A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue (NCT04141696), a randomized phase 1, phase 2 study. The primary outcome is Percentage Change in Self-reported Fatigue Visual Analog Scale (VAS) Scale.

2. Clinical Question

The central statistical question is about the size and precision of the observed fatigue changes under each treatment, not simply whether a change occurred. The registry reports median percentage changes for each treatment, along with bounds, but does not report a formal statistical comparison between treatments. Because the design is a crossover, participants received both study drugs in an assigned order, rather than being allocated to one treatment for the entire study. The treatment sequence and the period in which each drug was received are therefore relevant to interpreting a comparison.

The registry describes the objective as testing whether ketamine reduces fatigue in cancer survivors and people with chronic illness. The posted primary outcome is narrower: it concerns self-reported fatigue at a specified time after infusion. Other recorded outcomes address fatigue, physical activity, anxiety, depression, and sleep disturbance, among other measures. Results for those outcomes are not presented in the primary outcome figures discussed in the registry record.

3. Trial Design

This completed phase 1 and phase 2 study was randomized, double-masked, and used a crossover model. Enrollment was 10. Participants were assigned to one of two treatment sequences: ketamine followed by midazolam, or midazolam followed by ketamine. Each infusion was delivered intravenously over 40 minutes. The sequence descriptions specify a two week washout between infusions, followed by two weeks of observation after the second infusion.

The registry lists the study start as 2021-07-26 and the primary completion as 2024-03-21. Eligibility was described for adults aged 18 to 70 with fatigue who were cancer survivors or had a chronic illness. The screening description includes a physical exam, medical history, blood and urine tests, fatigue questions, and a breathalyzer test. During the study, fatigue questionnaires, thinking, memory, and motivation tests, and a handgrip test were planned. Follow-up visits and phone calls were also described.

The crossover structure means that the treatment periods and their order matter. An outcome observed after ketamine and an outcome observed after midazolam may come from the same participant at different times. This differs from a parallel-group study in which each participant receives only one assigned treatment. The registry identifies the treatment sequences but does not report the statistical method used to account for the paired, within-participant nature of crossover observations, treatment period, or sequence.

The primary outcome population is stated as all participants who completed the study. The outcome records list 8 observations for ketamine and 8 for midazolam, while enrollment was 10. The registry record does not explain how the outcome counts relate to enrollment or provide participant flow details. It also does not report the sample-size justification or a detailed protocol for the conduct and analysis of the crossover comparison.

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: 10 participants were consented and two were screen failure so were not randomized in the study.

Period 1

Period 2

Analysis population for the primary outcome, as defined in the registry: All participants who completed the study.

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 Percentage Change in Self-reported Fatigue Visual Analog Scale (VAS) Scale, measured over Baseline to three days post infusion for each study arm.

The primary endpoint is the percentage change in self-reported fatigue on the Fatigue Visual Analog Scale (VAS), measured from baseline to three days after infusion for each treatment period. The VAS is described as a 0-100 mm scale widely used to assess fatigue in people with chronic illness. Higher scores indicate worse fatigue. For the endpoint, the registry describes the change as the day-three score minus the baseline score, divided by the baseline score.

Using a percentage change expresses the observed shift relative to the participant’s baseline score, rather than reporting only the raw movement on the scale. This can make the result easier to interpret across participants who began with different baseline fatigue scores. It also means that the baseline value is part of the calculation, so the resulting percentage change should not be treated as a raw VAS-point difference.

The posted summary is a median, with inter-quartile range specified as the dispersion measure. The registry record lists the median percentage change as -21.0 for ketamine and -12.6 for midazolam. Since higher VAS scores indicate worse fatigue, a negative change corresponds to a lower score relative to baseline. These summaries describe the treatment-period observations; they are not, by themselves, a direct estimate of the difference between treatments. The registry does not report a formal comparative estimate for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a median describe?

