Clonidine Versus Adenosine to Treat Neuropathic Pain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clonidine Versus Adenosine to Treat Neuropathic Pain (NCT00349921), a randomized phase 2 study. The primary outcome is Number Meeting Success Criterion.

2. Clinical Question

The study is listed as phase 2 and completed. Its primary outcome is framed as a count of participants meeting a response threshold, based on verbal pain reports before injection and two hours after injection. This makes the question about whether a participant crossed the specified reduction threshold, rather than about the average amount of pain reduction.

The record reports 10 participants meeting the criterion in the clonidine group and 5 in the adenosine group. It also reports a chi-squared test with p >0.05 for the comparison. The registry record does not provide an effect estimate or confidence interval for that comparison. These results therefore describe the posted counts and the reported test; they do not establish the size or precision of a difference between the treatments.

Although placebo is listed among the interventions and treatment sequences, the reported primary analysis is limited to clonidine and adenosine. The placebo result is recorded separately as a count, with a denominator that is much smaller than the denominators for those two active-treatment results. The registry record does not explain the allocation or analysis details behind that small placebo denominator. The central statistical question remains the active-treatment comparison, interpreted in light of the crossover design and the limited information recorded about its conduct and analysis.

3. Trial Design

This is a randomized, triple-masked, phase 2 crossover study listed as completed. The registry record gives an enrollment of 24 and identifies Wake Forest University Health Sciences as the sponsor. The recorded study start is 2004-08, and primary completion is listed as 2008-01. These dates describe the record and do not supply details about the timing of individual treatment periods.

A crossover design means, in general, that participants can receive more than one treatment in a planned sequence, allowing comparisons within participants. The arm descriptions name sequences involving clonidine followed by adenosine and adenosine followed by clonidine. They also include descriptions involving placebo. The record does not report the period lengths, washout arrangements, sequence allocation counts, or how the analysis handled treatment period and order. Those details matter when interpreting a crossover comparison, so the design label alone cannot establish how these features were addressed.

Randomization indicates that assignment to the study's allocated treatment arrangements was randomized. Triple masking indicates masking at three levels, but the registry record does not identify the people or roles covered by that term. It also does not describe how masking was maintained or assessed. These labels communicate key design features but do not replace a full account of the methods.

The primary endpoint is a count of participants meeting a defined pain-response criterion, based on verbal pain reports at baseline and two hours after injection. The posted arm results list denominators of 21 for clonidine, 20 for adenosine, and 1 for placebo. These denominators do not match the enrollment figure, and the registry record does not explain their relationship to enrollment, treatment sequences, or the analysis population. They should be read as the denominators recorded for the outcome results, not as a full participant flow description.

The registry record reports one primary outcome measure and one analysis. It does not report a protocol-level statistical analysis plan, a sample-size justification, or details of interim analyses. Such details cannot be inferred from the phase, design, or enrollment labels.

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: 24 subjects consented and enrolled 2 subjects withdrawn prior to group assignment because they did not meet inclusion / exclusion criteria on second review

First Spinal Injection

Reasons for not completing this period:

Second Spinal Injection

Analysis population for the primary outcome, as defined in the registry: The primary outcome measure will be % change in pain report 2 hr following injection, using a response criterion of 30% reduction in ongoing pain.

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 Meeting Success Criterion, measured over baseline and 2 hours.

The primary endpoint is titled “Number Meeting Success Criterion.” It counts participants whose verbal pain report two hours after injection met a response threshold relative to their baseline verbal pain score. The stated criterion is a 30% reduction in ongoing pain. The time frame is baseline and two hours.

A threshold-based endpoint turns a continuous change in pain report into a yes-or-no classification for each participant: meeting or not meeting the specified criterion. The count therefore conveys how many participants crossed that threshold in each reported group. It does not show the distribution of individual pain changes, the average change, or how far participants who responded exceeded the threshold. Those quantities are not reported as the primary outcome in the registry record.

Such an endpoint can be used to express a response in terms that are directly tied to a prespecified level of change, rather than relying only on an average that may conceal variation among participants. Its interpretation depends on the threshold, the pain measurement, and the timing of assessment. Here, the record identifies the verbal pain report, the baseline reference, the two-hour assessment, and the 30% criterion. It does not provide further information about the measurement instrument or the handling of missing measurements.

