Oral Ketamine for Control of Chronic Pain in Children: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Oral Ketamine for Control of Chronic Pain in Children (NCT01369680), a non-randomized phase 1 study. The primary outcome is Number of Participants Tolerating Dose.

2. Clinical Question

3. Trial Design

This was a Phase 1, parallel, nonrandomized study of oral ketamine in children with chronic pain. The study summary describes its purpose as finding a maximum tolerated dose for chronic, daily administration. The registry lists enrollment as 12 and describes four dose cohorts, each comprising three subjects: 0.25 mg/kg/dose, 0.5 mg/kg/dose, 1 mg/kg/dose, and 1.5 mg/kg/dose. The arm descriptions refer to these as the first, second, third, and fourth groups, respectively.

The stated endpoint timeframe was up to 2 weeks. Tolerability was defined in relation to toxicity graded according to CTCae: a dose causing grade 2 or worse toxicity was considered untolerated, and tolerability meant taking the medication for 2 weeks without such toxicity. This endpoint is a dose-specific safety criterion, rather than a comparison of pain outcomes between a treatment group and a control group.

Allocation is listed as nonrandomized, masking as none, and the model as parallel. The registry’s own note cautions that the arms are not a like-for-like control comparison. The sequential descriptions identify the order of the dose cohorts, but formal dose-escalation rules, stopping criteria, and procedures for decisions between cohorts are not reported in the registry record. The record also does not report a control intervention.

The study is marked completed. Its start is listed as 2011-05 and its primary completion as 2012-10. The sponsor is the University of Rochester. The registry lists 4 outcome measures and names neurocognitive effect, Norketamine Cmax measured in ng/mL, and pain control among the secondary outcomes. How those secondary outcomes were measured and analyzed is 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:

Analysis population for the primary outcome, as defined in the registry: Number of participants was determined through negotiation with the FDA for safety of all participants.

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 of Participants Tolerating Dose, measured over Up to 2 weeks.

The primary endpoint is the number of participants tolerating dose, with the unit recorded as participants. Its definition is based on being able to take the medication for 2 weeks without grade 2 or worse toxicity according to CTCae. Any dose causing toxicity at or above that grade is defined as untolerated. The timeframe is up to 2 weeks.

This kind of endpoint is used in a dose-finding study to describe tolerability at the doses under study. It focuses on whether participants met a stated toxicity-based criterion during the specified treatment period. It is not a measure of pain improvement, and it does not by itself establish the balance of benefits and harms beyond the timeframe and definition recorded for this endpoint.

The registry record does not report the number of participants who met the tolerability definition in each dose cohort. As a result, the endpoint definition can be described, but the posted results do not establish which dose, if any, met the study’s tolerability criterion. The protocol’s detailed grading procedures and any additional endpoint rules are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a dose-finding study, an important first step is to distinguish the endpoint definition from its result. Here, the endpoint definition is the number tolerating dose, based on taking medication for 2 weeks without grade 2 or worse toxicity according to CTCae. A result would need to state how many participants met that criterion at each dose. Those primary endpoint counts are not reported in the registry record. Without them, the endpoint’s intended interpretation can be explained, but it cannot be estimated from the posted results.

What can counts tell us?

Counts are direct descriptions of how many participants were recorded as affected or not affected within a group. They are easy to interpret, but they do not by themselves show how uncertain the underlying event frequency is. Statistical uncertainty matters because a count from a small group can change substantially if the experience of even a participant differs. Confidence intervals are a general way to express uncertainty around an estimate: they describe a range of values compatible with the data under a specified method. No confidence intervals for the primary endpoint or adverse events are reported in the registry record.

The adverse-event data list participants at risk and participants affected, separately for serious and other adverse events. A count of participants affected is not necessarily a count of every event episode; the record’s stated meaning is participants with an event. The record does not provide additional detail on whether a participant could contribute to more than one event term, how event episodes were counted, or how repeat events were handled. Therefore the counts should be read as participant counts as recorded, not as a complete account of the number or timing of all event episodes.

Why does the cohort structure matter?

Random assignment is a general method for making comparison groups more similar, on average, with respect to factors other than the intervention. This study is listed as nonrandomized, and its dose cohorts are described in sequence. A difference in observed counts across those cohorts may reflect dose, but it may also reflect differences in who entered each cohort, timing, or other factors. The registry does not report enough detail to evaluate those possibilities. The arms are explicitly not identified as like-for-like control groups, so a direct comparative effect should not be inferred.

Masking is listed as none. In general, masking can reduce the influence of expectations on assessments or reporting, depending on the outcome and who is masked. The record does not describe additional safeguards that may have been used for outcome assessment. This is relevant context when interpreting outcomes such as pain control or neurocognitive effect, but their measurement details and results are not reported in the registry record.

What does a planning calculation mean?

