Study to Evaluate the Long-Term Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) in Patients Who Require Opioid Treatment for an Extended Period of Time: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Long-Term Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) in Patients Who Require Opioid Treatment for an Extended Period of Time (NCT01223365), a na phase 3 study. The primary outcome is Participants With Adverse Experiences.

2. Clinical Question

This is a safety-focused question, not a randomized test of comparative benefit. The record describes monitoring adverse events alongside clinical laboratory results, vital signs, electrocardiogram results, physical examination findings, pure tone audiometry, and concomitant medication usage. These measures cover different aspects of safety; the primary endpoint specifically concerns participants with adverse experiences.

The registry also lists secondary outcomes concerning the Participant Global Assessment of the method of pain control, risk category for aberrant drug misuse based on SOAPP-R, Addiction Behavior Checklist scores, and Current Opioid Misuse Measure scores. Their presence in the outcome list does not establish what those measures showed: corresponding results are not reported in the registry record. Nor does the listed objective itself establish how participants’ pain or safety would compare with another treatment, because no randomized control group is described.

3. Trial Design

The registry identifies this as a Phase 3, completed, open-label study with a single-group model. Allocation is listed as NA and masking as none. The study title describes a 12-month assessment of long-term safety in patients who require opioid treatment for an extended period of time. The registry reports enrollment of 330, a start date of 2010-10, and primary completion in 2012-09.

All participants were assigned to the study intervention in the sense that the record describes one treatment group, Hydrocodone ER; it does not describe random assignment to different treatments. Participants were titrated, or re-titrated if they were rollover participants, through escalating extended-release hydrocodone doses of 15, 30, 45, 60, or 90 mg orally every 12 hours until considered successful for managing their pain during the open-label titration period. The further wording of the arm description is incomplete in the registry record, so details beyond that point are not reported there.

The adverse-experience timeframe runs from Day 1 of open-label titration through Week 52 of open-label treatment. That endpoint window therefore encompasses both titration and treatment, rather than only a fixed-dose period. The record describes three safety subpopulations: New Opioid Naïve, New Opioid Experienced, and Rollover. These categories provide context for the reported adverse-experience counts, but they do not create randomized treatment comparisons.

The registry identifies the safety analysis set as the endpoint population, but does not report how that set was constructed or whether every enrolled participant was included. The protocol’s detailed design rationale, sample-size justification, monitoring rules, and statistical analysis plan are not reported in the registry record. In particular, the registry record does not describe a control group, treatment masking, or a prespecified between-group hypothesis test. The open-label, single-group design is important when interpreting both reported safety events and any observations concerning pain-related measures.

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: 330 enrolled patients came from 61 centers in the US: 166 rolled-over from study 3079, 52 were new opioid-naïve participants and 112 were new opioid-experienced participants. One enrolled patient was withdrawn before taking any study drug.

Open-label Titration Period

Reasons for not completing this period:

Open-label Treatment Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety analysis set

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.

Population: Enrolled patients

6. Primary Endpoint

The registry lists the primary outcome as Participants With Adverse Experiences, measured over Day 1 of open-label titration period - Week 52 of the open-label treatment period.

The primary endpoint is titled “Participants With Adverse Experiences” and is expressed as a count of participants. It covers events from Day 1 of open-label titration through Week 52 of open-label treatment in the safety analysis set. The protocol definition includes an untoward medical occurrence that develops or worsens during the study and does not require a causal relationship to the study drug. The investigator determined whether an adverse event was related to treatment.

This endpoint is used to describe the occurrence of adverse experiences during exposure and follow-up. Counting participants rather than only describing event types gives a reader a direct account of how many people in each reported subpopulation were affected. However, a participant count alone does not convey how long each person was observed, how many separate events occurred, or whether an event was judged treatment-related. Those details require additional reporting.

The registry definition also distinguishes serious adverse events by their consequences or clinical importance. Serious events include death, a life-threatening event, inpatient hospitalization or prolongation of an existing hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, or another important medical event that jeopardized the patient and required intervention to prevent such outcomes. This definition is part of the endpoint context; it does not mean that every event counted in the primary endpoint was serious.

