Pharmacokinetic Study of Hydrocodone/APAP in Chronic Pain Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetic Study of Hydrocodone/APAP in Chronic Pain Patients (NCT01517295), a randomized phase 4 study. The primary outcome is Peak Plasma Concentration of Hydromorphone.

2. Clinical Question

3. Trial Design

The registry identifies this as a Phase 4, randomized, unmasked, parallel-group study. It was marked completed and lists enrollment of 30. The study began in 2012-02, with primary completion in 2012-05. Further details about the randomization procedure, allocation concealment, recruitment, or reasons for selecting the enrollment target are not reported in the registry record.

The two groups followed different sampling schedules after one dose of hydrocodone/APAP. Group 1 was scheduled for blood draws at 0, 1, 3, and 5 hours, with urine collection at hour 0 and 3. Group 2 was scheduled for blood draws at 0, 2, 4, and 6 hours, with urine collection at hour 0 and 4. These schedules define when measurements were intended to be collected; the record does not describe other differences between the groups.

The study objective was to evaluate the pharmacokinetic profile of hydromorphone among people taking hydrocodone regularly for chronic pain and to relate hydromorphone levels to hydrocodone usage. The primary outcome was peak plasma concentration of hydromorphone, expressed in ng/mL, over up to 6 hours. Secondary outcomes listed in the registry were correlation of plasma pharmacokinetics of hydrocodone and peak urine concentration of hydromorphone.

The registry reports a key measurement problem: laboratory sensitivity was insufficient, and all subjects’ plasma hydromorphone concentrations were recorded as zero at all time points. Thus, although the design included repeated sampling, the record does not show that the intended plasma profile could be quantified. The rationale for the sampling times, any dose standardization, and the analysis plan 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:

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 Peak Plasma Concentration of Hydromorphone, measured over Up to 6 hours.

The primary endpoint was peak plasma concentration of hydromorphone, measured in ng/mL over up to 6 hours. A peak concentration is intended to describe the highest measured concentration after a dose during the observation period. In pharmacokinetic research, such a measure can help characterize how a drug or metabolite appears in blood over time. This is a general explanation of the endpoint, not a claim about what this study established.

In this study, the registry’s description says that the laboratory test was not sufficiently sensitive to determine plasma hydromorphone concentrations. Because every subject’s plasma concentration was recorded as zero at every time point, the recorded values do not establish that the true concentrations were absent or equal to zero. They indicate that the assay did not yield a measurable value under the conditions used. The lowest detectable concentration and any handling of values below that limit are not reported in the registry record.

The stated endpoint therefore cannot be interpreted as a successfully measured peak concentration profile. The record does not report a usable peak estimate, a group comparison, or an associated measure of uncertainty. The intended endpoint remains clinically and scientifically distinct from the values recorded when the measurement method cannot detect the analyte.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a peak concentration describe?

As a general statistical and pharmacokinetic concept, a peak concentration is the highest observed concentration during a specified sampling period. It condenses repeated measurements into one endpoint, but its usefulness depends on the measurements being capable of detecting the substance and on sampling occurring at suitable times. Here, the registry’s observation period was up to 6 hours, and the groups had different scheduled sampling times. The test sensitivity problem means the recorded plasma values cannot be treated as a reliable numerical profile from which to interpret a peak.

What does a standard deviation add?

The primary outcome is described as a mean with standard deviation. In general, the mean describes the center of a set of measurements, while the standard deviation describes how dispersed individual measurements are around that mean. A standard deviation is not a confidence interval and does not, by itself, describe the precision of the estimated mean. The registry record does not report a usable mean or standard deviation for the plasma endpoint. When every recorded value is set to zero because a test cannot detect the analyte, a summary of those recorded values would not repair the underlying measurement limitation.

Why does the assay limitation matter?

In general, a measurement method has a range within which it can reliably quantify an analyte. If values are below the method’s detection capability, recording them as zero can collapse different underlying concentrations into the same recorded value. That can conceal variation and make a true association or group difference difficult to estimate. This is a general explanation; the detection limit and any laboratory validation details for this study are not reported in the registry record. The registry explicitly attributes the zero plasma results to insufficient sensitivity, so those values should not be interpreted as measured biological concentrations of zero.

How should the randomized parallel design be understood?