The results list the number meeting the criterion as 10 for clonidine, 5 for adenosine, and 0 for placebo. The corresponding recorded denominators are 21, 20, and 1. These counts describe the posted endpoint results. They do not by themselves quantify uncertainty or establish a treatment effect, and the active-treatment comparison should be interpreted alongside the reported test and the limitations of the available summary statistics.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a count: the number of participants meeting a specified response criterion. For this study, success was defined as a 30% reduction in ongoing pain, comparing the verbal pain report two hours after injection with the baseline score. A count endpoint differs from a continuous endpoint such as mean change. It records whether each participant crossed the threshold, not the size of the change for every participant.

The registry record names a chi-squared test for the clonidine-versus-adenosine comparison. In general, a chi-squared test assesses whether observed category counts differ from what would be expected under a null hypothesis of no association or no group difference, according to the test's setup. For a binary response, the categories are commonly response and non-response. The record does not provide the full contingency counts, the test statistic, degrees of freedom, or a confidence interval, so the test cannot be reconstructed in detail from the posted summary.

The reported result is p >0.05. In general, a p-value is calculated under a statistical model and a null hypothesis. A result above a chosen threshold does not prove that the null hypothesis is true. It indicates that the analysis did not meet that threshold for declaring a statistically significant result. It does not tell readers the probability that the treatments are equal, and it does not measure the probability that the observed counts arose by chance in an unrestricted sense.

Precision is usually conveyed with an effect estimate and a confidence interval. The estimate describes the comparison on a chosen scale; the interval describes uncertainty around it under the method's assumptions. Neither an estimate nor a confidence interval is reported for the primary comparison. The posted counts make the response frequencies visible, but do not replace an interval estimate. A simple unadjusted recalculation is not estimable from the posted summary statistics for this count-other endpoint, as indicated by the record. Consequently, there is no recalculated effect estimate or interval to compare with the reported analysis.

The trial is identified as a crossover study. In general, this design can compare treatments within participants, which may account for some stable differences between participants. It also introduces analytic considerations: responses from the same participant are not independent, and outcomes may vary by treatment period or sequence. Carryover from an earlier treatment can also matter in a crossover study. These are general considerations, not claims that any particular problem occurred in this trial. The registry record does not report the analysis model, period effects, carryover assessment, washout details, or whether the chi-squared test accounted for within-participant dependence. The stated test name alone does not settle those questions.

The recorded outcome denominators are not the same across clonidine, adenosine, and placebo. The clonidine result lists 21, the adenosine result lists 20, and placebo lists 1. In general, unequal denominators can reflect different numbers contributing outcome data, but the reason in this trial is not reported in the registry record. They should not be interpreted as proof of a particular exclusion, missingness pattern, sequence structure, or analysis rule. The enrollment figure is also recorded as 24, and no participant-flow explanation is given to connect enrollment with the outcome denominators.

Planning sample sizes are a different kind of quantity from observed results. In general, a sample-size calculation uses assumptions about an effect to detect, variability or event rates, significance level, allocation, and a statistical method. The planning illustration described for this trial uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with effects defined as stated fractions of the observed effect. It is explicitly a planning illustration computed from the observed effect, not the trial's own design. The available record does not give numerical planning outputs in the registry record described for this analysis. Such illustrations are not observed power and do not show that the completed study had a particular probability of detecting an effect.

Over-dispersion is a general concern for count data when variability exceeds what a simple model assumes. It can make standard errors too small if the model does not allow for the extra variability. The posted primary endpoint is a participant count meeting a criterion, and the reported test is chi-squared; the registry record does not report a dispersion assessment or a model that permits one. This is a general methodological point, not an assertion that over-dispersion occurred.

Finally, statistical significance, effect size, and precision answer different questions. The reported p-value addresses a test under its assumptions. The counts describe observed threshold responses. An effect estimate would quantify the treatment contrast, and a confidence interval would show its precision. Because the record supplies the counts and test result without an estimate or interval, conclusions should remain limited to those reported quantities and to the uncertainties arising from the missing analysis details.

10. Analyses Reported by the Sponsor

The registry record reports a sponsor analysis using a chi-squared test for clonidine versus adenosine, with p >0.05. The outcome is a count of participants meeting the success criterion, and the record indicates that values are missing or not estimable for a two-arm recalculation of this count-other endpoint. There is therefore no simple unadjusted recalculated estimate or confidence interval to set alongside the reported test.