A sample-size calculation is a planning exercise: it asks what amount of information a future study might need under specified assumptions. It does not state what the current study observed, and it is not observed power. The planning assumptions associated with this record describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. For non-time-to-event outcomes, the stated convention is participants per arm; time-to-event calculations instead use a total number of events. These assumptions describe an illustration, not the design or analysis of this nonrandomized dose-finding study. The record does not report a sample-size justification for the trial itself.

For an unadjusted comparison, a recalculation from summary statistics would be a calculation based on the posted group-level values, not a replacement for the study sponsor’s analysis. No such primary endpoint recalculation is available in the registry record recorded because the primary outcome results are absent. The record lists 0 analyses. It does not report the sponsor’s statistical analysis, inferential estimates, confidence intervals, or a statistical plan. Any planning illustration based on an observed effect should be interpreted as hypothetical design information, not as evidence that the current trial had a particular probability of detecting an effect.

Why can over-dispersion matter?

Over-dispersion is a general concern for count data when variation is greater than a model assumes. If a model underestimates that variation, its uncertainty estimates may be too small and its inferential conclusions too confident. The registry record does not report a count model or an over-dispersion assessment for this study. The primary endpoint is recorded as a number of participants, and the adverse-event entries are participant counts; the posted information does not establish that a particular model was used or appropriate.

More broadly, model-based interpretation requires information about the analysis population, missing observations, outcome timing, and the prespecified analysis method. These details are not reported in the registry record. The descriptive counts can be stated as recorded, but more elaborate estimates or comparisons would require assumptions that cannot be checked from the available record.

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("Ketamine 0.25 mg/kg/Dose", "Ketamine 0.5 mg/kg/Dose", "Ketamine 1 mg/kg/Dose", "Ketamine 1.5 mg/kg/Dose")
n      <- c(3, 3, 3, 3)
events <- c(3, 3, 3, 1)
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  Ketamine 0.25 mg/kg/Dose  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Ketamine 0.5 mg/kg/Dose  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Ketamine 1 mg/kg/Dose  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Ketamine 1.5 mg/kg/Dose  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures and names neurocognitive effect, Norketamine Cmax measured in ng/mL, and pain control among the secondary outcomes. The primary outcome is the number tolerating dose. The record lists 0 analyses, so it does not provide an analysis plan showing which outcomes were tested, how outcomes were prioritized, or whether multiplicity adjustments were intended. No correction method or family of statistical tests is reported in the registry record.

Multiplicity is a general issue that arises when multiple outcomes, time points, groups, or statistical tests are considered. Without a prespecified plan, it may be difficult to distinguish a primary confirmatory finding from exploratory observations. That concern cannot be resolved from the outcome list alone. Detailed definitions, assessment schedules, statistical hypotheses, and adjustment procedures are not reported in the registry record.

Missing-data handling and analysis populations are also not reported in the registry record. The enrollment entry gives the planned or recorded enrollment figure, but the available information does not describe participant flow, withdrawals, exclusions, incomplete assessments, or the number analyzed for each outcome. It does not state whether participants were analyzed according to assigned cohort, treatment received, or another rule. The endpoint definition refers to ability to take medication for 2 weeks, but the record does not describe how an early discontinuation or an unavailable toxicity assessment was handled.

These omissions limit interpretation of both the primary endpoint and the secondary outcomes. The adverse-event counts can be described as recorded, but it is not possible to determine from the registry record whether all enrolled participants contributed complete assessments or whether missing observations affected the reported counts.

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: infection (33.3%), pain (33.3%).

The registry records serious adverse events separately from other adverse events. In the dose cohorts ordered as 0.25 mg/kg/dose, 0.5 mg/kg/dose, 1 mg/kg/dose, and 1.5 mg/kg/dose, the serious-event affected counts are 1, 1, 0, and 0, respectively. Each cohort lists 3 participants at risk. The other-adverse-event affected counts are 2, 3, 3, and 3, respectively, again with 3 participants at risk in each cohort. These entries are counts of participants with an event, not necessarily counts of event episodes.

The registry lists Infection and Pain as top serious adverse event terms, each at 33.3%. The denominator and method behind these term percentages are not reported in the registry record, so they should not be treated as cohort-specific rates. Death entries are null; deaths are therefore not reported in the registry record, rather than documented as zero.

These figures are descriptive. The cohorts were nonrandomized and are not like-for-like controls, and the small counts do not support a precise comparison of risk between doses. The serious-event counts also do not directly give the primary tolerability result, which applies the separate definition of no grade 2 or worse toxicity during 2 weeks.

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

The study addresses a relevant statistical task in early-phase research: describing tolerability across oral ketamine dose cohorts in children with chronic pain. Its endpoint is defined in terms of taking the medication for 2 weeks without grade 2 or worse toxicity according to CTCae. The record also gives serious and other adverse-event counts for the dose cohorts. These features allow the study question and selected safety information to be described.

