A Dose Linearity Study of the Labopharm Formulation of Tramadol HCl/Contramid®, 100 mg, 200 mg and 300 mg After A Single Oral Administration In Fasting Condition, In Healthy Human Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Dose Linearity Study of the Labopharm Formulation of Tramadol HCl/Contramid®, 100 mg, 200 mg and 300 mg After A Single Oral Administration In Fasting Condition, In Healthy Human Volunteers (NCT00834808), a randomized phase 1 study. The primary outcome is AUC(0-t).

2. Clinical Question

This is a pharmacokinetic question about measured drug exposure across dose conditions, rather than a question about clinical benefit. AUC captures concentration over time and can describe systemic exposure during the measurement interval. Comparing the dose-specific AUC summaries can show how the posted means vary across the studied conditions. Establishing dose linearity, however, requires an analysis of the relationship between dose and exposure and an account of uncertainty. The registry record does not post that analysis, confidence intervals, or inferential results.

The setting also defines the scope of the question. These were single-dose administrations in fasting, healthy volunteers, not repeated treatment or a clinical population with a reported condition. The record therefore addresses the stated pharmacokinetic objectives under the study conditions, while leaving other settings and outcomes outside what the posted data establish.

3. Trial Design

The registry describes a completed Phase 1, randomized, unmasked, crossover study sponsored by Labopharm Inc. The study start is listed as 2002-11 and primary completion as 2002-12. Enrollment is listed as 27. The intervention is tramadol HCl, with dose groups labelled 100 mg, 200 mg and 300 mg. The study summary describes a single oral administration of the Labopharm extended-release formulation prepared with Contramid under fasting conditions.

A crossover design means that treatment conditions are evaluated within participants over different periods, rather than assigning each participant permanently to only one treatment condition. In general, this can reduce the influence of stable differences between participants when treatment conditions are compared. The registry record does not report the sequence assignments, period structure, washout interval, or details of how the crossover was incorporated into the analysis. Those details matter for evaluating possible period or carryover effects and for understanding the comparison structure.

The posted primary outcome summaries list 9 participants for each dose condition. These are outcome-specific group counts and should not be read as evidence that only 9 people enrolled, or as a complete account of who completed each period. The registry lists enrollment of 27; participant flow, missing measurements, and the number contributing paired data are not reported in the registry record.

Masking is listed as none. This identifies the trial as unmasked in the registry, but the record does not specify who knew the dose condition or whether laboratory measurement procedures used any blinding. The primary endpoint is continuous: mean AUC(0-t) in ng.h/mL, with standard deviation. Its timeframe is 48 hours. Two secondary outcomes are listed, Tmax and t1/2. The registry lists five outcome measures, but does not provide the detailed analysis methods or results for all of them.

The trial's completed status and its design description are the registry entries; they do not establish how completely each endpoint was reported. The registry record does not report the allocation sequence method, sample-size justification, protocol deviations, or a statistical analysis plan.

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.

Treatment Period 1 (Day 1)

Treatment Period 2 (Day 8)

Treatment Period 3 (Day 15)

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 AUC(0-t), measured over 48 hours.

The primary endpoint is AUC(0-t), defined as the area under the plasma concentration-versus-time curve to the last measurable concentration. It is expressed in ng.h/mL and has a stated timeframe of 48 hours. The registry describes the posted statistic as a mean with standard deviation. The endpoint record does not identify whether this AUC is for tramadol or O-desmethyltramadol, although the study summary says the pharmacokinetic profiles of both were evaluated.

AUC is used in pharmacokinetics because it combines concentration measurements across time into a measure of exposure over the observed interval. It can therefore summarize the concentration-time profile more fully than a single concentration measurement. AUC(0-t) ends at the last measurable concentration, so it is tied to the measurement schedule and the endpoint definition; it is not necessarily the same as exposure over an unrestricted duration.

