreted with that method information unavailable, rather than as a complete account of all sources of uncertainty.

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 figures are planning illustrations based on the observed mean differences, not the trial’s original design justification. For these continuous outcomes, the figures refer to participants per arm, not total events. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The trial’s own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the illustrated number of participants per arm for an analysis designed to have an 80% chance of detecting the assumed effect under the stated planning assumptions, if that effect and assumptions hold. The 90% power column represents a higher target chance of detection under the same planning framework. These columns are planning quantities, not observed trial findings. This is not observed power.

Planning for 100% of an observed effect uses the full estimated contrast as the assumed effect; planning for 75% or 50% uses a smaller assumed contrast. Smaller effects need more participants to detect with the same target power and assumptions. The displayed illustrations are tied to the observed estimates and should not be read as a design recommendation or as evidence that the actual crossover trial used those sample sizes. They also do not incorporate unreported details of the crossover analysis, such as within-participant correlation.

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 = 20.500; pooled standard deviation σ = 10.297.
2. n = 2 × (1.96 + 0.842)² × 10.297² / 20.500² = 4.0, rounded up to 4 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 <- 20.5                      # observed difference in means
sigma <- 10.2972447771236                     # 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(1759446)
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 = 4 (80% power), 6 (90% power)
 75% of observed effect: n per arm = 8 (80% power), 10 (90% power)
 50% of observed effect: n per arm = 16 (80% power), 22 (90% power)
power.t.test: 5.1 
Simulated power at n = 4 per arm: 0.647 (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. Multiplicity, Missing Data and Analysis Populations

The registry reports one primary outcome measure, Emax—Maximum Drug Liking, and no posted secondary outcome results. It lists no analyses. The primary comparisons available in the posted results are unadjusted summary-statistic recalculations of each active condition against placebo. The registry record does not report a multiplicity adjustment, a family of comparisons defined in advance, or which comparisons were designated as primary in the original analysis plan.

In general, multiplicity matters when several hypotheses are tested: interpreting each p-value at the same threshold can increase the overall chance of at least one chance-positive finding. Methods such as a prespecified testing sequence or an adjustment can address that issue, but whether any such approach was planned or used is not reported in the registry record. The p-values should therefore be understood as unadjusted, and the record does not allow a reconstruction of an adjusted inferential result.

The record identifies the primary outcome population as completers of all doses per protocol. It does not report an intention-to-treat analysis population, participant flow by condition, reasons for non-completion, or the handling of missing outcome observations. Although enrollment is 44 and each condition’s outcome count is 40, the reason for the difference is not reported. The record also does not describe imputation, sensitivity analyses, or exclusion criteria beyond the per-protocol completer label.

The trial is described as a randomized five-way crossover, but the statistical analysis of repeated observations is not reported. In general, crossover analyses may need to account for within-participant correlation and may consider period or sequence effects. Whether those elements were included, and how they were handled, is not reported in the registry record. The original statistical analysis plan, interim analyses, and sample-size justification are also not reported. These omissions limit what can be concluded about prespecification and the analysis underlying the posted comparisons.

14. 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 non-serious adverse event terms

The registry reports zero serious adverse events for each of the five conditions, with 44 participants at risk in each condition. It reports zero deaths in every condition. These are the posted serious-event counts; they do not establish that no adverse events of any kind occurred.

The record separately lists other adverse events affecting 4 participants in the placebo condition, 5 with generic hydrocodone/acetaminophen, 13 with Vycavert, 18 with generic hydrocodone/acetaminophen plus additional inactive ingredients, and 5 with generic hydrocodone/acetaminophen plus one placebo tablet. These are counts, not rates or comparative statistical tests. The registry does not provide event terms in the listed serious-event section, and no serious-event terms are listed there.

In general, safety counts need context about event definitions, exposure time, repeated treatment periods, severity, and participant-level overlap. Those details are not reported in the registry record. The adverse-event figures should therefore be read as the reported counts for the listed conditions, not as a complete comparative safety analysis or a basis for conclusions beyond the recorded counts.

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

The posted endpoint results describe maximum drug-liking scores in participants who completed all doses per protocol. Mean scores were 54.5 for placebo and ranged from 72.1 to 75.6 across the four active conditions. The unadjusted recalculated mean differences against placebo ranged from 17.6 to 21.1, and each reported unadjusted p-value was < 0.001. The accompanying intervals communicate statistical uncertainty for these summary-statistic comparisons, subject to the limitations of the unreported analysis method.

