Buprenorphine 8 mg Sublingual Tablets Under Fasting Conditions: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Buprenorphine 8 mg Sublingual Tablets Under Fasting Conditions (NCT01157169), a randomized phase 1 study. The primary outcome is Cmax of Buprenorphine..

2. Clinical Question

3. Trial Design

This was a randomized, open-label, two-period, two-treatment, two-way crossover study. Participants received both treatments in a sequence, rather than being assigned to remain on just one treatment. In general, a crossover design allows each participant's response under one treatment to be compared with that participant's response under the other. The registry record does not report the washout duration, sequence details beyond the treatment-first group labels in the adverse-event data, or the procedures used to control period or carryover effects.

The study was listed as phase 1 and enrolled 40 healthy participants. The primary outcome description specifies that samples from participants who completed the study were analyzed. The posted summaries for the primary measure contain 33 participants for each product. Reasons for the difference between enrollment and the analyzed group counts are not reported in the registry record.

The treatment comparison followed an overnight fast of at least 10 hours. Blood samples were collected over a 144 hour period. The record identifies no masking; therefore, the study was not described as blinded. The registry lists the study as completed and gives the start as 2007-08 and primary completion as 2007-09.

The comparison focused on an investigational buprenorphine 8 mg sublingual tablet and Subutex® 8 mg sublingual tablets. The posted primary measure was buprenorphine Cmax. Three posted secondary measures concern norbuprenorphine: maximum concentration, area under the concentration-time curve through the last measured time, and area under the curve extrapolated to infinity. The protocol's original design rationale, planned sample size, and detailed statistical analysis plan are not reported in the registry record.

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.

First Intervention

Reasons for not completing this period:

Washout of 10 Days

Second Intervention

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants that completed the study had their samples analyzed.

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 Cmax of Buprenorphine., measured over Blood samples collected over a 144 hour period..

The primary endpoint was buprenorphine Cmax, measured in ng/mL. Cmax is the maximum observed concentration of a drug substance in plasma during the sampling period. It describes the peak concentration observed after administration and is one way to compare the rate and extent of absorption between formulations. The registry specifies that blood samples were collected over a 144 hour period and that the endpoint was summarized as a mean with a standard deviation.

In general, Cmax is useful in a formulation comparison because it captures the observed peak rather than total exposure across the whole sampling interval. It does not, by itself, describe the full concentration-time profile or total drug exposure. Other measures, such as the posted norbuprenorphine area-under-the-curve outcomes, address different features of concentration over time.

The endpoint description says the analysis population consisted of participants who completed the study and had their samples analyzed. The posted mean Cmax was 4.4 ng/mL for the test product and 3.88 ng/mL for the reference, with standard deviations of 2.16 and 1.82, respectively; each summary includes 33 participants. These group summaries describe the observed concentrations. The registry does not report the full analysis method for the sponsor's crossover comparison or the bioequivalence limits used to interpret the result.

7. Results Posted in the Registry

• Buprenorphine (Test): mean 4.40 versus 3.88 on control; difference 0.52 (95% CI -0.44 to 1.48), standardized effect d = 0.26; z-test p = 0.290.

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.

Cmax for Norbuprenorphine.

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Buprenorphine (Test): mean 1.58 versus 1.64 on control; difference -0.06 (95% CI -0.39 to 0.27), standardized effect d = -0.09; z-test p = 0.721.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Buprenorphine (Test) and the control. The interval gives the range of effects that remain compatible with the data.

AUC0-t for Norbuprenorphine.

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Buprenorphine (Test): mean 45.34 versus 47.58 on control; difference -2.24 (95% CI -11.08 to 6.60), standardized effect d = -0.12; z-test p = 0.619.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Buprenorphine (Test) and the control. The interval gives the range of effects that remain compatible with the data.

AUC0-inf for Norbuprenorphine.

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Buprenorphine (Test): mean 50.77 versus 51.04 on control; difference -0.27 (95% CI -12.71 to 12.17), standardized effect d = -0.01; z-test p = 0.966.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Buprenorphine (Test) and the control. The interval gives the range of effects that remain compatible with the data.

