Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT) (NCT00385684), a randomized phase 4 study. The primary outcome is Pain Assessment in Advanced Dementia (PAINAD).

2. Clinical Question

3. Trial Design

The registry classifies L-DOT as a randomized, quadruple-masked, crossover Phase 4 study. Its brief description calls it an eight-week clinical trial. The arm descriptions divide the study into a two-week closed-label phase and a six-week open-label phase. In the closed-label phase, participants were assigned to one of two sequences: A1 followed by A2, or A2 followed by A1. Each phase lasted one week, and the record describes each participant as serving as their own control.

A1 is the experimental regimen: hydrocodone/acetaminophen, with placebo available as needed. A2 is the placebo comparator, with hydrocodone/acetaminophen available as needed. The A1 description specifies a liquid formulation of hydrocodone/acetaminophen 2.5/167 mg per 5 ml, given three times daily. The registry’s general masking classification is quadruple; its description of Phase A calls that phase double-blind. Further details about who was masked are not reported in the registry record.

The open-label phase is described as six weeks of hydrocodone/acetaminophen for participants who tolerated the study medication during Phase A. Participants judged to be responders continued the same dose; others were moved to a higher dose. The available description ends before giving further dosing details, so those details are not reported in the registry record. The open-label phase is distinct from the randomized, closed-label comparison and should not be treated as if it were another randomized comparison.

The registry reports enrollment of 11. It posts PAINAD results for the experimental and placebo arms, with n of 8 for each arm. The outcome timeframe is two weeks. The registry lists the study as completed, with a start date of 2007-10 and primary completion date of 2011-12. It does not report the sequence allocation counts, the timing of outcome assessments within the two-week period, or a detailed account of participant flow through both phases.

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.

FIRST INTERVENTION OF PHASE A

Reasons for not completing this period:

SECOND INTERVENTION OF PHASE A

Reasons for not completing this period:

PHASE B

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: Veterans with severe dementia residing in VA nursing home.

6. Primary Endpoint

The registry lists the primary outcome as Pain Assessment in Advanced Dementia (PAINAD), measured over Two (2) weeks.

The primary endpoint is the Pain Assessment in Advanced Dementia (PAINAD), reported as a mean on a scale measured in units. The registry describes it as an observational assessment of pain intensity for people with severe dementia. Higher scores indicate more pain or discomfort, and the stated scale range is 0-10. The primary outcome timeframe is two weeks.

An observational measure can be used when a participant may not be able to describe pain reliably in words. PAINAD is therefore relevant to the study’s stated population of people with advanced dementia. In general, a scale score gives a structured way to record observations; it does not by itself identify the cause of a behavior or establish that a difference between groups is due to treatment.

The registry reports the endpoint as a mean with a standard deviation. The experimental arm mean is 2.2, with a standard deviation of 1.21, and the placebo comparator mean is 2.56, with a standard deviation of 1.41. These are group summaries, not a reported treatment-effect estimate with an interval or test. The record does not describe a threshold for a clinically important change, a minimum meaningful difference, or how assessors were trained to score PAINAD. Those details are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General: a mean describes the average value of a continuous outcome in a group. Here, the outcome is PAINAD, and the record reports the mean as 2.2 for A1 and 2.56 for A2. Because the scale assigns higher scores to more pain or discomfort, the lower posted mean is descriptively associated with less discomfort. This description alone does not show that treatment caused the difference, or how reliably the means estimate the underlying group values.

General: a standard deviation describes how dispersed individual observations are around a group mean. The posted standard deviations are 1.21 for A1 and 1.41 for A2. They describe variation in scores, not uncertainty in the comparison between treatment conditions. A confidence interval is a range of values compatible with a statistical analysis under its assumptions; it communicates uncertainty around an estimate. No confidence interval for the treatment contrast is reported in the registry record.

General: a randomized crossover design differs from a parallel-group design because participants receive the study conditions in sequence. Each participant can contribute observations under both conditions, and the comparison can use within-participant differences. Such an analysis can account for stable participant characteristics shared across periods. The record describes A1 and A2 as one-week periods in randomized order and says each participant serves as their own control. But it does not post individual paired outcomes or a summary of within-person differences. The arm means and standard deviations alone are not enough to reconstruct that paired analysis.

General: crossover analyses may also need to account for treatment order and period. A period effect is a systematic difference between measurement periods, while a sequence effect concerns the order in which participants receive conditions. Carryover refers to an effect of an earlier condition persisting into a later period. These are general design considerations, not findings about this trial. The registry record does not report whether these effects were assessed, how they were handled, or whether a washout period was used.

The record classifies the trial as randomized and quadruple-masked. Its Phase A description uses the term double-blind. Masking can reduce the risk that knowledge of treatment assignment influences behavior, care, or outcome assessment. The registry does not specify the roles of the people included in its masking classification, or how masking was maintained. These details are not reported in the registry record.

