An Efficacy, Safety and Effects on Quality of Life of Tramadol/Paracetamol as Add-on Therapy in Chronic Osteoarthritis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Efficacy, Safety and Effects on Quality of Life of Tramadol/Paracetamol as Add-on Therapy in Chronic Osteoarthritis (NCT01728246), a randomized phase 4 study. The primary outcome is Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) Score at Week 2.

2. Clinical Question

In statistical terms, the study was designed to assess whether pain scores changed over the stated period in participants assigned to the add-on regimen compared with those assigned to the Non-Tramadol/APAP group. The endpoint definition says that a decrease from baseline represents improvement, no change represents halting of progression, and an increase represents disease progression and/or joint worsening. Those definitions explain how a measured change should be interpreted; they do not reveal what changes were observed.

The registry record describes the study purpose as evaluating efficacy, safety, and quality-of-life effects. It does not report a numerical primary outcome result, a confidence interval, or a test result. Consequently, the clinical question can be identified, but the posted record does not establish the magnitude or precision of any difference between groups.

3. Trial Design

The record describes a completed, randomized, parallel-group Phase 4 trial with no masking. Enrollment is listed as 473. The sponsor was Janssen Pharmaceutica. The recorded start was 2007-10, and primary completion was 2008-05. These details describe the registered design and timing; they do not by themselves indicate what the trial found.

The intervention was tramadol/paracetamol (APAP), and the other group was labeled Non-Tramadol/APAP. The intervention is described in the study summary as add-on therapy, meaning medication taken in addition to another medication. The arm descriptions are blank, so the specific regimen in each group, including the background medication and any treatment rules, is not reported in the registry record. The comparator should therefore not be assumed to be placebo, usual care, or any particular alternative.

Randomization means assignment to groups was intended to be determined by chance, which can help balance prognostic characteristics on average. The method used to generate the assignments, concealment of assignments, and any stratification factors are not reported in the registry record. The trial was unmasked: participants and relevant study personnel were not described as blinded. The record does not specify who knew the assigned treatment or whether outcome assessors were masked.

The primary endpoint was change from baseline in VAS-pain score at Week 2. The stated endpoint population was an intent-to-treat population defined as participants who received at least 1 dose and had at least 1 post-baseline efficacy assessment. This is the population definition recorded for the endpoint, rather than an unrestricted definition that includes every randomized participant. Details of participant flow, withdrawals, adherence, and analysis procedures 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT) population included all the participants who received at least 1 dose of study medication and had at least 1 post-baseline efficacy assessment.

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 Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) Score at Week 2, measured over Baseline and Week 2.

The primary endpoint was change from baseline in Visual Analogue Scale for Pain (VAS-pain) score at Week 2, measured in mm. The scale is described as 100 millimeter, ranging from 0 mm for no pain to 100 mm for worst possible pain. Change was defined as the score at observation minus the score at baseline. Under that definition, a negative change indicates a lower pain score than at baseline; the record characterizes a decrease as improvement, no change as halting of disease progression, and an increase as disease progression and/or joint worsening.

A continuous pain scale retains gradations rather than reducing each participant’s experience to a simple yes-or-no category. Summarizing the change as a mean can describe the average direction and size of change in a group. The standard deviation describes how dispersed individual changes are around that mean. Neither statistic alone describes every participant’s response, and a group mean can conceal substantial variation.

Baseline-to-follow-up change is useful for describing how scores evolve over the stated observation period. Comparing group changes can address whether the average pattern differs between assigned groups, subject to the design and analysis assumptions. The registry record specifies the measure and timing but does not report either group’s mean change, standard deviation, or an estimated between-group contrast. Thus, the endpoint’s clinical meaning is defined, while its observed result and precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change describe?

The primary measure is continuous: pain is recorded on a millimeter scale, and the analysis is defined in terms of mean change. A mean is the arithmetic average of measured changes in the specified population. It offers a compact description of the group’s average direction and magnitude of change, but it does not mean that every participant changed by that amount. Individual experiences can vary around the average.

The standard deviation (SD) describes the spread of individual observations around the group mean. A larger SD indicates more variation in the measured changes; a smaller SD indicates that observations are more concentrated around the mean. SD is not the same as the uncertainty in the group mean. Estimating uncertainty in a mean or group contrast also depends on the amount of information in the analysis and on the analysis method.

How should a group contrast be understood?

For a randomized comparison, the central efficacy quantity is usually a contrast between outcomes in the assigned groups. For this endpoint, that would concern the difference between the groups’ changes from baseline. The registry record does not report this contrast or the group means and SDs needed to describe it. No estimate should be reconstructed from the enrollment figure or from unrelated safety counts.

