Long Term Safety of Naldemedine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Long Term Safety of Naldemedine (NCT01965652), a randomized phase 3 study. The primary outcome is Number of Participants With Adverse Events.

2. Clinical Question

The clinical question is principally about long-term safety. The trial record identifies the primary outcome as the number of participants with adverse events, with observation beginning at the first dose and continuing up to 14 days after the last dose. The stated timeframe is 54 weeks. Serious adverse events were defined by specified outcomes such as death, a life-threatening event, hospitalization or prolongation of hospitalization, persistent or significant disability, or a congenital anomaly or birth defect. The definition also included certain important medical events when medical judgment indicated that they jeopardized the participant or required intervention to prevent a listed outcome.

The record also lists secondary outcomes concerning bowel movements, laxative use, constipation symptoms, and constipation-related quality of life. These outcomes broaden the questions considered, but the primary endpoint is an adverse-event measure rather than a direct measure of symptom benefit. The posted results described in the registry record therefore address the occurrence of adverse events in the study groups; they do not, by themselves, resolve every question about symptom outcomes or individual treatment decisions.

3. Trial Design

This was a randomized, placebo-controlled, parallel-group phase 3 study with quadruple masking. The official title describes it as double-blind, while the registry’s masking classification is quadruple. The study was multicenter and completed. Its stated purpose was to evaluate the long-term safety of naldemedine for constipation due to opioid therapy.

The registry reports enrollment of 1246. Participants assigned to naldemedine received 0.2 mg tablets orally once daily for 52 weeks. Participants assigned to placebo received matching tablets on the same daily schedule and for the same duration. The trial record describes the target population as people with opioid-induced constipation who had non-malignant chronic pain and were receiving opioid therapy.

The recorded study start was 2013-09-24, and the primary completion date was 2016-01-12. The primary safety outcome was assessed from the first dose through up to 14 days after the last dose, with a stated timeframe of 54 weeks. The listed analysis population for that outcome is the safety population. The record does not report the roles covered by quadruple masking or further details about how randomization was generated or implemented.

The study also listed secondary outcomes covering changes in bowel movement frequency, laxative use, constipation symptoms, and constipation-related quality of life. The registry records 13 outcome measures and 50 analyses. Those counts do not establish that every outcome was measured at the same time or analyzed with the same method. Further details of 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.

Before assignment: Participants were randomized in a 1:1 ratio to receive naldemedine or placebo for 52 weeks. Randomization was stratified based on documented opioid use (average total daily dose \[TDD\] during the 14-consecutive-day qualifying period) as follows: * 30 - 100 mg equivalents of oral morphine sulfate. * \> 100 mg equivalents of oral morphine sulfate.

Overall Study

Reasons for not completing this period:

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

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: The safety population included all participants who received at least 1 dose of study drug. Five participants (2 in the naldemedine group and 3 in the placebo group) were excluded due to double enrollment at different sites. One participant in the placebo arm received naldemedine in error and is included in the naldemedine arm for safety analyses.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events, measured over From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks)..

The primary endpoint is the number of participants with adverse events. It is a safety outcome: it counts participants experiencing events during the specified observation period rather than measuring a change in constipation symptoms. The safety observation period began with the first dose and extended up to 14 days after the last dose; the registry gives a timeframe of 54 weeks.

The record distinguishes serious adverse events from other adverse events in its posted group summaries. A serious adverse event was defined by outcomes including death, a life-threatening event, hospitalization or prolonged hospitalization, persistent or significant disability, or a congenital anomaly or birth defect. Important medical events could also qualify when, in the investigator’s medical judgment, they jeopardized the participant or required medical or surgical intervention to prevent one of those outcomes.

Using participant counts is a direct way to describe how many people in each group had recorded events. It is relevant to a long-term safety evaluation because it describes events observed during treatment and follow-up. A count alone does not show the timing, duration, severity beyond the stated categories, or causal relationship of every event. The registry defines adverse drug reactions separately as events the investigator considered definitely, probably, or possibly related to study drug; serious adverse drug reactions apply that relatedness assessment to serious adverse events. The posted figures should not be treated as counts of events proven to have been caused by treatment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a binary safety outcome, each participant can be classified according to whether an event occurred under the endpoint definition. The posted summary gives a count of participants with events and a group denominator. In general, comparing such outcomes can involve reporting the event proportion in each group, a difference between proportions, a relative measure, or a model-based estimate. Those are distinct summaries and can answer different questions. The registry record does not report a single selected comparative estimate for the primary outcome, so no such estimate should be inferred from the counts.

What do the counts describe?

The serious and other adverse-event figures describe participants, not the total number of event episodes. A participant may have more than one event, and the count of participants with an event does not tell how many episodes occurred. Nor does a count describe event duration, recurrence, or timing. The registry’s outcome description and group summaries should be read according to their stated unit: participants.

