An Open-Label Long-term Safety Study of Tramadol HCl OAD (Once A Day) 300 mg in the Treatment of Pain Due to Osteoarthritis of the Knee: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Open-Label Long-term Safety Study of Tramadol HCl OAD (Once A Day) 300 mg in the Treatment of Pain Due to Osteoarthritis of the Knee (NCT00833911), a na phase 3 study. The primary outcome is Number of Patients Having Experienced an Adverse Event During the 6-12 Month Open-Label Safety Participation.

2. Clinical Question

The clinical question is descriptive: it concerns the number of participants reported to have adverse events during exposure to the study drug. Because there is no control group, the record does not estimate how these counts compare with an untreated group or with a group receiving another treatment. Nor does this design, on its own, distinguish events caused by treatment from events that occurred during treatment for other reasons.

3. Trial Design

This is a Phase 3, open-label, single-group study of Tramadol HCl OAD, once daily at 300 mg, for pain due to osteoarthritis of the knee. The sponsor is Labopharm Inc. The record lists study start as 2003-04, primary completion as 2004-07, and status as completed. Enrollment is reported as 392.

There is no randomized allocation and no masking: allocation is listed as NA, masking as none, and the model as single-group. All participants in the described treatment group received the study drug. The design is therefore a long-term safety follow-up study rather than a randomized comparison of treatments. Event counts in its duration-defined populations do not constitute estimates of comparative safety.

The primary outcome concerns participants having experienced an adverse event during the 6-month and 12-month open-label safety participation. Spontaneous adverse-event reports were recorded for the overall study population and for safety populations defined by treatment duration. The overall population includes people who took at least 1 dose. The 6-month safety population includes participants who completed at least 175 days on treatment; the 12-month safety population includes participants who completed at least 350 days.

These duration definitions describe who is included in each summary. They do not establish that every participant had the same length of observation, or that the groups can be treated as independent comparison arms. The record does not report a protocol-level statistical plan, a sample-size justification, or a planned comparison between these populations. Its central contribution is descriptive reporting of adverse-event counts under open-label exposure.

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.

Titration

Reasons for not completing this period:

Maintenance Phase I

Reasons for not completing this period:

Maintenance Phase II

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All patients having taken 1 dose of 300 mg Tramadol HCl OAD at a minimum are being assessed for adverse event occurence for up to 12 months. 6-months safety: patients who completed at least 175 days on treatment. 12-months safety: patients who completed at least 350 days on 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 Patients Having Experienced an Adverse Event During the 6-12 Month Open-Label Safety Participation, measured over 6 months and 12 months.

The primary endpoint is the number of participants reported to have experienced an adverse event during the safety participation. It is expressed as a participant count, rather than as a measure of symptom severity, time to first event, or change in a clinical scale. The registry describes spontaneous reporting for the overall study population and the safety populations defined by the 6-month and 12-month treatment-duration criteria.

A participant count is a direct way to describe how many people in a defined population had an event recorded. It can help readers understand the observed burden of reported events during follow-up. The count must be read with its population definition: the overall population required at least 1 dose, whereas the duration-defined populations required completion of at least 175 days or at least 350 days on treatment.

Counts alone do not describe when events began, how long they lasted, their severity beyond the separate serious-event classification, or whether they were judged related to treatment. The record does not report those details as part of this primary outcome. Nor does a count establish that treatment caused an event. Without a control group and further attribution information, the endpoint supports a descriptive account of reported events during exposure, not a causal or comparative conclusion.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

A participant count records how many people in a specified population were reported to have an event. It differs from a count of event episodes: one person can have more than one event, so the number of affected participants does not necessarily equal the total number of events. The primary outcome is expressed as participants, and the registry describes spontaneous reports. These features matter when interpreting the reported values: the counts describe people with recorded events, not the full event history of each person.

Every count depends on its population definition. The overall safety population includes participants who took at least 1 dose of 300 mg Tramadol HCl OAD. The 6-month and 12-month summaries use completion thresholds of at least 175 days and at least 350 days on treatment, respectively. A count in one such population answers a descriptive question about that group; it is not automatically comparable with a count in a group defined by a different follow-up requirement.

Why does the single-group design matter?

A randomized comparison can help separate treatment-group differences from differences that arise because groups began with different characteristics. This study has a single-group model and no randomized allocation, so it has no concurrent control group for that purpose. Its observed adverse events occurred during treatment participation, but the design cannot establish how many would have occurred without the study drug or under another treatment. This is a general limitation of interpreting uncontrolled safety observations, not a claim that any particular event was or was not caused by treatment.

The open-label design also means masking is listed as none. In general, awareness of treatment and study participation can affect how events are noticed, described, or reported. The registry says that adverse events were collected through spontaneous reports, but does not provide further detail about event elicitation or adjudication. These reporting features should be considered when reading counts from an open-label safety study.