The endpoint is relevant to a long-term safety objective because it tracks adverse experiences across the treatment period, including titration. It does not, by itself, determine causation, compare safety with another treatment, or summarize all laboratory, vital-sign, electrocardiogram, examination, audiometry, and medication findings. The registry record does not report an aggregate primary-endpoint result for the safety analysis set.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a binary outcome such as whether a participant experienced an adverse event, the basic descriptive result is a count of participants with the event alongside the number at risk. This presentation makes the denominator visible and helps distinguish a count from an event rate calculated over person-time. The registry’s primary endpoint is a participant count. The subgroup entries report counts at risk and counts affected, so the interpretation should remain tied to those posted quantities rather than treating them as event rates.

A participant count is not the same as a count of all event episodes. A person may experience more than one event, while still contributing only once to a measure of participants with an event. The registry endpoint is explicitly framed as participants with adverse experiences, but the subgroup labels for serious and other events do not provide episode-level detail. The number of recurrent events, their timing, duration, severity grades, and participant-level overlap are not reported in the registry record. It is therefore not possible to reconstruct those aspects from the counts alone.

The distinction between an adverse event and an adverse drug reaction is also important. In the protocol definition, an adverse event is an untoward medical occurrence that develops or worsens during the study and need not be caused by the study drug. The investigator determined the relation to treatment. Thus, the event counts are measures of what occurred during the study period, not a count restricted to events attributed to hydrocodone. The registry does not report the investigator’s treatment-related event counts in the posted results.

The serious-event category applies a separate clinical definition. It includes specified outcomes such as death, a life-threatening event, inpatient hospitalization, persistent or significant disability, congenital anomaly or birth defect, and an important medical event requiring intervention to prevent serious outcomes. This classification communicates seriousness, not necessarily causation. A serious adverse event may or may not be considered treatment-related, and a non-serious adverse experience may still be important to a participant. The registry’s serious-event term list is not a substitute for the full event-level record.

In a randomized trial, a treatment contrast can be estimated by comparing groups created through random assignment. Randomization helps balance prognostic factors on average, though it does not guarantee identical groups. This study is listed as single-group, with allocation NA and no masking. The three subpopulations are not described as randomized arms. Consequently, differences between their reported counts cannot be interpreted as the effect of assigning one treatment rather than another. Subgroup membership, prior opioid experience, participant characteristics, exposure duration, and other factors could influence the observed counts; the registry record does not report adjusted analyses to address such factors.

Uncertainty is often described with a confidence interval. In general, a confidence interval gives a range of values compatible with the data under the specified statistical method and assumptions. It conveys precision in a way a point estimate alone cannot. No confidence interval for the primary endpoint or subgroup contrasts is reported in the registry record. Since no comparative effect estimate is reported, the posted counts should be treated as descriptive rather than as evidence from a hypothesis test.

For event counts that vary more than a simple statistical model expects, over-dispersion can make standard errors from that model too small. In general, methods that account for over-dispersion may be appropriate for recurrent-event outcomes or clustered data. That consideration is distinct from the participant-level binary endpoint: a count of participants with at least one event does not itself report the number of recurrent events. The registry does not report a recurrent-event model, an over-dispersion assessment, or any other model for adverse events.

Time at risk can also matter in safety summaries. A participant observed for a longer period has more opportunity to experience an event than a participant observed for a shorter period. A person-time rate or time-to-event analysis can account for observation time in a different way from a simple participant count, but requires information about follow-up and event timing. The registry reports a broad endpoint timeframe through Week 52 of open-label treatment, but does not report participant-level follow-up durations, censoring, or time-to-event results. The counts alone cannot resolve differences in exposure duration.

The dose titration is relevant to interpretation because the arm description reports escalating doses of 15, 30, 45, 60, or 90 mg every 12 hours. The record does not report individual dose histories, time spent at each dose, or analyses by dose. Therefore, the listed overall subpopulation counts cannot establish whether adverse experiences were associated with a particular dose or period of exposure. The open-label setting also means participants and investigators were not masked to treatment; the registry does not report procedures designed to address potential reporting or assessment effects.