The three posted secondary measures concern norbuprenorphine: Cmax, AUC0-t, and AUC0-inf. Together, they describe peak concentration and exposure over the observed interval or its extrapolation. The sponsor's reported test-to-reference geometric mean ratios are 93.28, 94.19, and 95.06, respectively, each with a 90% confidence interval. The recalculated mean differences are close to zero relative to the reported variation, although their intervals are broad enough to include values on either side of zero.

Across these measures, the overall pattern is of sponsor ratio estimates near 100, with uncertainty that varies by endpoint. This is broadly consistent with the primary result in the sense that both sets of outcomes compare absorption-related measures for the same products; it does not make the secondary outcomes a substitute for the primary Cmax analysis. Each measure captures a different feature of the concentration-time profile, and the results should be interpreted on their own scales.

The secondary results carry less weight for a confirmatory claim because the registry identifies the primary endpoint separately, while a multiplicity adjustment is not reported for the secondary analyses. When several outcomes are examined, unadjusted results can produce apparently notable findings by chance. The registry record also does not report whether these outcomes were prespecified in the detailed protocol or how their testing was ordered. They are useful supporting pharmacokinetic descriptions, but should not be treated as independent confirmation of the primary result or as proof that a formal bioequivalence criterion was satisfied.

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

• Cmax for Norbuprenorphine.
• AUC0-t for Norbuprenorphine.
• AUC0-inf for Norbuprenorphine.

9. Statistical Interpretation

10. Statistical Methods Explained

General: A continuous endpoint records a measurement on a numerical scale. Cmax and area-under-the-curve measures are continuous outcomes. A mean describes the center of a set of observations, while a standard deviation describes how dispersed individual observations are around that mean. The registry reports means and standard deviations for the posted outcome groups.

For Cmax, the posted test mean was 4.4 ng/mL and the reference mean was 3.88 ng/mL. The corresponding standard deviations were 2.16 and 1.82. The simple recalculation reports an unadjusted mean difference of 0.52 ng/mL and p = 0.29. A mean difference remains in the endpoint's original units, which makes it directly interpretable as a concentration difference. It is not the same estimand as a ratio of geometric means.

General: A p-value describes how compatible the data are with a specified null model, assuming that model and the analysis assumptions hold. It is not the probability that a treatment effect is true, and it does not indicate whether a difference is important. The posted recalculated p-value is unadjusted. The sponsor's reported analyses do not include a p-value.

The trial used a crossover design. In general, the key comparison in a crossover study is within participant: each participant receives both products, and the analysis can use the difference between that participant's measurements under the two treatments. Such an analysis can account for participant-level variability. The registry record does not identify the method used in the sponsor's reported analysis, and the posted group means and standard deviations do not include the paired differences or their covariance. Consequently, the simple recalculation from group summaries is not a substitute for the full crossover analysis.

General: Geometric means are often used for pharmacokinetic measures whose distributions are analyzed on a logarithmic scale. A test-to-reference geometric mean ratio compares the two products multiplicatively. A ratio of 100 represents equal geometric means on that scale; values above 100 indicate a higher test geometric mean relative to reference, and values below 100 indicate a lower one. The sponsor reported this ratio for Cmax as 110.49 and a 90% confidence interval from 101.67 to 120.07. The record does not state the exact model or other implementation details behind these estimates.

General: A confidence interval expresses uncertainty about an estimate under the assumptions of the analysis. It gives a range of values compatible with the data and method at the stated confidence level; it is not a range that contains a known true value with certainty. For a ratio, whether an interval supports a formal equivalence conclusion depends on the acceptance limits chosen in advance. Those limits are not reported in the registry record. The sponsor's reported interval therefore describes the estimate and its precision, but the registry entry alone does not establish whether it fell within the protocol's decision boundaries.