For this study, the endpoint supports a descriptive comparison of the posted exposure means across the 100 mg, 200 mg and 300 mg conditions. The means are 2064.0, 4332.0 and 6568.0 ng.h/mL, respectively; the corresponding standard deviations are 707.0, 1149.0 and 2050.0. These summaries show the observed values and their spread within each listed condition. By themselves, they do not establish a linear dose-exposure relationship, quantify uncertainty in a between-dose comparison, or show the pattern for the metabolite. The registry does not post confidence intervals or an inferential analysis for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is continuous, and the registry reports a mean and standard deviation for each dose condition. A mean gives the arithmetic average of the observed measurements in a group. The standard deviation describes how spread out the measurements are around that average. These statistics answer different questions: the mean describes the group's central value, while the standard deviation describes variation among observations. Neither statistic alone gives the uncertainty around a contrast between dose conditions.

What does a crossover design change?

General statistical explanation: in a crossover study, each participant may receive more than one treatment condition over time. Comparisons can then use information from measurements made on the same person, which may account for stable participant-level differences. The analysis usually needs to respect the repeated-measures structure rather than treating all observations as independent. The registry identifies this study as a crossover but does not report the period, sequence, or model details. The posted dose-specific means and standard deviations do not contain enough information to reconstruct the within-person comparisons.

The design also makes sequence and period information relevant. In general, sequence describes the order in which treatment conditions are assigned, while period describes when a condition is received. Carryover refers to an effect of an earlier condition that persists into a later period. These are considerations for interpreting crossover studies, not findings about this trial. Sequence assignments, washout procedures, and carryover handling are not reported in the registry record, so their adequacy cannot be assessed from the posted summaries.

What does the standard deviation tell the reader?

The posted standard deviations are 707.0 ng.h/mL for 100 mg, 1149.0 ng.h/mL for 200 mg and 2050.0 ng.h/mL for 300 mg. They indicate the spread of individual AUC values within the reported groups. A standard deviation is not a confidence interval, and it does not show how precisely a treatment contrast has been estimated. In a crossover design, the variability of within-person differences may be especially relevant; that information is not reported. The group-level summaries cannot be used to infer it.

General statistical explanation: a confidence interval pairs an estimate with a range of values compatible with the data and the assumptions of the analysis. Its width conveys precision for the estimated quantity. The registry record posts no confidence intervals for AUC(0-t), so the precision of the means or dose comparisons cannot be evaluated using interval estimates. The absence of a posted interval is not evidence that the estimates are precise or imprecise.

How should dose linearity be assessed?

General statistical explanation: dose linearity concerns whether exposure changes proportionally with dose over a specified range, under a defined model and scale. A simple visual ordering of means is not equivalent to a formal linearity assessment. Such an assessment should identify the outcome and analyte, account for repeated observations when appropriate, state the model and contrast or trend being evaluated, and report estimates with uncertainty. The record does not report a linearity model, a parameter estimate, a test, or confidence intervals. Consequently, the posted means cannot establish the stated linearity objective on their own.

The registry describes the study as assessing tramadol and O-desmethyltramadol. Since the primary outcome description does not name the analyte, and separate metabolite estimates are not posted in the record, no metabolite-specific statistical interpretation can be made from these summaries. The secondary outcomes Tmax and t1/2 are listed, but numerical results and analysis details for them are not included in the registry information.

What can sample size summaries establish?

The registry lists enrollment of 27 and an outcome count of 9 for each dose condition. Neither value is a statistical test. A planning calculation based on an observed effect, if presented, is an illustration under its stated assumptions rather than evidence of the study's observed power. The registry record does not report a sample-size justification or the assumptions used for the original design. No power conclusion should be inferred from enrollment or from the posted outcome summaries.

General statistical explanation: power is a design property defined relative to a particular effect, variability, analysis, significance level, and sample size. Retrospective calculations based on an observed effect do not establish the probability that the trial detected a true effect; the observed effect itself is uncertain. Sample-size planning illustrations can help show how assumptions affect a future design, but they should not be read as a result of this trial. The record does not report a sponsor-planned power analysis.

What does the registry report about analysis?