Finally, planning calculations and observed results serve different purposes. A planning illustration based on an observed effect would be a hypothetical design exercise under stated assumptions, not a measure of the study’s observed power. The registry record does not report a sample-size justification or its statistical assumptions for the original design. It also reports no analysis entries. Those omissions mean that a reader cannot use the registry record to establish what statistical model, inferential procedure, or power calculation governed the trial.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 9 outcome measures, including the primary adverse-experience endpoint and secondary measures concerning pain control, misuse risk, and behavioral assessment scores. When several outcomes are examined, multiplicity can arise because repeated statistical tests increase the chance of at least one apparently notable result under a set of null hypotheses. General approaches include prespecifying a primary outcome, adjusting significance thresholds, or treating secondary analyses as exploratory. Which approach was used in this study is not reported in the registry record.

The record reports 0 analyses. This means analysis results and methods are not available in the registry entries; it does not establish that no analyses were conducted outside the registry. The record does not report an analysis hierarchy, multiplicity adjustment, subgroup-testing plan, or handling of repeated measurements. No inferential conclusions about secondary outcomes can be drawn from their listing alone.

The primary endpoint names the safety analysis set, but the record does not report the inclusion rules for that population or how missing safety observations were handled. It does not describe whether participants who discontinued, had incomplete follow-up, or lacked particular assessments were included in each analysis. The enrollment of 330 should not be assumed to equal the number contributing to every endpoint, and subgroup counts should not be interpreted as a complete accounting of all enrolled participants.

In general, missing data can affect interpretation when people with incomplete observations differ from those with complete observations. Appropriate handling depends on why information is missing and on the endpoint and analysis. The registry does not report missing-data assumptions, imputation methods, sensitivity analyses, or completeness of follow-up. These are limitations on assessing precision and the possibility of bias, rather than evidence that missing data were necessarily present or mishandled.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: prostate cancer (2.3%), thrombocytopenia (1.9%), cholecystitis acute (1.9%), listeria sepsis (1.9%), dehydration (1.9%).

The serious adverse-experience counts are reported separately for the New Opioid Naïve, New Opioid Experienced, and Rollover subpopulations. The registry reports 4 of 52 at risk in the first group, 16 of 112 in the second group, and 7 of 165 in the rollover group. The other adverse-experience counts are 47 of 52, 83 of 112, and 109 of 165, respectively. Read these as counts of participants in the named categories, not as randomized comparisons or estimates of treatment effect.

Seriousness is defined by specified outcomes and medical importance, including hospitalization, life-threatening events, significant disability, and other important events requiring intervention. It is not a judgment that the study drug caused the event. Although the investigator determined relation to treatment, those relatedness results are not reported in the registry record. Death counts are also not reported in the registry record.

The listed serious terms and percentages are Prostate cancer, 2.3%; Thrombocytopenia, 1.9%; Cholecystitis acute, 1.9%; Listeria sepsis, 1.9%; Dehydration, 1.9%; and Hemiparesis, 1.9%. The registry does not provide enough detail in these entries to infer causation or make direct comparisons across terms. These figures describe reported events during the study, not the excess risk attributable to treatment.

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

The registry record documents a completed Phase 3, open-label, single-group study focused on the long-term safety of extended-release hydrocodone in people with chronic pain who required opioid treatment for an extended period. It reports participant counts for serious and other adverse experiences across three named subpopulations, as well as a short list of serious event terms and percentages. These data are descriptive evidence about events recorded during the study timeframe.

They do not establish that hydrocodone caused any particular event. The protocol definition includes events without requiring a causal relationship, and although investigators judged relatedness, relatedness results are not reported in the registry record. Nor do the figures show how safety compares with another drug, no treatment, or usual care. The study has no randomized comparator, and the named subpopulations are not a like-for-like control comparison.

The figures also do not provide a complete measure of every safety domain assessed. The study objective names clinical laboratory results, vital signs, electrocardiogram results, physical examination findings, pure tone audiometry, and concomitant medication usage, but their results are not reported in the registry record. The record likewise lists secondary pain and misuse-related measures without reporting their results. The posted adverse-experience counts therefore cannot stand in for the full set of intended assessments.

Counts alone do not show event timing, duration, recurrence, severity beyond the serious classification, or the relationship between dose and events. The record does not provide confidence intervals or adjusted estimates for the primary endpoint. Without those details, precision and potential differences in exposure time cannot be evaluated from the entries.