What do the serious and other event counts show?

The record separates serious adverse events from other adverse events. The counts are reported for the overall population and for the two treatment-duration-defined safety populations. They describe observed reports in each group; they are not measures of relative risk or evidence of a treatment effect. No confidence intervals or inferential analyses are reported in the registry record, so the precision of the counts as estimates of a broader population is not quantified there.

In general, a confidence interval communicates the range of values compatible with an estimate under a statistical model and its assumptions. Without such an interval, readers should not treat a count as if it had no uncertainty. A zero observed count is also not equivalent to certainty that the underlying event risk is zero. The registry’s count of 0 serious adverse events in the 12-month safety population describes what was recorded for that group, rather than establishing absence of risk.

Why is follow-up duration relevant?

Participants who meet a longer treatment-duration threshold necessarily satisfy a different participation criterion from the overall population. Their follow-up opportunity and selection into the summary may differ. In general, event counts collected over unequal observation periods do not by themselves provide an exposure-adjusted comparison. A time-to-event analysis or a rate using person-time can address different questions, but neither is reported in the registry record. The record also does not state how event timing was handled in the posted summaries.

It would be inappropriate to infer that the lower serious-event count in a duration-defined group reflects a protective effect or a change in hazard. The group definitions, possible overlap, observation time, and event ascertainment all matter. The record does not provide enough detail to make a formal comparison between the duration-defined groups.

What statistical analysis is reported?

The record lists one outcome measure and no analyses. It supplies descriptive counts for adverse events but reports no inferential procedure, adjusted estimate, test statistic, or confidence interval. The statistical plan, including any planned handling of repeated events or follow-up differences, is not reported in the registry record.

The sample-size assumptions described in the record concern a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. They do not establish that this single-group safety study was designed around a particular sample-size target, and no sponsor sample-size justification is reported in the registry record. Planning illustrations are not observed power and do not add evidence about the precision or reliability of the posted safety counts.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("6-months Safety", "12-months Safety")
n      <- c(275, 168)
events <- c(188, 121)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  6-months Safety  275  188  68.4  62.5  73.8  62.6  73.6  62.6  73.6
ARM  12-months Safety  168  121  72.0  64.6  78.7  64.8  78.3  64.8  78.3

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure and no analyses. It does not report a multiplicity adjustment or a statistical testing strategy. The posted safety summaries include the overall population and populations defined by 6-month and 12-month treatment-duration thresholds, as well as separate serious and other adverse-event counts. Those descriptive summaries do not, by themselves, establish that multiple hypotheses were tested. If inferential comparisons or many event-specific tests had been planned, their handling would matter, but such a plan is not reported in the registry record.

Missing-data methods are not reported in the registry record. The entry does not state how participants with incomplete follow-up were handled in the overall adverse-event summary, whether event reporting was complete for each participant, or how missing event information was classified. It is therefore not possible to determine from the record whether missing observations could affect the reported counts.

The analysis populations are described by exposure and treatment duration: at least 1 dose for the overall population, at least 175 days completed for the 6-month safety population, and at least 350 days completed for the 12-month safety population. The record does not report an intention-to-treat analysis or another named analysis population. It also does not clarify whether participants in the duration-defined groups overlap, so those summaries should not be treated as independent groups.

These omissions constrain interpretation. They do not show that an appropriate procedure was or was not used outside the registry entry; they mean that the registry record does not document it.

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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: back pain (0.4%), acute pulmonary oedema (0.3%), cerebrovascular accident (0.3%), cholecystectomy (0.3%), cholecystitis, not otherwise specified (nos) (0.3%).

The serious adverse-event figures are participant counts within the named safety populations. The overall group reports 9 affected participants among 392 at risk; the 6-month safety group reports 1 among 275; and the 12-month safety group reports 0 among 168. The registry also reports other adverse events in these same summaries: 321, 169, and 101 participants, respectively. These categories should be read as the record presents them, rather than added together or treated as mutually exclusive.

The record lists the following serious-event terms with associated percentages: Back pain, 0.4%; Acute pulmonary oedema, 0.3%; Cerebrovascular accident, 0.3%; Cholecystectomy, 0.3%; Cholecystitis, Not Otherwise Specified (NOS), 0.3%; and Constipation, 0.3%. The denominator for these term-specific percentages is not reported in the registry record, so they should not be interpreted as directly comparable with the participant counts without that information. Deaths are not reported in the registry record.

Serious adverse-event counts describe events classified as serious in the posted safety data. They do not establish that an event was caused by the drug, and a count of affected participants does not describe every episode or its timing. The study is open-label and has no control group, so these figures are descriptive safety observations rather than comparative estimates.