General: a p-value evaluates how compatible observed data are with a specified statistical model and null hypothesis; it does not measure the probability that a treatment works. A confidence interval complements a test by showing a range of effect estimates supported by the data and model. Neither a p-value nor an interval for the primary treatment contrast is posted. The record reports zero analyses, so no sponsor analysis or inferential result for the primary comparison is available in the registry entry.

The record provides no estimate of the within-participant treatment effect, no standard error for that effect, and no reported statistical model. It is not possible to infer from the marginal summaries whether the analysis used paired methods, a repeated-measures model, or another approach. It is also not possible to determine whether the posted arm summaries represent all randomized participants, only those with outcome data, or a particular analysis population.

The record includes a sample-size planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It describes planning for fractions of the observed effect. General: such calculations explore how many participants per arm might be needed under stated assumptions to detect an assumed effect. They are planning illustrations, not evidence about the power of the completed study. In particular, they are not observed power, and the observed effect used in planning may be uncertain. The registry record does not report the trial’s own sample-size justification, target enrollment rationale, or a prospective power calculation.

General: over-dispersion occurs when outcomes vary more than a model assumes; ignoring it can make uncertainty appear too small. It is a possible consideration for some outcome types, but the posted primary outcome is a continuous PAINAD score summarized by a mean and standard deviation. The record does not report a model or evidence of over-dispersion, so no claim about its presence or handling can be made for this study.

In short, standard statistical concepts clarify what the posted means, standard deviations, and crossover description can convey. They do not fill gaps in the analysis record. A treatment-effect estimate with uncertainty, an account of the paired analysis, and details of the analysis population would be needed to assess the primary contrast statistically; these are not reported in 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("Experimental: A1", "Placebo Comparator: A2")
n   <- c(8, 8)
m   <- c(2.2, 2.56)
sp  <- c(1.21, 1.41)
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  Experimental: A1  8  2.200  1.210  1.188  3.212
CARM  Placebo Comparator: A2  8  2.560  1.410  1.381  3.739

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one secondary outcome, PAINAD, and identifies PAINAD as the primary outcome as well. It reports two outcome measures and zero analyses. The record does not clarify the relationship between the primary and secondary listing, or whether additional outcome measures were collected but not posted. A statistical plan identifying the primary comparison and any hierarchy among outcomes is not reported in the registry record.

Multiplicity arises when several outcomes, time points, or treatment contrasts are tested. In general, the more inferences considered, the greater the chance that at least one result appears notable by chance if no adjustment or prespecified hierarchy is used. The record does not report whether multiplicity was considered or how it would have been handled. Since no inferential analyses are posted, the effect of any multiplicity procedure on the reported results cannot be assessed.

The outcome summaries have n of 8 in each arm, whereas overall enrollment is listed as 11. The record does not explain this difference or state which participants were included in the outcome analysis. It does not report reasons for missing outcome values, missingness by treatment sequence, or whether any participants withdrew or did not complete both periods. These details are not reported in the registry record.

General: missing data can affect a result if the availability of an outcome is related to the outcome itself, treatment, or participant characteristics. Statistical approaches make different assumptions about why measurements are missing. The record does not report an approach to missing data, an imputation method, a sensitivity analysis, or an analysis of participants according to randomized sequence. The analysis population and treatment of incomplete crossover observations are also not reported. Consequently, the potential effect of missing outcomes on the PAINAD comparison cannot be evaluated from the registry entry.

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: death (9.1%), respiratory distress (9.1%).

The safety entry reports 2 serious adverse events among 11 at risk and 1 other adverse event among 11 at risk. These are registry-level counts for the group titled “ALL STUDY PARTICIPANTS”; the entry does not divide them by randomized treatment or crossover period. The record therefore does not provide a treatment-specific comparison of serious or other adverse events.

Death and respiratory distress are each listed among the top serious adverse-event terms at 9.1%. The separate deaths field is null. A null entry is not a reported count of zero, and the registry does not explain the relationship between that field and the listed serious terms. The adverse-event information should therefore be read as recorded, without inferring a separate death count or attributing an event to a particular treatment.

General: an adverse event is an event recorded during a study; its occurrence does not by itself establish that study medication caused it. A safety comparison requires suitable information about exposure, timing, treatment assignment, and event counts by group. Those details are not reported in the registry record. The small number of recorded events and the lack of treatment-specific data limit what can be concluded about comparative safety from this entry.

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

The posted results establish that the registry contains PAINAD summaries for two closed-label arms: a mean of 2.2 and standard deviation of 1.21 for A1, and a mean of 2.56 and standard deviation of 1.41 for A2. Since higher scores indicate more pain or discomfort, the A1 summary is descriptively lower. The record also identifies the outcome timeframe as two weeks and describes the trial as a randomized crossover study.