In general, random allocation is intended to reduce systematic differences between assigned groups, while a parallel design means each participant is assigned to one group’s schedule rather than crossing between schedules. Unmasked means the study was not described as blinded. These design features do not guarantee that all sources of bias are removed, and they cannot overcome an outcome measurement that fails to quantify the substance. The randomization method and details about concealment or implementation are not reported in the registry record.

What can be inferred from the sampling schedules?

The schedules specify collection times, not the resulting concentration curves. Group 1 was scheduled for blood at 0, 1, 3, and 5 hours and urine at hour 0 and 3. Group 2 was scheduled for blood at 0, 2, 4, and 6 hours and urine at hour 0 and 4. As a general matter, samples taken at different times can affect the observed peak, especially when concentration changes over time. The registry does not report a model that accounts for the distinct schedules, nor does it report numerical plasma or urine results that would allow their influence to be assessed.

What does the planning illustration represent?

The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation; the effect to detect is stated as a fraction of the observed effect. These are planning assumptions, not observed power. No planning estimates or observed-effect values are reported in the registry record. The primary outcome is also flagged as having several categories or time points and not being reduced to one comparison. Consequently, no single comparison or planning estimate can be interpreted from the available record. A sample-size illustration would not establish the study’s actual power or prove that an outcome was measured adequately.

What is absent from the statistical reporting?

The registry lists three outcome measures and zero analyses. The detailed statistical analysis plan, model specifications, handling of below-detection values, confidence intervals, hypothesis tests, and analysis populations are not reported in the registry record. These omissions matter because the intended concentration profile requires a clear approach to repeated measurements and values the assay cannot quantify. Without those details and interpretable outcome estimates, the posted record supports a description of the design and measurement problem, but not a statistical estimate of the intended pharmacokinetic relationship.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures: the primary plasma hydromorphone endpoint and secondary outcomes concerning plasma pharmacokinetics of hydrocodone and peak urine concentration of hydromorphone. It reports zero analyses. A procedure for addressing multiplicity across outcomes, time points, or group comparisons is not reported in the registry record. In general, multiplicity matters because evaluating several outcomes or comparisons can increase the chance of finding an apparently notable result by chance. That general concern cannot be resolved without knowing which analyses were prespecified and how they were handled.

The record does not report an analysis population, exclusions, participant flow, or a description of missing observations. These details are not reported in the registry record. The laboratory limitation is described separately: plasma hydromorphone concentrations were recorded as zero at all time points because the test sensitivity was insufficient. This is a measurement limitation, not a reported account of missing data, and the record does not explain whether any values were handled in another way for analysis.

The registry does not report how incomplete sampling, if any, was treated, or whether the secondary outcomes were analyzed in all enrolled participants. It also does not describe a prespecified statistical plan for the distinct sampling schedules. Without this information, the scope and robustness of any analysis cannot be assessed from the registry record.

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.

The adverse-event entries report zero participants affected by serious adverse events in Group 1 and Group 2. The groups list 16 and 14 participants, respectively, as at risk for serious adverse events. The entries also report zero participants affected by other adverse events, with 16 and 14 listed at risk in the respective groups. No serious adverse-event terms are listed.

These are registry counts for the categories recorded, not proof that no adverse events occurred outside the recorded information. The record does not provide event narratives, severity details beyond the serious-event category, or a description of how events were collected. Death counts are shown as null rather than as zero; deaths are therefore not reported in the registry record, rather than affirmatively reported as none.

Adverse-event counts should also be read separately from the pharmacokinetic result. Zero recorded events do not resolve the assay’s inability to measure plasma hydromorphone. The safety entries describe the recorded adverse-event categories, while the primary endpoint concerns a concentration measurement that the registry says was limited by inadequate laboratory sensitivity.

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

The registry record documents a randomized, unmasked, parallel study intended to evaluate hydromorphone pharmacokinetics in chronic pain patients taking hydrocodone/APAP. It describes two post-dose sampling schedules and identifies peak plasma concentration of hydromorphone as the primary endpoint. The most important result for interpretation is the stated assay limitation: the laboratory test was not sensitive enough, and all subjects’ plasma concentrations were recorded as zero at every time point.

This does not establish that plasma hydromorphone was truly absent, that concentrations were identical across people, or that the two sampling schedules produced equivalent results. It also does not establish a particular concentration, a group difference, or a relationship between hydromorphone levels and hydrocodone usage. Those conclusions would require measurable values and analyses, neither of which is reported for the primary question.

