Study of D-Methadone in Patients With Chronic Pain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of D-Methadone in Patients With Chronic Pain (NCT00588640), a randomized phase 1, phase 2 study. The primary outcome is Number Who Reached a Safe Dose.

2. Clinical Question

In clinical terms, the stated primary question is about dose attainment and tolerability, not a quantified comparison of pain relief between d-methadone and placebo. The record does not define a threshold for what counted as a safe and well-tolerated dose, or describe the dose-adjustment rules used to determine attainment. Those details are not reported in the registry record.

The enrollment is recorded as 10. This figure does not resolve which participants contributed to the primary endpoint or whether they completed the intended assessments. The registry describes no Phase II accrual, and it does not provide a participant flow or an analysis population. Thus, the clinical question is identifiable, but the posted record does not provide the endpoint result needed to answer it.

3. Trial Design

The registry identifies the study as a Phase I/II trial of d-methadone in patients with chronic pain and lists Memorial Sloan Kettering Cancer Center as sponsor. Its status is completed. The recorded enrollment is 10. The study's stated purpose was to determine the safest dose that could be given without causing severe side effects in most patients with chronic pain.

The design fields classify the study as randomized, double masked, and crossover. Separately, the Phase I group description calls that part of the study an open-label dose-ranging trial. It says the first cohort of 8 patients would receive 40mg of d-methadone every 12 hours. These descriptions refer to different aspects of the record and do not explain how masking, randomization, or crossover applied to that Phase I cohort. The registry record does not report further operational detail that reconciles them.

Two Phase II groups are described: patients receiving around-the-clock opioid therapy and patients not receiving that therapy. The record states that no patients were accrued to either group. Although placebo is listed as an intervention, the registry does not report an accrued placebo group for the primary endpoint. It also does not provide treatment sequences, crossover periods, washout details, or information on how treatment assignment was implemented.

The primary endpoint is the number of patients who reached a safe and well-tolerated dose of d-methadone, with a timeframe of 2 years. The record lists one outcome measure and no analyses. The registered design and endpoint therefore describe the intended study question, while the missing outcome result and analysis details limit what can be concluded from the record about how the study was conducted or what it found.

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 Number Who Reached a Safe Dose, measured over 2 years.

The primary endpoint is titled “Number Who Reached a Safe Dose.” It measures the number of patients who reached a dose of d-methadone described as safe and well tolerated, with a timeframe of 2 years. This is a count of participants reaching a stated clinical milestone, rather than a reported mean dose or a measure of pain change.

A dose-attainment endpoint can be useful in a dose-ranging study because it focuses on whether a dose can be reached while meeting a tolerability criterion. It is distinct from an endpoint that measures symptom benefit: reaching a tolerated dose does not, by itself, establish the amount of pain relief or whether pain improved relative to a comparator. The registry does not define the precise safety and tolerability criteria or explain how the endpoint was assessed.

The endpoint's recorded parameter is a number, and its unit is participants. The registry record does not report the observed number who reached a safe dose. It also does not report a comparison between groups, an uncertainty interval, or an analysis of the endpoint. Consequently, the posted information identifies what the primary outcome was intended to measure but does not establish the observed outcome or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a Phase I/II study and identifies its primary outcome as a number of participants reaching a safe and well-tolerated dose. Interpreting that outcome requires distinguishing the endpoint definition, the study design, and the analysis actually reported. The record gives the endpoint title and timeframe, but no primary result or analysis. General statistical concepts can clarify what such information would ordinarily mean, but they cannot fill in the missing study-specific details.

What does a participant count represent?

A count endpoint records how many participants meet a defined condition. For this study, the condition is reaching a safe and well-tolerated dose of d-methadone. A count is meaningful only in relation to the participants assessed and the rule used to determine whether the condition was met. The registry lists the unit as participants, but does not report the observed count, the assessed population, or a detailed operational definition of safe and well tolerated.

When a count is used to compare groups, denominators matter: the same count can have different interpretations depending on how many participants were eligible, treated, and assessed. A comparison also needs a clearly described contrast and a statistical method suited to the outcome and design. The registry does not provide the group-specific primary endpoint counts or an analysis, so no such comparison can be reconstructed.

How should the design fields be read?

Randomization is a method for assigning participants to treatment conditions using a chance-based process. In general, it can reduce systematic differences between groups at assignment, although it does not guarantee that groups will be identical. Double masking generally means that participants and at least one other relevant party are unaware of assigned treatment, but the registry does not specify who was masked. Crossover designs generally expose participants to more than one treatment condition in an ordered sequence, allowing within-participant comparisons when the design and analysis support them.