The sponsor reported 90% confidence intervals for the primary and secondary geometric-mean ratios. The method field for those analyses is not reported, and the record gives no corresponding p-values. The recalculated results use a different scale and a simple unadjusted approach; they should not be read as reproducing the sponsor's model. Because the discrepancy indicator is false, there is no flagged disagreement between a sponsor result and the recalculation. Even so, the sponsor's own analysis is the relevant analysis for its stated bioequivalence assessment.

General: Over-dispersion means that observed variability is greater than a model expects. When present, it can make standard errors too small and confidence intervals too narrow if the analysis fails to account for it. The registry record does not report a specific over-dispersion assessment, and no such assessment can be inferred from the posted means and standard deviations alone.

General: Multiple testing arises when several outcomes or comparisons are examined. Each additional test creates another opportunity for a result to appear noteworthy by chance. Adjustment methods can control this issue, but they may also change the uncertainty or decision threshold used for individual outcomes. The record posts three secondary outcomes and does not report a multiplicity procedure. These secondary findings therefore warrant more cautious interpretation than a prespecified primary analysis.

The detailed statistical plan, including the model, treatment of period and sequence, handling of missing measurements, and the original sample-size justification, is not reported in the registry record. The distinction between a posted sponsor estimate and a summary-statistic recalculation is important: the sponsor's analysis uses a geometric-mean ratio, while the recalculation describes an arithmetic mean difference. They answer related but nonidentical statistical questions.

11. Confidence Intervals and Precision

The sponsor's primary Cmax ratio estimate was 110.49, with a 90% confidence interval from 101.67 to 120.07. The interval communicates uncertainty around the ratio estimate: values across that range are compatible with the reported analysis at its stated confidence level. The width reflects both the observed data and the analysis method. It should not be interpreted as a probability that the true ratio lies within those particular endpoints.

For a bioequivalence assessment, precision alone is not enough. The interval must be interpreted against the acceptance limits specified by the study. Those limits are not reported in the registry record. The interval's position relative to 100 can describe the direction of the ratio estimate, but without the acceptance limits it cannot establish the formal bioequivalence conclusion.

The posted group standard deviations also show that individual Cmax values varied around their means. The recalculated unadjusted comparison gives a mean difference of 0.52 ng/mL and p = 0.29, but that summary does not capture the within-participant covariance expected in a crossover comparison. The sponsor's ratio interval and the recalculated mean-difference comparison use different scales and methods, so their precision should not be compared as though they were estimates of exactly the same quantity.

The sample size for the posted primary summaries is 33 participants per product, while enrollment was 40. The registry record says completed participants with analyzed samples contributed to the primary outcome, but reasons for the smaller analysis count are not reported. That difference, the absent paired-data details, and the missing equivalence limits restrict how fully the precision of the formal crossover comparison can be assessed from the registry entry.

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 figures are participants per arm, not total events. They are illustrations based on the observed effect, not a description of the trial's original design. The calculation assumptions are a two-sided significance level of 0.05, equal allocation between the 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 and justification are not reported in the registry record.

The 80% power column gives the planned number of participants per arm for a design that would have an 80% chance of detecting the specified effect under the stated assumptions, if the assumptions and effect were correct. The 90% power column gives the corresponding number for a higher chance of detecting that effect. Power is a property of a planned study under assumptions; it is not a measure of how likely the observed result is to be true.

Each planning row considers a different fraction of the observed effect. Planning for 75% or 50% of the observed effect means targeting a smaller effect than planning for 100% of it. Smaller effects are harder to distinguish from random variation, so they require more participants for the same target power. For example, for the primary endpoint the planning illustration lists 232 participants per arm for 80% power at 100% of the observed effect, and 927 participants per arm at 50% of the observed effect.

These figures are planning illustrations, not observed power estimates. They are not evidence that the completed study was designed around the observed effect, and they do not establish what the original protocol expected to detect. The assumptions and effect fractions should be considered when interpreting the large differences among the planning figures.

