Safety of Buprenorphine Transdermal System (BTDS) in Subjects With Acute Postoperative Pain After Total Knee Replacement: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of Buprenorphine Transdermal System (BTDS) in Subjects With Acute Postoperative Pain After Total Knee Replacement (NCT00403234), a randomized phase 2 study. The primary outcome is Number of Participants With Adverse Events (AEs) as a Measure of Safety.

2. Clinical Question

The official study description identifies a multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study after total knee arthroplasty. The treatment period was described as 28 days. The registry summary says the sponsor terminated the trial early for administrative reasons not related to efficacy or safety, after which the study focus became safety evaluations. The registry record does not report a completed efficacy comparison or a conclusion about pain relief or rehabilitation. The clinical question that can be addressed from the posted results is therefore descriptive: what adverse-event counts were recorded in the listed treatment groups, and how limited are those counts as evidence about safety?

3. Trial Design

The registry describes a randomized, double-blind, placebo-controlled, parallel-group pilot study in people with acute postoperative pain after total knee replacement. The listed groups were placebo, BTDS 10, BTDS 20, and BTDS 30. The active patches were described as delivering 10 mcg/h, 20 mcg/h, or 30 mcg/h and being applied for 7-day wear. Placebo patches were described as similar to BTDS 10 and 20. The registry does not report further details about randomization procedures or how treatment assignments were concealed.

The double-blind treatment period was described as 28 days, with supplemental analgesic medication to be provided to all participants in addition to study drug. Enrollment was 10. The registry lists the study status as terminated and gives administrative reasons unrelated to efficacy or safety as the reason for early termination. It also states that the study focus became safety evaluations. The registry record does not report the planned enrollment target or how early termination affected recruitment or follow-up.

The recorded primary outcome was the number of participants with adverse events, assessed from signed informed consent through 7 days after the end of study, approximately 35 days. The description also notes follow-up of certain serious adverse events through 30 days following the last study visit. The safety population comprised participants who were randomized, received at least one dose of double-blind study drug, and had at least one safety assessment during double-blind treatment. The registry record does not report the statistical analysis plan, details of any interim analyses, or a sample-size justification. No inferential analyses are posted.

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: Enrolled: N = 14. Following surgery and recovery from anesthesia, subjects had to demonstrate moderate to severe pain within 6 hours postsurgery ("Pain Right Now" rating of ≥ 2 on a 4-point scale where 0 = no pain and 3 = severe pain), then their intravenous patient-controlled analgesia morphine device was activated. N = 10 were randomized.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety Population consisted of subjects who were randomized, received at least 1 dose of double-blind study drug and had at least 1 safety assessment during double-blind treatment.

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 Number of Participants With Adverse Events (AEs) as a Measure of Safety, measured over From signed informed consent to 7 days after end of study (approx. 35 days).

The primary endpoint is the number of participants with adverse events as a measure of safety. It is a participant count: it indicates how many people in each group had an event, rather than how many separate events occurred in total. A participant who experienced more than one adverse event would still contribute as a participant with an event to this endpoint. The registry’s description does not provide event-level detail for every participant.

The stated observation period begins at signed informed consent and extends to 7 days after the end of study, approximately 35 days. The description says adverse events arising during that period were followed until they resolved, and that serious adverse events occurring up to 30 days following the last study visit were followed. The safety population is restricted to randomized participants who received at least one dose of double-blind study drug and had at least one safety assessment during treatment. Consequently, the endpoint is not a count of all enrolled participants regardless of treatment exposure or assessment.

General statistical context: participant-level adverse-event counts are useful for describing how often participants experienced events in each group. They do not, by themselves, establish that an observed difference between groups is caused by treatment. Interpretation also depends on the number of participants assessed, event definitions, follow-up, and uncertainty around the counts. The registry record does not report a formal comparison or an uncertainty estimate for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical context: trial methods determine which participants contribute to an outcome, how outcomes are summarized, and whether comparisons account for the design. A randomized design assigns participants to groups by chance, which is intended to reduce systematic differences between groups at baseline. Randomization does not guarantee that groups will be alike, particularly when group sizes are small. The registry identifies the study as randomized, but does not report the sequence-generation method, allocation concealment procedures, or other implementation details.

What does a participant count represent?

The primary outcome is the number of participants with adverse events. This is a binary participant-level outcome: each person is classified according to whether an adverse event was recorded during the defined period. It is different from a total count of all events, because one participant can experience multiple events while still being counted once for the participant-level measure. The adverse-event results separately identify participants at risk and participants affected for serious and other adverse events. The registry record does not explain every event’s severity, timing, duration, or relationship to treatment in the posted results.

For descriptive interpretation, the affected count should be considered alongside the number at risk in the same group. The counts are small in every group in this study. General statistical context: when there are few participants, the observed count is a limited and potentially unstable estimate of how often an event might occur in a broader population. A difference in counts across groups can arise from chance variation, and sparse data make it difficult to estimate group differences precisely. The registry does not report confidence intervals or a formal comparison for these adverse-event counts.

What can a confidence interval tell a reader?