These are general meanings, not confirmation of how this study operated. The registry's design fields say randomized, double masked, and crossover, while the Phase I description calls the dose-ranging trial open label. The record does not explain how these design features applied across phases. It does not report treatment sequences, period lengths, washout arrangements, or a method accounting for within-participant dependence in a crossover analysis. Since no patients were accrued to the described Phase II groups, the record does not show a completed Phase II comparison.

What can confidence intervals and p-values tell readers?

In general, a confidence interval describes the statistical uncertainty around an estimated quantity under the assumptions of the analysis. A narrower interval indicates greater precision than a wider interval, while an interval that includes values compatible with different conclusions may leave the result uncertain. A p-value evaluates how compatible the observed data are with a specified null hypothesis under a statistical model; it is not the probability that a treatment works or that the null hypothesis is true.

No confidence interval or p-value for the primary endpoint is reported in the registry record. Accordingly, there is no posted estimate whose precision can be evaluated and no reported hypothesis test to interpret. A confidence interval or test statistic should not be inferred from the enrollment or adverse-event entries.

Why do design and analysis need to match?

Statistical analysis should reflect how observations were collected. In a crossover study, measurements from the same participant are generally related, so treating them as independent can give an inappropriate estimate of uncertainty. Period effects, treatment order, and carryover may also matter in general, depending on the protocol. The registry does not report whether these features were assessed or how they were handled.

For a dose-ranging safety endpoint, the definition of dose-limiting or unacceptable effects is important to interpreting attainment. The record's stated purpose refers to avoiding severe side effects in most patients, but it does not report a formal dose-escalation rule, stopping criterion, or protocol-level definition of severe effects. These details are not reported in the registry record and should not be inferred from the endpoint title.

What do the planning assumptions mean?

Any sample-size figures described as planning illustrations based on an observed effect are not the trial's original design justification. Such illustrations depend on assumptions, including the stated two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is expressed as a stated fraction of the observed effect. These are planning assumptions, not observed power and not evidence that the trial was designed to achieve a particular power.

For a general sample-size calculation, changing the target effect or other assumptions changes the calculated requirement. A planning illustration cannot establish that a trial had adequate information for its outcome, especially when the primary result and analysis population are not reported. The registry record does not report the study's own sample-size justification or any interim-analysis plan.

Overall, the record permits a descriptive account of the intended endpoint, design labels, and adverse-event entries. It does not permit an inferential reading of the primary outcome. Statistical concepts help identify what information is needed, but they do not replace the absent endpoint result, analysis method, or participant-level flow.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Phase I, Cohort l")
n      <- c(8)
events <- c(8)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Phase I, Cohort l  8  8  100.0  63.1  100.0  67.6  100.0  66.4  99.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure and zero analyses. It does not report a statistical analysis plan, prespecified hypothesis tests, or a method for controlling multiplicity. Multiplicity arises when several outcomes, comparisons, or repeated analyses are considered; in general, without an appropriate plan, the chance of finding an apparently notable result can be difficult to interpret. The registry does not establish which outcomes or comparisons were tested, so no multiplicity adjustment can be assessed.

Missing-data handling is not reported in the registry record. There is no account of participants who discontinued, missed assessments, or lacked endpoint information, and no description of imputation or sensitivity analyses. The recorded enrollment does not show how many participants contributed to the primary endpoint. The record also does not identify an intention-to-treat, per-protocol, or safety analysis population.

These omissions matter because the endpoint is a participant count and its interpretation depends on who was assessed and how missing endpoint status was handled. For a crossover design, the analysis population and availability of measurements across treatment periods would also affect interpretation in general. The registry record does not report those details. Consequently, neither the completeness of the primary outcome data nor the robustness of any treatment comparison can be evaluated from the posted results.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pain - neck (11.1%), pain - back (11.1%).

The safety entry is for “Patients Receiving D-methadone 40 mg.” It records serious adverse events affecting 2 of 9 at risk and other adverse events affecting 5 of 9 at risk. These are separate categories in the registry record; the counts should not be added or treated as a single total. The record does not explain whether the categories overlap at the participant level.

Pain - Neck and Pain - Back are each listed as top serious terms with 11.1%. These percentages are recorded for the terms, but the registry does not provide further detail about event timing, duration, recurrence, or treatment attribution. They should not be interpreted as evidence of causation. The death count is not reported in the registry record.

Adverse-event entries are descriptive safety information, not a randomized comparison. The record does not present corresponding safety figures for a comparator group in this entry, and the Phase II groups had no accrual. The listed at-risk denominator is 9, while the recorded overall enrollment is 10; the registry does not explain that difference. These data therefore should not be used to infer a comparative risk or a complete safety profile.