These details do not establish whether hydrocodone/acetaminophen changed discomfort compared with placebo. The registry does not report an inferential comparison, a confidence interval, a p-value, or an estimated within-participant effect. A difference in displayed group means is not, on its own, evidence that an effect is statistically distinguishable from chance variation or clinically important. The record also gives no threshold for a meaningful PAINAD change.

The design description indicates that the intended closed-label comparison used both treatment conditions in each participant, in randomized order. However, the posted summaries are not paired comparisons. They do not show how each participant’s score changed between periods, whether the treatment sequences behaved similarly, or how the analysis accounted for period and sequence. The record does not report whether the crossover analysis followed the stated design.

Nor can the posted safety entries establish a comparative safety effect. They record serious and other adverse events for all study participants, without a treatment-specific breakdown. The death term appears among the top serious terms, while the separate deaths field is null; the record does not resolve that distinction. No causal attribution is reported.

The results are therefore best read as limited descriptive information from a completed trial record. They do not establish that the medication is effective or ineffective, and they do not establish that it is safe or unsafe. The record leaves key questions about the treatment-effect estimate, uncertainty, outcome completeness, and analysis methods unanswered.

14. Why This Trial Matters Statistically

This trial is statistically notable for its crossover design in a population with advanced dementia. Each participant was intended to receive both the active regimen and placebo in randomized order, making the within-participant contrast central to the design. Such designs can be informative when measurements under both conditions are available and the analysis reflects the paired structure. The registry record describes that structure but does not post the paired outcomes or the corresponding analysis.

The example also illustrates why group summaries need careful interpretation. Means and standard deviations describe the observed outcome distributions in each arm, but they do not supply the uncertainty around a treatment contrast. In a crossover study, the relationship between each participant’s scores across periods matters. Marginal summaries do not reveal that relationship, so they cannot substitute for a reported within-person estimate and its precision.

The record further shows the distinction between enrollment and outcome denominators. Enrollment is listed as 11, while each posted arm summary has n of 8. Without participant flow or missing-data details, a reader cannot determine why those figures differ or how complete the outcome data were. This is an important reporting issue because the analysis population and missing outcomes affect how results are interpreted.

Finally, the safety entries are aggregate rather than treatment-specific, and the record does not include an inferential primary analysis. These gaps make the trial useful as an example of the limits of registry outcome summaries: design labels and descriptive statistics are not a substitute for a transparent account of the analysis, uncertainty, and participant data contributing to each result.

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 primary limitation in interpreting this record is that it posts descriptive arm summaries but no treatment-effect estimate or inferential analysis. No confidence interval, test statistic, or p-value is reported. The record therefore does not show the precision of the randomized comparison or whether its result is compatible with a range of possible effects.

The crossover design creates a further limitation: the posted means and standard deviations do not show the paired, within-participant differences that the design is intended to compare. The record does not report treatment sequence counts, period-specific outcome data, an account of carryover considerations, or the statistical model. The consistency of results across sequences cannot be assessed.

The outcome summaries list n of 8 for each arm, while enrollment is 11. Participant flow, completion of both periods, and reasons for missing outcomes are not reported in the registry record. The analysis population and missing-data approach are also not described. This prevents assessment of whether the posted summaries reflect all randomized participants or a subset with available measurements.

The PAINAD description identifies the scale and direction of scoring, but the record does not report a threshold for meaningful change or the reliability of assessments in this study. The safety entry is aggregate, lacks treatment-specific counts, and includes a null deaths field alongside death among the listed serious terms. It does not establish event attribution. Finally, the sample-size material is a planning illustration based on the observed effect, not a report of the trial’s original design rationale or observed power.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT) — NCT00385684.
• Registry record last updated 2015-11-20; status last verified 2015-11.
• Results first posted 2015-11-20.
• 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

L-DOT is listed as a completed, randomized, quadruple-masked crossover Phase 4 study of hydrocodone/acetaminophen and placebo for discomfort in veterans with advanced dementia. The registry describes an eight-week study: a randomized, two-week closed-label crossover phase followed by a six-week open-label phase for participants who tolerated the medication. Enrollment is listed as 11.

The primary outcome is PAINAD over two weeks, reported as a mean with standard deviation. The posted summaries are 2.2 (standard deviation 1.21) for A1 and 2.56 (standard deviation 1.41) for A2, with n of 8 in each arm. No inferential analysis is posted. Safety entries report 2 serious adverse events and 1 other adverse event among 11 at risk; death and respiratory distress are each listed among the top serious terms at 9.1%.

The registry record does not report a treatment-effect estimate, confidence interval, p-value, analysis population, or approach to missing data. It also does not provide treatment-specific adverse-event comparisons.