The registry lists five outcome measures, two secondary outcomes, and zero analyses. It does not report inferential methods, adjustment for the crossover structure, handling of missing data, or a statistical analysis plan. This leaves the posted primary result as a descriptive summary rather than a fully documented estimate from a specified inferential model. The numerical summaries can be accurately described, while conclusions that require model assumptions or uncertainty estimates remain unavailable from the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("1: Tramadol HCl 100mg", "2: Tramadol HCl 200mg", "3: Tramadol HCl 300mg")
n   <- c(9, 9, 9)
m   <- c(2064, 4332, 6568)
sp  <- c(707, 1149, 2050)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  1: Tramadol HCl 100mg  9  2064.000  707.000  1520.552  2607.448
CARM  2: Tramadol HCl 200mg  9  4332.000  1149.000  3448.800  5215.200
CARM  3: Tramadol HCl 300mg  9  6568.000  2050.000  4992.231  8143.769

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and identifies Tmax and t1/2 as secondary outcomes. The primary outcome is AUC(0-t). The registry does not report a multiplicity strategy, such as whether the study treated any outcomes as confirmatory, adjusted tests across outcomes, or used a prespecified hierarchy. Without that information, the implications of testing or interpreting several outcomes cannot be evaluated. No inferential analyses are posted for the primary endpoint, and the registry lists zero analyses.

Missing-data handling is not reported in the registry record. Although enrollment is listed as 27 and the primary outcome summaries show 9 participants for each dose condition, the record does not provide a participant flow account, numbers with complete measurements across dose conditions, reasons for missingness, or an imputation method. In a crossover study, it is also important to know which participants contributed observations in each period and whether paired measurements were available. The posted group counts do not answer those questions.

Analysis populations are not described. The registry record does not say whether the outcome summaries include all enrolled participants, only participants who completed the study, or another defined population. It also does not report protocol deviations or exclusions. The posted safety risk counts and pharmacokinetic outcome counts have different denominators, but the record does not explain the relationship between those sets of participants.

These omissions limit reproducibility and interpretation. They do not establish that missing observations occurred or that any particular analytic approach was used; they mean those details are not reported in the registry record. A reader can describe the posted summaries but cannot verify the analysis population, missing-data assumptions, or control of multiplicity.

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.

For each of the 100 mg, 200 mg and 300 mg conditions, the registry lists 27 participants at risk for serious adverse events and 0 affected. Thus, the posted serious adverse event counts show no affected participants in the listed treatment groups. This statement describes the registry counts; it does not establish that the risk of serious adverse events is absent.

The registry also lists 27 participants at risk and 0 affected for other adverse events in each condition. The death fields are null, rather than a posted zero, so deaths are not reported in the registry record. No serious adverse event terms are listed. These entries should not be interpreted as a detailed description of event definitions, collection procedures, follow-up, or causal attribution, none of which are specified in the posted safety information.

The adverse event counts use 27 at risk for each dose condition, whereas the primary pharmacokinetic summaries list 9 participants per condition. The registry does not explain the different denominators or provide participant flow. Because the design is crossover, the safety counts should not be added across dose conditions to infer a unique number of people exposed; the same participants may contribute to multiple conditions. The record does not provide enough detail to establish the exposure accounting.

Zero posted events in these counts should be read as a limited observation in this study, not as proof of no risk. The registry safety record also does not supply an event-level narrative or estimate of uncertainty.

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

The registry records a small pharmacokinetic study in healthy volunteers, with single oral administrations of tramadol HCl/Contramid at 100 mg, 200 mg and 300 mg under fasting conditions. The posted primary outcome summaries show mean AUC(0-t) values of 2064.0, 4332.0 and 6568.0 ng.h/mL, respectively, with standard deviations of 707.0, 1149.0 and 2050.0. These are descriptive measurements over the stated 48-hour timeframe.

The observed means increase across the listed dose conditions. That pattern is relevant to the study's dose-linearity objective, but it does not by itself establish a proportional relationship between dose and exposure. The registry does not post an analysis of linearity, confidence intervals, p-values, or the model needed to evaluate uncertainty. Nor does the primary outcome record identify whether the AUC results are for tramadol or its metabolite. The metabolite was part of the stated study aim, but separate numerical results are not reported in the registry record.

The results do not establish a clinical benefit or lack of benefit. AUC is a pharmacokinetic measure, not a clinical outcome. This trial's stated setting also does not support conclusions about repeated dosing, populations other than healthy volunteers, or conditions beyond fasting single-dose administration. The registry describes the study as unmasked and crossover, but does not report enough design and analysis detail to judge all features of the comparison.

Likewise, the safety counts do not demonstrate that adverse events cannot occur. They show 0 participants affected by serious adverse events among 27 at risk in each listed condition, within the registry's reporting. The record does not describe how events were collected or provide deaths as a numeric count.