The definitions matter. Seriousness is based on specified consequences and medical judgment, rather than simply on how unpleasant or common an event is. Relatedness is a separate judgment: the registry defines an adverse drug reaction as an adverse event considered definitely, probably, or possibly related to study drug by the investigator. Without a reported event-level account or a single comparative analysis, the posted summaries cannot show which individual events were judged related.

How should uncertainty be understood?

General: estimates based on observed participants are subject to sampling variation. A confidence interval is a range of values compatible with the data under a statistical model and its assumptions; it communicates precision, not the probability that a particular treatment effect is true. A hypothesis test assesses compatibility with a specified null hypothesis under its assumptions, but a p-value does not measure the size or importance of an effect. Neither a confidence interval nor an inferential test for the primary comparison is reported in the registry record.

General: adjustment can be important when a comparison must account for baseline characteristics or other design features. An adjusted estimate may differ from an unadjusted comparison because it uses additional information and assumptions. The registry record does not report an adjusted primary estimate or enough details to reconstruct the sponsor’s analysis. The raw group summaries should not be mistaken for an adjusted result.

What does the planning illustration mean?

General: sample-size planning asks how many participants may be needed to detect a specified effect under stated assumptions. The registry’s planning description uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It describes planning for a stated fraction of the observed effect. These are planning assumptions, not evidence about the trial’s original design or its achieved statistical power. Any sample-size value in such an illustration is a planning result, not an observed trial outcome and not “observed power.”

The planning description says time-to-event illustrations give a total number of events, while other illustrations give participants per arm. These formats are not interchangeable. A participant target per arm is not the number enrolled in the trial, and an event target is not a participant count. The record does not report the trial’s own sample-size justification, so the illustration should not be treated as documentation of the protocol’s rationale.

Why do multiple outcomes affect interpretation?

General: when many outcomes, time points, or analyses are examined, the chance of at least one apparently unusual result can increase if each is assessed separately without an appropriate strategy. Multiplicity procedures can control or otherwise address that issue, but they depend on which outcomes and comparisons were prespecified and on the analysis plan. Although the registry records 13 outcome measures and 50 analyses, the multiplicity approach is not reported in the registry record. The count of analyses does not reveal which results were confirmatory or how any statistical testing was controlled.

General: missing observations can affect estimates if participants do not contribute data at all intended assessments. The direction and extent of any effect depend on why data are missing and how the analysis handles them. The registry record does not report missing-data methods, participant flow by analysis, or sensitivity analyses for the primary outcome. That absence limits assessment of robustness, but it does not establish that data were missing or that a particular method was used.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures and 50 analyses. The secondary outcomes include bowel movement frequency, laxative use, constipation symptom scores, and constipation-related quality-of-life scores. Considering multiple outcomes or time points can complicate interpretation because separate analyses create multiple opportunities for an apparently notable result. General statistical practice may use prespecified testing hierarchies or other multiplicity procedures, but the method used for this study is not reported in the registry record.

The primary outcome is not reduced to one comparison in the registry record because it has several categories or time points. This means the displayed safety counts do not identify a single primary contrast with a reported inferential result. The registry record does not report the statistical plan needed to determine the intended testing hierarchy, adjustment strategy, or treatment of secondary analyses.

The listed population for the primary outcome is the safety population. Other analysis populations, their definitions, and the number of participants included in each analysis are not reported in the registry record. Missing-data procedures, reasons for missing observations, and sensitivity analyses are also not reported. These omissions prevent a detailed assessment of how incomplete follow-up may have affected the results. They do not justify assuming that data were missing or that a particular analysis method was used.

Interpretation should therefore distinguish the posted descriptive safety counts from any unreported confirmatory analysis. The number of listed outcomes and analyses is useful context, but it is not evidence that multiplicity was or was not adequately addressed.

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: pneumonia (1.1%), back pain (0.8%), osteoarthritis (0.8%), chronic obstructive pulmonary disease (0.5%), non-cardiac chest pain (0.5%).

The serious adverse-event summaries report 60 participants with an event among 621 in the naldemedine group and 73 among 619 in the placebo group. The other adverse-event summaries report 225 participants among 621 and 179 among 619, respectively. These figures are participant counts within the registry’s serious and other adverse-event categories; they should not be added together to create a total because the record does not establish that the categories are mutually exclusive.

The serious-event definition includes specified outcomes such as death, life-threatening events, hospitalization or prolonged hospitalization, and significant disability, as well as certain important medical events judged to require intervention to prevent such outcomes. Seriousness is not the same as relatedness. The registry defines serious adverse drug reactions as serious adverse events considered definitely, probably, or possibly related to study drug by the investigator.

The listed serious-event terms include pneumonia at 1.1%, back pain at 0.8%, osteoarthritis at 0.8%, chronic obstructive pulmonary disease at 0.5%, non-cardiac chest pain at 0.5%, and cellulitis at 0.3%. The record does not provide a group attribution for these listed term percentages in the registry record used for this analysis. These summaries are descriptive and do not show whether events were caused by treatment, how long they lasted, or whether a statistical comparison was made. Death counts are not reported in the registry record.