These results concern a subjective visual analog scale response during an 8-hour assessment period among non-dependent recreational opioid users in a single-center crossover study. They do not establish responses in other populations, with other formulations or doses, or under other routes of administration. They also do not directly measure later drug use, misuse, dependence, or outcomes outside the trial. The registry’s stated aim was to assess relative abuse potential, but the posted primary endpoint is a measure of maximum drug liking rather than a direct behavioral outcome.

The reported comparisons use placebo as the reference. The record does not report a direct statistical comparison of Vycavert with generic hydrocodone/acetaminophen, so the two arm means and their separate comparisons with placebo should not be treated as a test of equivalence or difference between those products. Nor do the unadjusted p-values establish results from a crossover model or an adjustment for multiple comparisons.

These data describe the posted outcomes; they do not by themselves determine clinical benefit, risk, or suitability for an individual. The registry record does not report the full statistical plan, missing-data methods, or an adjusted analysis. Conclusions should remain limited to the measured score, the stated population, the recorded conditions, and the uncertainty represented by the posted estimates.

16. Why This Trial Matters Statistically

This trial illustrates why the design and analysis need to be read together. The study is described as a randomized, double-blind, five-way crossover, so participants received more than one condition. That structure can permit comparisons within the same participant, but statistical interpretation depends on accounting for the relationships among repeated measurements. The registry identifies the crossover design but does not report the model used to analyze it. The posted summary-statistic recalculations therefore offer contrasts that are easy to interpret on the original score scale, while leaving the design-specific analysis question unresolved.

The outcome also illustrates the distinction between a measurement and a broader construct. Maximum drug liking is a subjective score collected over a defined post-dose timeframe. It is relevant to the trial’s stated assessment of abuse potential, but does not directly record subsequent behavior. The score’s scale anchors clarify what its values mean; the means and standard deviations then describe group-level location and variability without showing the full distribution of individual responses.

Finally, the record shows why uncertainty and multiplicity deserve attention alongside point estimates. All four placebo comparisons have reported unadjusted p-values below 0.001 and confidence intervals, but the analysis plan and any multiplicity strategy are not reported. Statistical strength in an unadjusted comparison does not answer every design or interpretation question. Separating descriptive results, recalculated contrasts, and missing analysis details helps keep the conclusions aligned with what the registry actually records.

17. 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 provides limited information about how the crossover design was implemented and analyzed. It does not report the washout interval, the detailed treatment sequence, the statistical model, or whether period and sequence effects were assessed. The posted mean differences are unadjusted summary-statistic recalculations and do not reconstruct within-participant correlations. The crossover design therefore cannot be fully evaluated from the reported summaries alone.

The primary outcome population is described as completers of all doses per protocol, with 40 participants reported for each condition, while enrollment is 44. The reasons for this difference, participant flow, and missing-data handling are not reported. The record does not report an intention-to-treat analysis or sensitivity analyses. It also does not report a direct statistical comparison between Vycavert and generic hydrocodone/acetaminophen.

The four comparisons against placebo are reported with unadjusted p-values. A multiplicity plan, original statistical analysis plan, interim analyses, and the trial’s own sample-size justification are not reported. The planning illustrations based on observed effects do not fill those gaps. The primary endpoint is a subjective maximum liking score over 8 hours; the registry does not report individual score distributions or longer-term behavioral outcomes. The trial’s single-center setting and specified participant population also limit how broadly these results can be applied. These are limits on interpretation of the posted record, not evidence about unreported outcomes.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Abuse Potential of Intranasal VYCAVERT Tablets (Hydrocodone Bitartrate/Acetaminophen) in Recreational Opioid Users — NCT01759446.
• Registry record last updated 2018-11-01; status last verified 2018-08.
• Results first posted 2018-11-01.
• 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.

21. Record Summary

The registry describes a completed Phase 2, randomized, double-blind, active- and placebo-controlled, single-center, five-way crossover study of intranasal Vycavert and comparator conditions in non-dependent recreational opioid users. Enrollment was 44. The primary outcome was maximum drug liking over 8 hours on a 100-point bipolar visual analog scale, assessed in participants who completed all doses per protocol.

Each condition has 40 participants in the posted primary outcome results. Mean scores were 54.5 for placebo, 75.0 for generic hydrocodone/acetaminophen, 72.1 for Vycavert, 75.6 for generic hydrocodone/acetaminophen plus additional inactive ingredients, and 73.0 for generic hydrocodone/acetaminophen plus one placebo tablet. Unadjusted summary-statistic recalculations compare each active condition with placebo; a direct Vycavert-versus-generic comparison and a reported crossover analysis are not available in the registry record.