The absence of a recalculation does not contradict the sponsor's result. It means that the posted summary statistics do not support the additional unadjusted calculation used for other types of outcomes. The reported test remains the only inferential result recorded for this primary comparison. The discrepancy indicator is false, so the record does not flag a conflict between a recalculation and the reported analysis.

The sponsor result should still be read within its limits. The record does not provide an effect estimate, confidence interval, full analysis details, or an account of how the crossover structure was handled. The test's p-value alone does not show the size or precision of the comparison and cannot establish equivalence. The interpretation is therefore based on the reported test and counts, without implying that unavailable recalculated results would confirm or overturn them.

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary outcome measure and one analysis. It reports no secondary posted outcomes. This limits what can be said about the scope of the results, but it does not establish whether the study examined additional outcomes or analyses that were not posted.

Multiplicity arises when several hypotheses or outcomes are tested. In general, performing many tests can increase the chance of at least one result crossing a significance threshold by chance. Researchers may address this through a prespecified testing hierarchy or adjustment procedure. The registry record does not report whether any such approach was planned, whether interim analyses were conducted, or whether other analyses were performed. Those details are not reported in the registry record, so no adjustment method or testing strategy should be assumed.

The record does not describe missing-data handling, reasons for missing outcome measurements, or an analysis population such as intention-to-treat or per-protocol. It also does not report a participant flow account connecting the enrollment figure of 24 to the outcome denominators of 21 for clonidine, 20 for adenosine, and 1 for placebo. The differing denominators are visible in the outcome results, but their explanation is not reported in the registry record.

In general, missing outcomes can affect both the estimated response frequency and its uncertainty, particularly if the likelihood of missingness is related to treatment or outcome. That is a general concern, not evidence that missingness biased these results. Without the number and reasons for missing observations, and without a description of the analysis population, the direction or magnitude of any potential effect cannot be assessed.

The crossover design adds further questions about which treatment periods contributed outcome data and how repeated observations were handled. Those details are also not reported. The available record therefore supports a narrow description of the listed primary endpoint and its single reported comparison, but not a full assessment of multiplicity, missing-data assumptions, or population-level analysis decisions.

12. 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.

The adverse-event record gives results by treatment sequence. For clonidine first, then adenosine, 0 serious adverse events and 0 other adverse events are recorded among 11 at risk. For adenosine first, then clonidine, the record likewise lists 0 serious and 0 other adverse events among 11 at risk. For each sequence that includes placebo, the record lists 0 serious and 0 other adverse events among 1 at risk.

These figures describe the adverse-event entries recorded for the listed groups. They should be read as sequence-specific reporting, not as a direct comparison of the safety of clonidine, adenosine, and placebo. In a crossover study, a sequence can include more than one treatment, and the registry record does not provide treatment-specific exposure or event attribution for these entries.

The registry record does not report death counts. It also does not provide further adverse-event details in the listed serious-event terms. A recorded zero in a group means no event was entered for that category in the posted result; it does not establish that no adverse events occurred outside the scope or reporting represented by these entries. The small placebo denominator in particular provides very limited information about events in that sequence.

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

The result establishes what the registry record reports: 10 participants in the clonidine group and 5 in the adenosine group met the defined 30% pain-reduction criterion, while the placebo result records 0 participants meeting it. The denominators are 21, 20, and 1, respectively. For the active-treatment comparison, the reported chi-squared test has p >0.05.

This does not establish that clonidine and adenosine are equivalent. A non-significant test does not demonstrate equality, and the absence of an effect estimate and confidence interval leaves the size and precision of the comparison unclear. Nor does the result establish that one treatment is superior. The observed counts differ, but the reported test did not meet the conventional 0.05 significance threshold, and the record supplies no interval for judging plausible effect values.

The counts also do not show how much pain changed for individual participants, whether changes were sustained beyond two hours, or how the response threshold relates to outcomes at other times. The endpoint captures whether the specified threshold was met at the stated assessment, not the full pattern of pain reports.

The placebo result cannot support a robust comparison with either active drug because its recorded denominator is 1. The record does not explain why that denominator is so small or how the placebo sequences were incorporated into the study's analysis. In addition, the registry record does not clarify the link between enrollment and the denominators used for the outcome.