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

The posted safety results describe participants with serious and other adverse events during a long-term randomized comparison of naldemedine and matching placebo. They give counts and group denominators, and the registry provides definitions for serious events and investigator-assessed relatedness. This information is useful for understanding what kinds of safety observations were recorded and how the primary outcome was framed.

The figures do not establish that treatment caused or prevented any particular event. An adverse event is not automatically an adverse drug reaction, and the latter requires an investigator judgment about relationship to study drug. The counts also do not describe event severity beyond the registry’s serious-event classification, the number of separate episodes, when events occurred, or whether events resolved. The registry’s listed serious-event terms provide descriptive context but do not supply a full account of each event.

The record does not report a single primary comparison, a confidence interval, or an inferential test for the primary outcome. Thus the group summaries alone do not show how precisely a comparative effect was estimated or whether a formal analysis supported a difference. They should not be interpreted as proof of equivalence, proof of a difference, or proof of causation.

The trial also listed outcomes related to bowel movements, laxative use, symptoms, and quality of life, but numerical results for those outcomes are not reported in the registry record details for this analysis. The safety summaries cannot answer those symptom questions. They also do not establish what would happen in populations or settings beyond the trial’s stated population and treatment schedule. The record is best read as a description of observed safety counts, with key comparative, causal, and outcome-specific questions left unresolved by the reported information.

13. Why This Trial Matters Statistically

This trial is statistically relevant because its primary focus was long-term safety in people receiving opioid therapy for opioid-induced constipation, and it used a randomized placebo-controlled parallel-group design. Random assignment can support a fair comparison when implemented and analyzed as planned, while masking can help limit some forms of influence on treatment and outcome assessment. The registry records quadruple masking; the specific roles covered by that classification are not reported.

The trial also illustrates why an endpoint’s definition and reporting format matter. “Number of participants with adverse events” sounds like one outcome, but the registry notes several categories or time points and does not reduce the primary outcome to one comparison. Seriousness and investigator-assessed relatedness are separate concepts, so readers need to distinguish event counts from judgments about attribution.

The registry includes both safety outcomes and secondary outcomes concerning bowel movements, laxative use, symptoms, and quality of life. Multiple outcomes can require a clear prespecified analysis strategy to guide interpretation. The record’s counts of 13 outcome measures and 50 analyses make that question pertinent, but the statistical plan and multiplicity method are not reported.

Finally, descriptive counts are not a substitute for comparative estimates with uncertainty. The posted group summaries allow a reader to see how many participants were recorded with serious and other adverse events, but the record does not report a single primary comparison or its precision. This distinction is central to responsible interpretation: observed counts provide evidence about what was recorded in the trial, while a complete statistical conclusion also depends on analysis methods, uncertainty, missing-data handling, and the prespecified questions.

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 registry record does not provide a single primary comparison for the adverse-event outcome, which it says has several categories or time points. It also does not report a confidence interval, p-value, or adjusted estimate for that outcome. The serious and other adverse-event counts are therefore descriptive and do not show the precision of a comparative effect.

Details needed to assess the analysis are not reported in the registry record. These include the randomization procedure, the roles covered by quadruple masking, the statistical analysis plan, the handling of multiplicity, missing-data methods, sensitivity analyses, and definitions of analysis populations beyond the safety population. The trial’s own sample-size justification is also not reported.

The listed serious adverse-event terms and percentages do not specify group attribution in the record details used for this analysis. The registry does not report death counts. The posted information also does not provide event-level timing, duration, recurrence, or outcomes, and the participant counts do not establish investigator-assessed relatedness for every event.

Although secondary outcomes cover bowel movements, laxative use, constipation symptoms, and quality of life, their numerical results are not reported in the registry record details for this analysis. Consequently, the safety summaries cannot be used to assess those outcomes. These limitations constrain what can be concluded from the registry results; they should not be filled in with assumptions about the protocol or analysis.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Long Term Safety of Naldemedine — NCT01965652.
• Registry record last updated 2018-04-18; status last verified 2018-04.
• Results first posted 2017-05-30.
• 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

NCT01965652 is a completed randomized, placebo-controlled, parallel-group phase 3 study of long-term naldemedine for opioid-induced constipation in people with non-malignant chronic pain receiving opioid therapy. The naldemedine group received 0.2 mg orally once daily for 52 weeks; the placebo group received matching tablets on the same schedule.

The primary outcome was the number of participants with adverse events in the safety population, assessed from the first dose through up to 14 days after the last dose. The registry reports serious adverse-event counts of 60 among 621 participants assigned to naldemedine and 73 among 619 assigned to placebo. It reports other adverse-event counts of 225 among 621 and 179 among 619, respectively. The primary outcome is not reduced to one comparison, and a comparative inferential result is not reported in the registry record.

Secondary outcomes addressed bowel movements, laxative use, constipation symptoms, and quality of life. Their numerical results, missing-data methods, and multiplicity approach are not reported in the registry record details for this analysis.