The appropriate statistical reading is limited but useful: the record reports that adverse experiences occurred in each named subpopulation during the study, with separate counts for serious and other experiences. It does not support a causal or comparative efficacy conclusion. The design and reporting omissions leave substantial questions about comparative safety, treatment attribution, completeness of follow-up, and the results of the broader safety assessments.

13. Why This Trial Matters Statistically

This trial matters statistically because its design and endpoint illustrate the difference between describing events and estimating a treatment effect. A single-group safety study can document adverse experiences observed during treatment and can organize them by subpopulation. Without a randomized control group, however, the study cannot separate events associated with treatment from events that would have occurred for other reasons in the same population.

The registry’s adverse-event definition makes this distinction explicit: an event need not have a causal relationship to the study drug, while an investigator separately determined relation to treatment. Reporting event counts and relatedness results together would help readers distinguish occurrence from attribution, but relatedness counts are not reported in the registry record. The reported serious-event terms likewise describe what was recorded, not proof of drug causation.

The subpopulation structure also shows why denominators matter. The reported numbers at risk differ across the New Opioid Naïve, New Opioid Experienced, and Rollover categories. Counts should therefore be read with their corresponding denominators and not compared as if the categories were randomized arms with equivalent participant composition. Any apparent difference could reflect group composition, exposure, or other factors as well as chance; the registry does not report adjusted analyses.

Another statistical lesson is that safety results depend on how outcomes are defined and summarized. A participant-level count answers whether people experienced an event, but does not describe all event episodes, timing, duration, or person-time. The registry’s broad observation window covers titration and treatment, while detailed follow-up and event timing are not reported. This limits assessment of exposure-adjusted risk and event patterns over time.

Finally, an outcome list is not the same as a results report. Although the record identifies multiple safety and secondary measures, it does not report analysis methods or results for many of them. Clear distinctions among planned assessments, observed counts, causal attribution, and comparative inference are essential when interpreting registry-based evidence.

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 single-group, open-label design is a central limitation for interpretation. There is no randomized comparator, allocation is listed as NA, and masking is listed as none. Consequently, the registry counts cannot estimate how event occurrence would differ under another treatment or without the study intervention. Comparisons across the three named subpopulations are descriptive and cannot remove confounding or selection differences.

The registry describes titration through 15, 30, 45, 60, or 90 mg every 12 hours but does not report individual dose exposure, duration at each dose, or dose-specific safety results. The arm description is incomplete after the titration statement, and further treatment details are not reported in the registry record. It is therefore not possible to assess dose-response patterns or connect events with a particular exposure period.

Although the primary endpoint names the safety analysis set, construction of that set and the amount of missing follow-up are not reported. The registry provides no analysis methods, confidence intervals, adjusted comparisons, or missing-data procedures. It also does not report death counts, investigator-assessed treatment-related event counts, or detailed event timing and recurrence. The event percentages do not supply the full context needed to evaluate their denominators or causal interpretation.

The study objective includes several other safety domains, but results for those assessments are not reported in the registry record. Secondary outcomes are listed without corresponding results. The registry reports 0 analyses, so the statistical plan, multiplicity handling, and any subgroup or sensitivity analyses cannot be assessed from the record. These limitations restrict the conclusions to the descriptive adverse-experience counts that are posted.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Evaluate the Long-Term Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) in Patients Who Require Opioid Treatment for an Extended Period of Time — NCT01223365.
• Registry record last updated 2017-06-05; status last verified 2017-05.
• Results first posted 2017-04-05.
• 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 identifies NCT01223365 as a completed Phase 3 study of Hydrocodone ER in people with chronic pain requiring opioid treatment for an extended period. It is described as a 12-month, open-label, single-group study with allocation listed as NA and no masking. Enrollment is reported as 330; the listed start date is 2010-10 and primary completion is 2012-09.

The primary objective was safety assessment, and the primary endpoint counts participants with adverse experiences from Day 1 of open-label titration through Week 52 of open-label treatment. The registry reports serious and other adverse-experience counts for the New Opioid Naïve, New Opioid Experienced, and Rollover subpopulations, along with selected serious-event terms and percentages. The record lists other safety assessments and secondary outcomes but does not report their results or analysis methods.

Because the study has no randomized comparator, the adverse-experience figures are descriptive. The registry record does not report treatment-related event counts, a complete primary endpoint result for the safety analysis set, missing-data procedures, or comparative statistical analyses.