Finally, the crossover label does not by itself reveal whether period, sequence, or within-participant dependence were accounted for in the reported test. The statistical conclusion is therefore limited to the posted counts and the reported p-value, interpreted with the missing precision and analysis details in mind. It is not a basis for medical advice or a broader claim about treatment effects.

14. Why This Trial Matters Statistically

This trial illustrates why an outcome definition matters. A threshold response count answers how many participants reached a specified level of pain reduction. It is not interchangeable with an average change, and it cannot show how far each participant's pain report changed. Reading the endpoint correctly prevents a count from being mistaken for a continuous measure.

It also shows the distinction between observed data and an inferential result. The counts describe the participants meeting the criterion; the chi-squared p-value summarizes a test under its assumptions. Neither supplies the effect size and precision that an estimate with a confidence interval would provide. A result with p >0.05 cannot be treated as proof of no difference or equivalence.

The crossover design makes the analysis method especially relevant. General considerations include repeated measurements within participants and possible period or sequence effects. The record names a chi-squared test but does not describe how the analysis relates to those features. Statistical interpretation must distinguish what the design label says from what the reported method documents.

The record also demonstrates the importance of denominator context. Enrollment is recorded as 24, while the outcome results use denominators of 21, 20, and 1. Without a participant-flow account, readers cannot determine how those denominators arose. The small placebo denominator further illustrates why a listed group result may carry little information for comparison.

Finally, planning illustrations should not be confused with study design or observed power. A sample-size illustration based on an observed effect is a planning exercise, not evidence that the completed trial was adequately powered or that a result is conclusive. Keeping these distinctions clear supports careful reading of clinical trial statistics without overstating what a registry record can establish.

15. 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 primary comparison lacks a reported effect estimate and confidence interval. The posted counts and p-value therefore do not quantify the magnitude or precision of the clonidine-versus-adenosine result. A simple unadjusted recalculation is not estimable from the posted summary statistics for this endpoint.

The outcome denominators differ across the reported groups, and the registry record does not explain how they relate to the enrollment figure or to participant flow. The denominator of 1 for placebo makes that result particularly limited as a basis for comparison. Reasons for missing outcome data, if any, are not reported in the registry record.

Although the design is identified as crossover, the record does not describe treatment-period lengths, washout arrangements, sequence allocation, or the handling of repeated observations. It does not state whether period, sequence, or carryover effects were considered. These omissions make it difficult to assess whether the reported chi-squared analysis reflects the structure of the trial.

The endpoint is tied to a verbal pain report at two hours and a 30% reduction threshold. The record does not provide further detail about the measurement instrument or report continuous pain changes alongside the threshold count. The results therefore do not describe the distribution or persistence of pain changes.

The registry record also does not report a statistical analysis plan, sample-size justification, interim-analysis details, or analysis population definition. The single posted primary analysis should not be taken as proof that no other analyses occurred. The available safety entries are grouped by sequence, and deaths are not reported in the registry record. These limitations constrain interpretation of efficacy-related statistics, safety reporting, and the completeness of the trial account.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Clonidine Versus Adenosine to Treat Neuropathic Pain — NCT00349921.
• Registry record last updated 2018-09-10; status last verified 2018-08.
• Results first posted 2014-02-26.
• 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.

19. Record Summary

NCT00349921 is a completed, randomized, triple-masked, phase 2 crossover study sponsored by Wake Forest University Health Sciences. The recorded study start is 2004-08, primary completion is 2008-01, and enrollment is 24. The study concerns pain and examines clonidine and adenosine, with placebo also listed in the interventions and sequence descriptions.

The primary outcome counts participants meeting a 30% reduction in ongoing pain by verbal report at two hours after injection compared with baseline. The posted results are 10 of 21 for clonidine, 5 of 20 for adenosine, and 0 of 1 for placebo. The reported clonidine-versus-adenosine chi-squared result is p >0.05.

No effect estimate or confidence interval is reported for that comparison, and a simple unadjusted recalculation is not estimable from the posted summary statistics. The registry record does not explain the differing outcome denominators or describe key crossover-analysis details. Safety entries list no serious or other adverse events in the reported sequence groups; deaths are not reported in the registry record.