However, the primary endpoint results are not reported in the registry record. The posted results therefore do not show the number of participants meeting the tolerability definition at each dose, and they do not establish a maximum tolerated dose. The presence of adverse-event counts does not fill that gap: the serious and other event categories are separate registry entries, and the record does not map them to the primary endpoint criterion.

The design also limits what can be inferred from comparisons across doses. The study was nonrandomized and unmasked, with dose cohorts described in sequence rather than a control group. An observed difference between cohorts would not, by itself, identify a dose effect. The registry does not report enough information about cohort assignment, participant characteristics, statistical adjustment, or outcome assessment to address potential differences between groups.

The event counts should not be read as precise estimates of the frequency of harm in a wider population. Counts from small cohorts have considerable uncertainty, and the record does not provide confidence intervals or a statistical model for them. The listed top serious event terms have percentages whose denominator is not reported in the registry record. The null death entries likewise do not establish an absence of deaths.

In short, the record documents a completed Phase 1 dose-finding study and presents a tolerability definition plus selected adverse-event counts. It does not report the primary result or a statistical analysis that would support a comparative conclusion. The data are not a basis for medical advice or for concluding that a dose is effective or safe.

14. Why This Trial Matters Statistically

This trial matters statistically because it illustrates the distinction between a dose-finding question and a conventional treatment-versus-control question. The study’s aim was to identify a maximum tolerated dose for chronic, daily oral ketamine in children with long-term daily pain. Its primary endpoint focuses on tolerability under a specific toxicity criterion, rather than on a randomized estimate of treatment benefit.

The cohort structure is central to interpretation. Participants were assigned to nonrandomized dose groups described in sequence, and no control intervention is reported. This can be suitable for describing early dose-specific experience, but it does not create a controlled comparison. Differences between groups may have explanations beyond dose, and the record does not provide details that would permit those explanations to be assessed.

The registry also demonstrates why outcome definitions and outcome results must be distinguished. The tolerability definition and timeframe are recorded, but the primary endpoint counts are not. Without the counts, readers cannot assess how often the stated criterion was met in the cohorts. Safety counts, while informative as descriptions of recorded events, are not substitutes for the missing endpoint result or for a complete statistical analysis.

Finally, the study highlights the limits of interpreting small descriptive counts. A count can be transparent and useful while still being imprecise. Statistical reporting that includes analyzed populations, missing-data handling, uncertainty estimates, and the planned analysis would make findings easier to evaluate. Those details are not reported in the registry record, so interpretation must remain focused on the design and entries that are documented.

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 endpoint is defined, but its results are not reported in the registry record. This is the most direct limitation for interpreting the study’s stated dose-finding purpose: the posted information does not show which participants met the tolerability criterion or whether a maximum tolerated dose was identified.

The study is nonrandomized and unmasked, and its dose groups are described in sequence. There is no reported control arm, and the registry cautions that the arms are not like-for-like control groups. Consequently, comparisons across dose cohorts cannot be interpreted as randomized causal contrasts. The record does not report cohort-entry rules, dose progression criteria, stopping rules, or measures to address differences between cohorts.

The group counts are small, with three subjects described in each dose cohort. This limits the precision of descriptive event counts and makes the absence of a recorded event in a cohort insufficient to establish that the event cannot occur. No confidence intervals or statistical comparisons are reported for the primary endpoint or adverse events.

Participant characteristics beyond the chronic pain population are not reported in the registry record. Neither are detailed outcome-assessment methods, adverse-event observation periods beyond the primary endpoint timeframe, analysis populations, missing-data procedures, or the statistical plan. The record lists 0 analyses. The serious adverse event term percentages are reported without a denominator, and death entries are null rather than reported as zero. These limitations restrict both safety interpretation and assessment of the reliability or completeness of the posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Oral Ketamine for Control of Chronic Pain in Children — NCT01369680.
• Registry record last updated 2013-02-15; status last verified 2013-02.
• Results first posted 2013-02-11.
• 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

NCT01369680 is a completed Phase 1, nonrandomized, unmasked, parallel study sponsored by the University of Rochester. It examined daily oral ketamine for chronic pain in children, with the stated purpose of finding a maximum tolerated dose. Enrollment is listed as 12. The arm descriptions identify cohorts at 0.25 mg/kg/dose, 0.5 mg/kg/dose, 1 mg/kg/dose, and 1.5 mg/kg/dose, with three subjects described in each cohort.

The primary endpoint was the number tolerating dose, defined as taking medication for 2 weeks without grade 2 or worse toxicity according to CTCae. Primary endpoint results are not reported in the registry record. Serious and other adverse-event counts are recorded by cohort; Infection and Pain are listed as top serious terms, each at 33.3%, without a reported denominator. The record lists 4 outcome measures and 0 analyses. It does not report a control group, statistical analysis, missing-data handling, or primary endpoint estimates.