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

The registry record establishes that the study asked whether patients with chronic pain could reach a safe and well-tolerated dose of d-methadone. It also records a Phase I dose-ranging description, a stated 2-year primary-outcome timeframe, and adverse-event entries for patients receiving D-methadone 40 mg. These details describe the study question and selected recorded safety information.

The record does not report how many patients reached a safe dose. It therefore does not establish the observed primary endpoint result or its precision. No primary-outcome analysis, confidence interval, or p-value is reported. A completed status is not a substitute for those findings, and the recorded enrollment is not enough to determine the number of participants with evaluable endpoint data.

The safety entries likewise do not establish a treatment effect. They do not provide a reported comparator analysis, and the Phase II groups are described as having no accrual. The adverse-event counts and serious-term percentages should be read as registry entries rather than as proof that d-methadone caused or prevented any event. The registry does not report a causal assessment or enough comparative information to evaluate relative safety.

The design metadata and Phase I description also leave important questions about implementation unanswered. Randomized, double-masked, and crossover are the recorded design labels, while the Phase I description says open label. The registry does not explain the relationship between those descriptions. It also does not report the detailed protocol, analysis populations, or missing-data methods.

In short, the record documents an intended safety and dose-attainment question and some adverse-event data, but it does not provide the primary finding needed to answer that question. No conclusion about clinical benefit or comparative treatment performance follows from the posted information.

14. Why This Trial Matters Statistically

This study is statistically notable because its registered primary endpoint is a count tied to a safety and dose-attainment criterion, while the posted record does not report the count itself. That gap illustrates a basic distinction between a registered question and a reported result: an endpoint definition says what investigators intended to measure, but not what they observed or how precisely they estimated it.

The record also illustrates why design labels need context. Randomization, masking, and crossover each have statistical implications, but the Phase I description calls the study open label and dose-ranging. The Phase II groups had no accrual. Without detail about treatment assignment, sequences, and analysis, readers cannot determine which comparisons were actually estimable or whether an analysis accounted for the design.

Safety reporting requires similar care. At-risk denominators and event counts describe the entries in the record, but a comparator and a clearly defined analysis population are needed to interpret differences as comparative evidence. The listed serious-event terms and adverse-event counts do not resolve the missing primary outcome or provide a complete assessment of comparative risk.

The record is therefore useful as an example of how registry information can identify a clinical question while leaving key statistical evidence unavailable. Clear endpoint definitions, transparent participant flow, complete outcome results, and methods aligned with the design are essential for readers to assess both the magnitude and uncertainty of findings. Those elements are not all reported in this record.

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 is that the registry record does not report the observed primary endpoint count. It also provides no estimate of uncertainty or analysis for that endpoint. The clinical question is stated, but the main result cannot be evaluated.

The endpoint's operational definition is incomplete in the record. It does not specify the criteria for a safe and well-tolerated dose, the dose-adjustment process, or the rules for determining whether a participant reached the endpoint. Without those details, even a reported count would require additional context.

The design descriptions are not fully reconciled. The general fields identify randomization, double masking, and crossover, while the Phase I group description identifies an open-label dose-ranging trial. The registry does not report treatment sequence, period structure, allocation details, or how the stated designs related to each other. No patients were accrued to the described Phase II groups.

Participant flow and analysis populations are also not reported. Although enrollment is recorded as 10, the safety entry lists 9 at risk, and the record does not explain the difference. It does not state how many participants completed treatment, had endpoint data, or were included in an analysis. Missing-data handling is not reported.

Finally, the adverse-event entries are limited and lack a reported comparator analysis. The registry does not report event attribution, timing, or a death count. These limitations mean the available record supports only a cautious description of the stated study and posted safety figures, not a full evaluation of its efficacy or safety findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of D-Methadone in Patients With Chronic Pain — NCT00588640.
• Registry record last updated 2016-08-10; status last verified 2016-06.
• Results first posted 2016-08-10.
• 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

NCT00588640 is a completed Phase I/II study of d-methadone in patients with chronic pain, sponsored by Memorial Sloan Kettering Cancer Center. The registry records enrollment of 10 and a primary endpoint of the number of patients reaching a safe and well-tolerated dose during a timeframe of 2 years. The Phase I description calls the study open label and dose-ranging, with the first cohort of 8 receiving 40mg every 12 hours. No patients were accrued to either described Phase II group.

The design fields list randomized, double-masked, and crossover. The registry record does not explain how these labels relate to the open-label Phase I description. It lists one outcome measure and zero analyses, and does not report the primary endpoint result. Safety entries record serious adverse events affecting 2 of 9 at risk and other adverse events affecting 5 of 9 at risk for the D-methadone 40 mg group. The posted information does not provide a primary-outcome comparison or enough detail for a comprehensive statistical assessment.