In general, random assignment supports comparison because it is intended to make groups comparable on average at the start of the study. It does not guarantee exact balance in a particular trial, and the interpretation still depends on how participants were analyzed, how missing outcomes were handled, and whether the recorded outcome was measured consistently. Details of the randomization method and the statistical model are not reported in the registry record.

What do confidence intervals and p-values tell readers?

General statistical explanation: a confidence interval expresses uncertainty around an estimate under the assumptions of the method used. A narrow interval indicates greater precision than a wide interval, but precision is not the same as clinical importance. Whether values within an interval would be considered important requires a clinical interpretation that is not specified in this record.

General statistical explanation: a p-value measures how unusual the observed data would be under a specified null hypothesis and analysis model. It does not give the probability that a treatment works, and it does not measure the size or importance of an effect. A p-value should be interpreted alongside an effect estimate, its confidence interval, and the study design. The registry record does not report a primary endpoint p-value or confidence interval.

Why can variation affect an analysis?

General statistical explanation: continuous outcomes are often analyzed using methods that rely on assumptions about the distribution of observations or model errors. Skewness, outliers, or unequal variability can affect how well a simple model describes the data. If outcomes are more variable than a model allows, uncertainty may be understated unless the analysis accounts for that extra variation. Over-dispersion is a term used especially for count data when observed variability exceeds what a model expects; it is not a reported feature of this continuous primary endpoint.

The endpoint uses a mean and SD, but the record does not give the observed values, their distributions, or diagnostics. It is therefore not possible to assess whether model assumptions were checked, whether transformations or robust methods were used, or whether the analysis was adjusted for baseline values. Such methods are not reported in the registry record.

What do the planning assumptions mean?

The recorded sample-size assumptions describe a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not evidence about what the trial observed and not an account of the original design justification. The registry record does not report a sample-size justification, nor does the available information include the resulting planning estimates or the observed effect used in that illustration.

General statistical explanation: a planning calculation estimates how much information a future study might need under specified assumptions about an effect, variability, allocation, and error rates. It depends on those assumptions and does not establish the probability that a completed trial’s conclusion is correct. Such planning values are not observed power and cannot replace the missing endpoint results.

What can be inferred from the posted record?

The record identifies a randomized, parallel, unmasked design and defines the primary endpoint and its analysis population. It does not report the primary outcome estimates, an inferential test, or the statistical model. The design information is useful for framing the intended comparison; it is not enough to recreate the analysis or judge the endpoint result. Any interpretation beyond the recorded details would require results and methods that are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 6 outcome measures and 3 analyses. It does not report how those outcomes or analyses were prioritized beyond identifying the primary endpoint, nor whether any adjustment for multiple comparisons was planned or applied. When several outcomes or analyses are examined, the chance of obtaining at least one apparently notable result can increase. General methods for addressing this include prespecifying a primary comparison or adjusting inference, but the record does not say which approach was used for the reported analyses.

The primary outcome is defined as change from baseline in VAS-pain score at Week 2. Its result is not reported in the registry record. Without the outcome estimates and analysis details, multiplicity cannot be assessed in relation to the observed findings, and no claim about a prespecified statistical hierarchy or correction is warranted.

The specified intent-to-treat population included participants who received at least 1 dose and had at least 1 post-baseline efficacy assessment. This definition does not include participants without any post-baseline efficacy assessment. The number excluded under that definition, the handling of missing Week 2 values, and any imputation or sensitivity analyses are not reported in the registry record.

General statistical explanation: missing outcome data can affect a comparison when the chance of having an observed measurement is related to prognosis or treatment response. Different assumptions about unobserved values can lead to different estimates. The record does not report the extent or pattern of missing primary outcome data, so the consequences of missingness cannot be evaluated. Details about analysis populations beyond the stated definition are also not reported.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: vaginal bleeding (0.4%), severe hypertension (0.4%), generalized body rashes (0.4%), dizziness / nausea (0.4%).

For tramadol/paracetamol (APAP), the registry reports 1 serious adverse event among 242 participants at risk. For Non-Tramadol/APAP, it reports 1 serious adverse event among 231 participants at risk. These are descriptive counts with their recorded denominators. They are not adjusted comparisons and do not establish that the groups have equivalent or different risks.

The record also reports other adverse events affecting 19 participants in the tramadol/paracetamol (APAP) group and 10 participants in the Non-Tramadol/APAP group, with 242 and 231 participants at risk, respectively. The serious-event terms listed are Vaginal Bleeding, Severe Hypertension, Generalized Body Rashes, and Dizziness / Nausea, each recorded as 0.4%. The registry does not specify in this list which group each term belongs to, so those terms should not be assigned to a group.

Counts alone do not show event timing, duration, severity beyond the serious classification, or whether investigators considered an event related to treatment. Deaths are not reported in the record. These safety figures are limited registry summaries and should not be treated as a complete safety profile or as a causal comparison.