The most defensible interpretation is therefore bounded: the posted group means are higher at the higher listed doses, and the registry states that assessing dose linearity was an objective. The numerical summaries alone do not answer that objective with an inferential result or establish implications beyond the measured pharmacokinetic setting.

14. Why This Trial Matters Statistically

This study illustrates the distinction between a scientific objective and a posted statistical result. The objective was to assess dose linearity for tramadol and O-desmethyltramadol between 100 mg and 300 mg. The registry provides dose-specific AUC means and standard deviations, but no reported model, uncertainty interval, or formal linearity analysis. Readers can see the pattern in the group summaries while recognizing that the stated objective is not fully answered by those summaries alone.

It also illustrates why design details matter. A crossover can make within-participant comparisons informative, but interpretation depends on sequence, period, repeated-measures analysis, and the availability of paired observations. The registry labels the design as crossover and posts dose-specific counts, but does not report the details needed to reconstruct that analysis. Marginal means and standard deviations cannot substitute for the within-person data structure.

The record further shows why outcome labels and analytes need to be explicit. The study summary names tramadol and O-desmethyltramadol, while the primary outcome record names AUC(0-t) without identifying the analyte. Separate metabolite results are not reported. Clear endpoint definitions and analyte-specific estimates are essential when a study has multiple pharmacokinetic targets.

Finally, registry summaries distinguish observed data from inferential conclusions. The means describe the sample; standard deviations describe spread; neither is a confidence interval for a dose contrast. Without the analysis plan and uncertainty estimates, claims about precision or proportionality would go beyond the record. This makes the study a useful example of how much interpretation depends not only on numerical values, but also on transparent reporting of the design and analysis.

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 registry record contains limited details for evaluating the study's execution and analysis. It reports randomized, unmasked, crossover design, but does not describe the allocation method, treatment sequence, period structure, washout interval, or whether carryover was assessed. These details are relevant to interpreting dose comparisons in a crossover study.

The primary outcome record gives the AUC definition, unit, timeframe, mean, standard deviation, and group counts, but does not identify the analyte. The study summary names both tramadol and O-desmethyltramadol, yet separate metabolite results are not reported in the registry record. Tmax and t1/2 are listed as secondary outcomes without posted numerical results in the information available for this analysis.

Enrollment is listed as 27, while the primary outcome summaries list 9 participants in each dose condition. Participant flow, completion by period, reasons for missing data, analysis populations, and the handling of missing observations are not reported in the registry record. The relationship between safety and pharmacokinetic denominators is also not explained.

No confidence intervals, p-values, dose-linearity model, statistical analysis plan, or sample-size justification are reported. The registry lists zero analyses. Consequently, precision, statistical significance, and the adequacy of the analysis for the crossover design cannot be assessed from the posted summaries. The safety entries do not include event definitions, detailed follow-up, or a numeric death count. These reporting limitations constrain interpretation; they do not establish that the unreported procedures or analyses were absent from the original study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Dose Linearity Study of the Labopharm Formulation of Tramadol HCl/Contramid®, 100 mg, 200 mg and 300 mg After A Single Oral Administration In Fasting Condition, In Healthy Human Volunteers — NCT00834808.
• Registry record last updated 2012-04-27; 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

The registry record describes NCT00834808 as a completed Phase 1 randomized, unmasked crossover study sponsored by Labopharm Inc. Enrollment was 27. The study examined single oral administrations of tramadol HCl in the Labopharm extended-release formulation prepared with Contramid at 100 mg, 200 mg and 300 mg under fasting conditions in young, healthy volunteers.

The primary outcome is AUC(0-t), defined as area under the plasma concentration-versus-time curve to the last measurable concentration, measured over 48 hours in ng.h/mL. The registry posts means and standard deviations for each dose condition and lists 9 participants per condition. The study summary identifies tramadol and O-desmethyltramadol as pharmacokinetic targets and states dose linearity as an aim.

Tmax and t1/2 are listed as secondary outcomes. The registry does not report a dose-linearity analysis, inferential methods, confidence intervals, participant flow, missing-data handling, or analysis populations. Serious adverse event counts list 0 affected among 27 at risk for each condition; the death fields are not reported as numeric counts.