General statistical context: a confidence interval expresses the uncertainty around an estimated quantity under a specified statistical procedure. A narrow interval indicates greater precision than a wide interval, while an interval spanning a range of plausible values signals uncertainty about the estimate. An interval does not resolve design limitations or establish causation. No confidence intervals are reported in the registry record for the primary outcome. Readers therefore cannot use the posted adverse-event counts to assess a registry-reported interval for the group-specific rates or a between-group contrast.

Why does the absence of an analysis matter?

The registry lists zero posted analyses. It does not report p-values, adjusted estimates, or a model for the primary endpoint. The record also notes that the primary outcome has several categories or time points and was not reduced to one comparison. That prevents a single inferential contrast from being identified from the posted results. General statistical context: a p-value, if reported, would describe how compatible data are with a specified statistical model and null hypothesis; it would not measure the size or clinical importance of an effect. No such value is available in this record, and none should be inferred from the counts.

The registry’s sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The assumed effect to detect is described as a stated fraction of the observed effect. For this outcome, however, the registry notes that several categories or time points were not reduced to one comparison, and no analysis is posted. The record does not report an observed effect estimate for a single comparison or a trial-specific sample-size justification. Any planning illustration is a design exercise, not observed evidence about the trial’s power or the treatment effect.

How should the design features be read?

The registry identifies the study as double-blind and parallel-group. General statistical context: blinding is intended to limit the influence of knowledge of treatment assignment on participant experience, care, and outcome assessment. A parallel-group design assigns each participant to a treatment group rather than comparing repeated treatment periods within the same participant. The record does not report who was blinded, how blinding was maintained, or whether it was assessed. The described supplemental analgesic medication for all participants is relevant context for interpreting the study’s stated efficacy objectives, but the registry record does not provide an analysis of its use or its relation to the safety results.

Finally, the registry’s outcome population definition matters. It includes participants who were randomized, received at least one dose of double-blind study drug, and had at least one safety assessment during treatment. General statistical context: analysis populations can differ from the full group enrolled or randomized, and the distinction can affect interpretation if participants are excluded from a particular analysis. The record does not provide a participant-flow account explaining exclusions or missing safety assessments. These methodological limits leave the posted counts useful for description, but insufficient for a precise treatment comparison.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan specifying how multiple outcomes, treatment groups, categories, or time points were to be handled. It identifies a primary safety outcome, while the study objectives also included analgesic efficacy and functional rehabilitation measures. The registry notes that the primary outcome has several categories or time points and was not reduced to one comparison. No inferential analyses are posted, so there is no reported multiplicity adjustment or stated hierarchy of tests.

General statistical context: when many outcomes or comparisons are examined, the chance of finding an apparently notable result by chance can increase. A prespecified analysis plan can clarify which comparisons are primary and how multiple testing will be addressed. The record does not report whether such procedures were planned or used. That absence is not evidence that multiplicity was or was not controlled; the approach is not reported in the registry record.

The safety population definition requires randomization, receipt of at least one dose, and at least one safety assessment during double-blind treatment. The registry record does not report how many participants were excluded from that population, whether any outcomes were missing, or how missing safety information was handled. It does not report a missing-data strategy, imputation procedure, or sensitivity analysis. General statistical context: missing outcomes can affect estimates when the likelihood of missingness is related to treatment or event status, and assumptions about missingness should be made explicit when analyses are performed.

The record also does not report a detailed participant-flow account, interim-analysis plan, or rules for stopping the study. It states that termination was early for administrative reasons not related to efficacy or safety and that the focus became safety evaluations. The registry record does not report whether early termination changed any analysis procedures. These omissions limit assessment of prespecification and completeness, rather than allowing conclusions about how the unreported procedures were conducted.

11. 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 4.5% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse-event display lists 0 affected participants in each group: placebo, BTDS 10, BTDS 20, and BTDS 30. The corresponding numbers at risk are 2, 3, 3, and 2. The registry’s top serious-event terms list is empty. These entries indicate that no serious adverse events are counted in the posted affected fields for the listed groups; they do not establish that the risk is absent beyond the participants observed.

The other adverse-event counts are 2 affected among 2 at risk for placebo, 2 among 3 for BTDS 10, 3 among 3 for BTDS 20, and 2 among 2 for BTDS 30. These are participant counts, not totals of separate events. The registry record does not give a detailed breakdown of the other adverse events in these results. Group sizes are small, and the counts alone do not support a precise comparison or a conclusion about cause.

The death entries are null. A null entry is not a reported numerical zero, so the record does not give a death count in those fields. The stated follow-up includes adverse events from signed informed consent through 7 days after the end of study, approximately 35 days, with serious adverse events occurring up to 30 days following the last study visit followed as described. Interpret all counts within this specified safety follow-up and population.

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

The posted results document adverse-event counts among participants in the safety population of a small, early-terminated pilot study. They show 0 affected participants for serious adverse events in each listed group, and they show affected participants for other adverse events in every group. Those observations describe what was recorded in this trial’s safety results. They do not, on their own, establish that any patch dose is safer or less safe than placebo.