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

The registry record establishes the question the trial set out to address: a randomized comparison involving tramadol/paracetamol (APAP) as add-on therapy for chronic osteoarthritis, with change in VAS-pain score at Week 2 designated as the primary endpoint. It also records some adverse event counts. These details help describe the design and the reporting that is available.

The record does not report the primary endpoint’s group means, SDs, between-group estimate, confidence interval, or p-value. It therefore does not show the observed direction or magnitude of the pain-score comparison. The outcome definition explains how to interpret an increase or decrease, but it cannot reveal whether either occurred in the trial. The registry record also does not report a numerical quality-of-life result.

The safety counts should be interpreted narrowly. They indicate the numbers recorded for the stated adverse event categories and denominators, but do not establish causation, comparative risk, or a complete account of harms. The listed serious-event terms are not assigned to a treatment group in the record. Deaths are not reported.

These limitations do not mean that the trial had no findings; they mean that the relevant findings are not reported in the registry record. Nor do they establish that the intervention is beneficial or ineffective, safe or unsafe. A treatment conclusion would require the outcome results, statistical analysis, and fuller context for safety reporting. The appropriate reading is that this record describes a registered trial and selected outcomes, while leaving the primary efficacy result and important analysis details unavailable.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between a registered research question and a reported result. The record identifies randomization, a parallel-group comparison, the intervention label, the comparator label, and a continuous primary pain endpoint. It also defines the direction of score change and the population used for the endpoint. Those details clarify what the intended analysis concerned.

At the same time, a well-defined endpoint does not make an efficacy estimate available. Without the group changes and their uncertainty, readers cannot assess how large or precise the comparison was. This distinction is fundamental: knowing what was measured is not the same as knowing what the study found. A title or stated purpose cannot substitute for outcome data.

The record also illustrates why safety summaries need careful reading. Event counts and denominators are useful descriptive information, but they do not alone address timing, relatedness, completeness, or uncertainty. Unassigned event terms should not be interpreted as group-specific findings.

Finally, the stated analysis population and the absence of missing-data details matter for interpretation. An intent-to-treat label does not remove the need to understand who contributed outcome data and how missing observations were handled. Since those details and the primary results are not reported in the registry record, conclusions must stay bounded by what is documented. The statistical value of the record lies in defining the intended comparison and making clear which information remains unavailable.

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.

Important design and analysis details are not reported in the registry record. The arm descriptions are blank, and the comparator label does not explain the medication or care participants received. The record does not specify the tramadol/paracetamol dosing regimen, the background therapy, adherence procedures, or rules for other treatments. These omissions limit interpretation of what the assigned groups actually received.

The randomization method, allocation concealment, and any stratification are not described. The study is recorded as unmasked, but the record does not clarify which study personnel knew assignment or whether outcome assessors were masked. It also does not report participant flow, withdrawals, protocol deviations, or the amount and pattern of missing primary outcome data.

The primary endpoint is defined, but its group-level results and inferential statistics are not reported. The analysis model, any adjustment for baseline score, handling of outliers, sensitivity analyses, and method for addressing multiple outcomes are not reported in the registry record. The listed intent-to-treat population requires receipt of at least 1 dose and at least 1 post-baseline efficacy assessment; further details about other analysis populations are not available.

The safety summary is also limited: deaths are not reported, and the serious adverse event terms are not linked to a treatment group in the listed terms. Timing, treatment relatedness, and event-level descriptions are not reported. These are limitations of what can be learned from the registry record, rather than evidence that any particular procedure or analysis was absent from the trial.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: An Efficacy, Safety and Effects on Quality of Life of Tramadol/Paracetamol as Add-on Therapy in Chronic Osteoarthritis — NCT01728246.
• Registry record last updated 2013-02-12; status last verified 2013-02.
• Results first posted 2013-01-14.
• 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 completed, randomized, parallel, unmasked Phase 4 trial of tramadol/paracetamol (APAP) as add-on therapy in chronic osteoarthritis. Enrollment is listed as 473; the recorded start was 2007-10 and primary completion was 2008-05. The comparator is labeled Non-Tramadol/APAP.

The primary endpoint was change from baseline in VAS-pain score at Week 2, measured in mm. The stated intent-to-treat population required receipt of at least 1 dose and at least 1 post-baseline efficacy assessment. The registry record does not report the primary endpoint results, a confidence interval, or a p-value.

Serious adverse event counts were 1 among 242 at risk in the tramadol/paracetamol (APAP) group and 1 among 231 at risk in the Non-Tramadol/APAP group. Deaths are not reported. Further details on the treatment regimens and statistical analyses are not reported in the registry record.