The record lists urine concentration and hydrocodone plasma pharmacokinetics as secondary outcomes, but their numerical results are not reported in the registry record. The registry also does not provide confidence intervals, statistical tests, or an analysis plan that could support a more detailed interpretation. The information therefore describes the study’s intent and a constraint on measurement, rather than a quantified pharmacokinetic finding.

This distinction is important in statistical interpretation. A recorded zero produced by a test with insufficient sensitivity is not interchangeable with a precise estimate near zero. It cannot be used to conclude that a metabolite was absent or that a treatment did or did not produce a biological effect. The evidence in the record is limited to the planned design, the recorded outcome description, and the acknowledged sensitivity problem.

13. Why This Trial Matters Statistically

This trial illustrates how outcome measurement can determine whether a study’s statistical question is answerable. The objective was to characterize hydromorphone concentrations after hydrocodone/APAP and relate those levels to hydrocodone usage. The primary endpoint required the laboratory method to quantify plasma hydromorphone. The registry states that the test sensitivity was insufficient and that all subjects’ concentrations were recorded as zero at every time point. As a result, the planned pharmacokinetic question cannot be answered from the recorded plasma values.

The design also highlights the distinction between a study’s schedule and its evidence. Randomization and parallel groups organize the comparison, while blood and urine collection times define the planned observations. Neither feature substitutes for valid measurements. Different sampling times can be relevant to a concentration profile, but interpretation requires outcome values and a suitable analysis. The registry does not report a numerical profile or a model addressing the schedules.

For clinical researchers and biostatisticians, the record is a reminder that assay sensitivity, endpoint definition, sampling, and analysis planning need to align. A study may specify a clear biological question yet remain unable to estimate its target when the measurement method cannot detect the analyte adequately. In that setting, recorded zeros should not be mistaken for evidence of no concentration or no group difference.

The registry’s sparse analysis reporting also limits what can be learned about secondary outcomes, missing data, and multiplicity. The record identifies outcome measures but reports no analyses. Its statistical importance lies chiefly in exposing these interpretive boundaries, not in providing a quantified estimate of hydromorphone pharmacokinetics.

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.

The assay sensitivity limitation is the principal outcome-specific limitation. The registry says all subjects’ plasma hydromorphone concentrations were recorded as zero at every time point because the laboratory test was not sufficiently sensitive. The detection limit, validation characteristics, and approach to below-detection values are not reported in the registry record. Consequently, the recorded zeros cannot be interpreted as exact measured concentrations.

The two groups were scheduled for blood collection at different times, and their urine schedules also differed. The registry does not explain the rationale for these schedules or report an analysis that accounts for them. Because plasma results were not measurable according to the record, the effect of sampling schedule on any estimated peak cannot be assessed.

The registry does not report numerical results for the listed secondary outcomes, an analysis population, participant flow, missing-data procedures, a detailed statistical plan, or confidence intervals. It also does not describe the hydrocodone dose, the randomization procedure, or additional eligibility and baseline characteristics. These details are not reported in the registry record, so their influence cannot be evaluated.

Finally, the record lists enrollment of 30, but it does not provide a sample-size justification or usable planning estimates. The planning assumptions described in the record are not accompanied by numerical illustrations, and they should not be read as observed power. Taken together, these reporting and measurement limitations prevent a quantitative assessment of the primary pharmacokinetic question.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetic Study of Hydrocodone/APAP in Chronic Pain Patients — NCT01517295.
• Registry record last updated 2016-07-28; status last verified 2016-06.
• Results first posted 2016-07-28.
• 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

NCT01517295 is a completed Phase 4 randomized, unmasked, parallel study sponsored by NEMA Research, Inc. It lists enrollment of 30 and concerns chronic pain patients taking hydrocodone/APAP. The study began in 2012-02, and primary completion was in 2012-05.

The primary endpoint was peak plasma concentration of hydromorphone in ng/mL over up to 6 hours. The registry states that laboratory sensitivity was insufficient and all subjects’ plasma concentrations were recorded as zero at every time point. Secondary outcomes concerned hydrocodone plasma pharmacokinetics and peak urine hydromorphone concentration. The registry reports zero analyses; numerical results for the secondary outcomes are not reported in the registry record.

Adverse-event entries list zero affected participants for serious and other adverse events in both groups. Deaths are not reported as zero. Overall, the record describes the intended pharmacokinetic study and its sampling schedules, while the plasma measurement limitation prevents interpretation of a quantified primary outcome.