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

The results document adverse-event counts during open-label exposure to once-daily Tramadol HCl OAD at 300 mg among people with pain due to osteoarthritis of the knee. They distinguish the overall safety population from groups defined by completion of at least 175 days and at least 350 days on treatment. The posted counts show that adverse events, including events classified as serious, were reported in the overall population and in the 6-month safety population. The 12-month safety population has a reported serious-event count of 0 and a reported other-event count of 101.

These findings do not establish whether treatment caused any reported event. There is no untreated or active-treatment comparator, and the study is open-label. The record does not report event-level timing, exposure-adjusted rates, adjudication, or an inferential analysis that could support a comparative estimate. The duration-defined groups are not randomized treatment arms, and the counts cannot be read as evidence that event risk rises or falls with longer treatment.

The data also do not show that no serious events can occur in a similar population, even though the 12-month summary reports 0. That is a count observed in the defined group, not a guarantee about future participants or a statement that underlying risk is zero. Likewise, the presence of events during follow-up is not proof of drug causation.

The value of the record is therefore bounded but useful: it gives descriptive information about reported safety events in a long-term, open-label study and makes the population definitions explicit. It does not provide a controlled estimate of treatment effects, a complete account of uncertainty, or a basis for drawing conclusions beyond the populations and reporting summarized in the registry record.

14. Why This Trial Matters Statistically

This study illustrates why a safety count needs to be read alongside its design and population definition. A count of participants with adverse events is concrete, but its meaning depends on who was observed, how events were collected, and whether there is a comparison group. Here, the record identifies an overall population requiring at least 1 dose and two duration-defined safety populations. Those criteria make clear that the summaries refer to different eligibility definitions rather than to randomized treatment arms.

The open-label, single-group design is also statistically important. It can describe what was reported during treatment participation, but it cannot isolate treatment-related risk from background events or provide a like-for-like comparison with another intervention. The spontaneous-reporting description further signals that event ascertainment is part of the interpretation, not merely a clerical detail.

The record also demonstrates the distinction between event counts and event rates. A participant count does not incorporate each person’s observation time, and the entry does not report an exposure-adjusted analysis. Because the safety populations are defined by duration completed, comparisons across them would require care even if they appear to share an outcome label. No formal comparison or uncertainty estimate is reported.

For clinical researchers and biostatisticians, the central lesson is to keep the inferential scope aligned with the design. Descriptive safety evidence can contribute to understanding what was recorded during a study, while remaining distinct from causal or comparative evidence. Transparent reporting of the population, event definitions, missing-data handling, and analysis plan would help readers assess how far such findings can be generalized. Several of those methodological details are not reported in the registry record.

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 absence of a control group is a central limitation for interpretation. Since the study is single-group and open-label, the posted counts cannot show whether the frequency of reported events differs from what would have occurred without treatment or with another therapy. They also cannot establish that reported events were caused by the study drug.

Adverse events were collected as spontaneous reports. The registry record does not describe additional procedures for eliciting, verifying, coding, or adjudicating events. In general, spontaneous reporting may depend on recognition and reporting, so the observed record may not capture every event in the same way for every participant. The registry entry does not quantify the impact of this issue.

The duration-defined populations introduce another interpretive constraint. Inclusion required completing at least 175 days or at least 350 days on treatment. The record does not report a time-to-event or exposure-adjusted analysis, and it does not specify whether these populations overlap. Their counts should not be treated as independent groups or as a direct comparison of event risk over time.

Statistical uncertainty is not quantified with confidence intervals or tests in the registry record, which lists no analyses. Missing-data procedures and the handling of incomplete follow-up are also not reported. The denominator for the listed serious-event term percentages is not stated in the record. Finally, deaths are not reported in the registry record. These gaps limit how fully the safety findings can be assessed, but they do not imply that unreported procedures or outcomes had any particular value.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Open-Label Long-term Safety Study of Tramadol HCl OAD (Once A Day) 300 mg in the Treatment of Pain Due to Osteoarthritis of the Knee — NCT00833911.
• Registry record last updated 2012-04-30; status last verified 2012-04.
• Results first posted 2009-06-02.
• 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

NCT00833911 is a completed Phase 3, open-label, single-group safety study sponsored by Labopharm Inc. It evaluated once-daily Tramadol HCl OAD at 300 mg for pain due to osteoarthritis of the knee. Enrollment is reported as 392. The study start is listed as 2003-04 and primary completion as 2004-07.

The primary outcome is the number of participants having experienced an adverse event during the 6-month and 12-month open-label safety participation. The overall safety population includes participants who took at least 1 dose. The duration-defined populations required completion of at least 175 days or at least 350 days on treatment.

The registry reports serious and other adverse-event counts for each population, but no analyses. It does not report a control group, inferential estimates, missing-data methods, or a statistical plan. The results are descriptive observations from an open-label study and do not provide a randomized comparison or establish causation.