The counts are based on only 2 or 3 participants at risk in each group. General statistical context: such sparse data give limited precision and make group comparisons especially sensitive to the outcome status of individual participants. No confidence intervals, p-values, or other inferential comparisons are reported in the registry record. It is therefore not possible to assess a registry-reported estimate of the size or precision of a difference between groups. Lack of a reported difference is not evidence of equivalence.

The study’s objectives included efficacy on postoperative pain, functional rehabilitation measures, and safety. However, the posted primary outcome is safety, and the registry summary states that the focus became safety evaluations after early administrative termination. No efficacy analysis is posted in the registry record. The adverse-event results cannot answer whether BTDS changes pain or rehabilitation outcomes.

The results also do not establish how common these events would be in a broader population, whether an individual event was caused by a study treatment, or how event patterns might vary outside the recorded follow-up. The registry does not report detailed event descriptions in the posted primary outcome, a full analysis plan, or a missing-data account. Those gaps matter when judging what can be learned from a small set of counts.

The most defensible reading is descriptive and bounded: the registry records no serious adverse events in the affected fields and records other adverse events among participants in all listed groups. The numbers are too limited and the inferential results too sparse to support a reliable comparative safety conclusion from this record alone.

13. Why This Trial Matters Statistically

This trial illustrates a recurring statistical challenge in clinical research: a randomized design can still yield very limited evidence when few participants contribute outcome data. Randomization is valuable for reducing systematic differences between groups, but it cannot make small groups large or eliminate uncertainty in rare or variable outcomes. Here, only a few participants are listed at risk in each group, so the safety counts are primarily descriptive.

The record also shows why the endpoint definition and analysis population matter. The primary measure counts participants with adverse events, while the safety population excludes anyone not meeting the stated treatment-exposure and assessment criteria. A reader needs both details to understand what the count represents. The record does not provide a full participant-flow account, leaving the relation between total enrollment and the analyzed safety population incompletely described.

Early termination and a shift in focus to safety are important context, but do not by themselves determine whether the posted counts are biased. The record attributes termination to administrative reasons unrelated to efficacy or safety. It does not report the trial’s original sample-size justification, interim-analysis procedures, or how termination affected analysis. Statistical interpretation should not fill those gaps by assumption.

Finally, the registry has no posted inferential analyses and notes that the primary outcome was not reduced to one comparison. This makes clear the difference between seeing group-specific counts and having a prespecified, quantified comparison with uncertainty. For biostatisticians and clinical researchers, the study is a useful example of why registry completeness, analysis-population definitions, and cautious interpretation are essential when outcomes are sparse and a trial ends early.

14. 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.

Several limitations specific to this study constrain interpretation. Enrollment was 10, and the adverse-event results list only 2 or 3 participants at risk in each group. These small counts provide limited information about event frequency and cannot support a precise comparison across placebo and the three BTDS dose groups. No confidence intervals or inferential comparisons are reported in the registry record.

The study was terminated early for administrative reasons not related to efficacy or safety, according to the registry summary. The record does not report the planned enrollment target, a trial-specific sample-size justification, or how termination affected recruitment, follow-up, or analysis. It also does not report whether all planned outcomes were collected or analyzed. The registered summary says the study focus became safety evaluations, while efficacy and rehabilitation were among the stated objectives.

The primary outcome is described as having several categories or time points and was not reduced to one comparison. No analysis is posted. The record therefore does not provide a single statistical contrast for the primary endpoint, an adjustment strategy for multiple comparisons, or estimates of uncertainty. The detailed statistical analysis plan is not reported in the registry record.

The safety population includes randomized participants who received at least one dose and had at least one safety assessment during double-blind treatment. A participant-flow account and details about exclusions or missing assessments are not reported. The death fields are null, rather than numerical counts, and the top serious-event terms list is empty; neither field supplies additional detail about event narratives. The registry also does not report a detailed breakdown of other adverse events in the posted results. These limitations restrict the conclusions to a description of the recorded counts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety of Buprenorphine Transdermal System (BTDS) in Subjects With Acute Postoperative Pain After Total Knee Replacement — NCT00403234.
• Registry record last updated 2012-09-03; status last verified 2012-08.
• Results first posted 2010-09-21.
• 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.

18. Record Summary

The registry describes a randomized, double-blind, placebo-controlled, parallel-group pilot study of BTDS after total knee replacement. Listed groups were placebo and BTDS 10, BTDS 20, and BTDS 30. Enrollment was 10, and the double-blind treatment period was described as 28 days with supplemental analgesic medication for all participants. The trial status is terminated; the registry summary attributes early termination to administrative reasons unrelated to efficacy or safety and states that the focus became safety evaluations.

The primary outcome is the number of participants with adverse events, using a safety population defined by randomization, receipt of at least one dose, and at least one safety assessment. The posted results list no affected participants for serious adverse events and affected participants for other adverse events in every group. The registry does not report inferential analyses, confidence intervals, or a single comparison for the primary outcome. The results support descriptive reading only, not a precise comparative safety conclusion.