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 = 0.520; pooled standard deviation σ = 1.997.
2. n = 2 × (1.96 + 0.842)² × 1.997² / 0.520² = 231.6, rounded up to 232 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 <- 0.52                      # observed difference in means
sigma <- 1.99724810677091                     # 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(1157169)
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 = 232 (80% power), 311 (90% power)
 75% of observed effect: n per arm = 412 (80% power), 552 (90% power)
 50% of observed effect: n per arm = 927 (80% power), 1,241 (90% power)
power.t.test: 232.5 
Simulated power at n = 232 per arm: 0.800 (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 sponsor's primary analysis is reported as a test-to-reference geometric mean ratio multiplied by 100, with a 90% confidence interval. For buprenorphine Cmax, the ratio was 110.49 and the interval was 101.67 to 120.07. The registry does not report the analysis method or the acceptance limits for the bioequivalence decision. The ratio and interval can therefore be described, but a formal conclusion against an unreported criterion cannot be verified from the registry record.

The recalculated result is a simple, unadjusted arithmetic mean difference of 0.52 ng/mL, with p = 0.29. It is based on posted group summaries and does not reproduce a paired crossover analysis. The geometric-mean ratio and arithmetic mean difference use different scales and answer different statistical questions; they are not competing versions of an identical estimate.

The discrepancy indicator is false, so the record does not flag a conflict between the sponsor's result and the recalculation. The sponsor's own analysis takes precedence for the study's bioequivalence assessment. The registry record does not provide enough methodological detail to independently reproduce that analysis, and the recalculated comparison should be treated only as a supplementary, unadjusted description.

15. Multiplicity, Missing Data and Analysis Populations

The registry posts one primary endpoint and three secondary norbuprenorphine endpoints. It reports six outcome measures and six analyses overall. The record does not describe a multiplicity adjustment, a hierarchy for testing the outcomes, or a plan for interpreting secondary results after the primary analysis. Without those details, the three secondary results are best treated as descriptive or supportive rather than as a set of independent confirmatory tests.

The primary endpoint description identifies the analyzed population as participants who completed the study and had samples analyzed. Its posted summaries include 33 participants for each product, whereas enrollment is recorded as 40. The registry does not report why some enrolled participants are not represented in the primary summaries, whether missingness differed by treatment sequence, or how incomplete profiles were handled. It also does not report the number of participants with missing values for each secondary endpoint.

In a crossover study, period, sequence, and within-participant effects can be relevant to analysis. The detailed statistical model and the handling of these features are not reported in the registry record. Nor are the protocol's original analysis populations, data exclusions, interim analyses, or sample-size justification reported. The absence of these details limits assessment of how closely the posted analyses follow the planned analysis and whether missing observations could affect the comparison.

These omissions do not invalidate the posted summaries, but they restrict independent verification and the strength of conclusions that can be drawn from them. The sponsor's own method is not identified in the reported analysis entry, and the equivalence margins are not given. Thus, the record permits a description of the observed estimates and their uncertainty, but not a complete audit of the confirmatory decision process.

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 non-serious adverse event terms

The adverse-event record lists serious adverse events for two treatment-sequence groups: Buprenorphine (Test) First and Subutex® (Reference) First. In each group, 0 of 40 participants at risk had a serious adverse event recorded. No serious adverse-event terms are listed. These figures describe the registry's serious-event entries for the groups and do not establish that no events of any kind occurred.

The record separately lists other adverse events for 22 of 40 participants in the test-first group and 13 of 40 in the reference-first group. Because this was a crossover study, the sequence labels should not be interpreted as simple parallel treatment groups without further details about event timing and attribution. The registry record does not report the types of these other events in this summary. Death counts are not reported in the registry record.

These data are descriptive. They do not establish comparative safety, particularly without event-level detail, timing, severity information for non-serious events, or the analysis plan for safety outcomes. The serious-event counts should be read as the entries recorded, rather than as proof of absence of risk.

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

The posted results describe pharmacokinetic measurements after a single dose of two buprenorphine sublingual tablet products in healthy participants under fasting conditions. The primary measure, Cmax, summarizes the maximum observed plasma concentration. The sponsor's reported test-to-reference geometric mean ratio was 110.49, with a 90% confidence interval from 101.67 to 120.07. The registry does not provide the bioequivalence limits needed to determine whether that interval met the study's formal criterion.

The simple recalculated arithmetic mean comparison is supplementary and does not reproduce the sponsor's crossover analysis. Nor do the posted concentration measures directly answer questions about clinical benefit, symptom control, long-term outcomes, or effects in people with a medical condition. The study enrolled healthy participants, and its results should be understood within that setting and its fasting administration conditions.

The three secondary norbuprenorphine measures add information about related concentration and exposure measures. They do not resolve the missing protocol details, acceptance limits, or uncertainty about analysis methods. The sample-size planning illustrations are based on the observed effects and stated calculation assumptions; they do not reveal the study's original design rationale.

Accordingly, the registry supports a statistical description of the posted measurements and sponsor ratios, with the stated uncertainty. It does not support a medical recommendation, a conclusion about long-term safety, or an independent determination of formal bioequivalence without the prespecified limits and fuller analysis details.

18. Why This Trial Matters Statistically

This trial illustrates why a crossover design and its analysis need to be considered together. In a crossover study, the same participant receives both treatments, so the statistical comparison commonly uses within-participant information. The registry posts group means and standard deviations, but not the paired differences or the analysis method. A simple recalculation from group summaries can describe the data but cannot reproduce all features of the sponsor's crossover analysis.

It also demonstrates that the scale of an estimate matters. The sponsor reports a geometric-mean ratio, while the recalculation reports an arithmetic mean difference. Both concern the same primary endpoint, but they are not interchangeable quantities. Confidence intervals need to be interpreted on the scale and against the decision criteria for which the analysis was designed. The bioequivalence limits are not reported in the registry record.

Finally, planning illustrations based on observed effects can be mistaken for a trial's original sample-size rationale. The listed planning figures instead show how required participant counts vary under specified assumptions and target effects. They are not evidence about the study's original design or the strength of its completed analysis. These distinctions are useful when assessing what registry results can establish and where additional protocol or analysis details would be needed.

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 acceptance limits for the sponsor's bioequivalence assessment. It also does not identify the method used for the sponsor's reported ratio analysis, provide the detailed statistical model, or show the paired participant-level data. Those omissions prevent independent verification of the crossover analysis and its formal decision.

Although 40 participants were enrolled, the primary summaries include 33 participants for each product. The primary description says that participants who completed the study and had samples analyzed were included, but reasons for the smaller analysis count and details about missing measurements are not reported. The original sample-size rationale and the trial's planned analysis populations are also not reported.

The posted secondary results have no reported multiplicity procedure, and the registry does not describe how the secondary outcomes were prioritized. Safety data are summarized by treatment sequence, with limited detail about event types and timing. The record also does not provide information needed to assess generalizability beyond healthy participants receiving a single dose under fasting conditions.

These limitations do not change the numerical summaries, but they constrain interpretation. In particular, they prevent a complete assessment of the sponsor's equivalence decision, the influence of missing data, and whether the posted analyses match the full prespecified plan.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Buprenorphine 8 mg Sublingual Tablets Under Fasting Conditions — NCT01157169.
• Registry record last updated 2020-01-18; status last verified 2020-01.
• Results first posted 2010-09-13.
• 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

The registry describes a completed, randomized, open-label, phase 1, two-period, two-treatment crossover study of buprenorphine 8 mg sublingual tablets in healthy participants under fasting conditions. Enrollment was 40. The primary endpoint was buprenorphine Cmax, measured in ng/mL from samples collected over 144 hours; the posted summaries include 33 participants for each product.

The sponsor reported a Cmax test-to-reference geometric mean ratio of 110.49 and a 90% confidence interval from 101.67 to 120.07. A simple unadjusted recalculation gives an arithmetic mean difference of 0.52 ng/mL and p = 0.29, but it does not reproduce the crossover analysis. The record does not report the bioequivalence limits, detailed statistical method, original sample-size rationale, or multiplicity plan.

Three norbuprenorphine secondary outcomes and descriptive adverse-event counts are also posted. The results characterize absorption measures in this study setting; they do not, by themselves, establish a formal bioequivalence conclusion or clinical outcomes.