The median is the middle of the ordered observed values. It is a measure of the typical location that is less influenced by unusually high or low observations than the mean can be. The registry specifies the median for the primary endpoint and identifies the inter-quartile range as its dispersion measure. The posted arm records include a median and lower and upper bounds, but the record does not explicitly identify those bounds as the inter-quartile range. They should therefore be reported as bounds without assigning them a different statistical meaning.

With a small set of observations, a median is a concise description, but it does not show the full distribution. Different patterns of individual responses can produce the same median. A median also does not convey the precision of a treatment comparison. That requires a comparative estimate and an appropriate measure of uncertainty, neither of which is reported for the primary outcome in the registry record.

How should the crossover structure affect interpretation?

In a crossover design, participants receive the treatments in different sequences. The registry describes a ketamine-then-midazolam sequence and a midazolam-then-ketamine sequence, with a two week washout between treatments. Each participant can therefore contribute observations under both treatment conditions. General statistical practice for crossover data takes account of the fact that observations from the same participant are related. It may also consider period and sequence effects, because outcomes can vary over time or according to treatment order.

The registry record does not report which statistical method was used for the treatment comparison or whether period, sequence, or within-participant dependence was addressed. The reported medians for each treatment are useful descriptive summaries, but they cannot establish how a paired treatment effect was estimated. Treating the two treatment records as independent groups, or deriving a treatment contrast from the difference between their medians, would not be justified by the information reported.

What does a confidence interval add?

General explanation: a confidence interval describes the uncertainty around an estimated quantity under the assumptions of the analysis. For a treatment comparison, it can indicate which effect sizes are compatible with the data and the chosen method. The registry record does not label the listed bounds as confidence intervals and does not provide a confidence interval for a treatment contrast. Consequently, those bounds cannot be used as a substitute for an interval around the comparative effect.

The absence of a reported p-value or interval does not establish that the treatments are the same or that a difference is present. It means the registry record, as described, does not provide those inferential results. The primary outcome figures support a description of the observed medians and bounds, but not a claim about statistical significance or a precise comparative effect.

Why does dispersion matter?

General explanation: dispersion shows how widely individual observations vary around a central summary. In a small study, one or a few observations can have substantial influence on the shape of the distribution, even when a median is used. Reporting both a central value and a suitable measure of spread helps readers see that the center alone does not describe all responses. Here, the registry names the inter-quartile range as the dispersion measure but does not state how that measure corresponds to the posted lower and upper bounds.

Over-dispersion is a general concern when observed variation is larger than a statistical model assumes. If a model underestimates variability, uncertainty may be understated and inference can be too optimistic. The registry record does not describe a model for the primary result, so it is not possible to assess whether over-dispersion was evaluated or relevant to the posted summaries.

What can planning calculations tell readers?

General explanation: sample-size planning calculations estimate how many participants might be needed under specified assumptions to detect a chosen effect with a chosen statistical procedure. They are planning illustrations, not observed power and not evidence that a study was designed to achieve those assumptions. The registry describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is a stated fraction of the observed effect. The record does not report that these assumptions were the trial’s original design plan, and the sample-size justification is not reported in the registry record.

The registry identifies the study as a crossover trial, while the planning description refers to equal allocation between two arms. Such illustrative calculations should not be mistaken for the analysis of the crossover data or for proof that the trial had adequate precision. Planning estimates depend on assumptions about the effect, variability, allocation, and analysis. A planning illustration based on an observed effect is especially not a substitute for a prespecified design justification.

What analysis details remain unclear?

The registry reports 0 analyses and labels the outcome kind as other, with no single comparison indicated. It does not report the test or model used, a comparative effect estimate, a p-value, or a confidence interval for the primary outcome. It also does not say whether any adjustments were made for baseline values or treatment order. These omissions limit the ability to reproduce the analysis or judge its statistical assumptions from the registry record alone.

10. Multiplicity, Missing Data and Analysis Populations

The record lists multiple outcomes: the primary fatigue VAS measure and secondary measures covering fatigue, activity, anxiety, depression, and sleep disturbance. It reports 11 outcome measures and 10 posted secondary outcomes. Testing several outcomes can increase the chance of finding an apparently notable result by chance if no multiplicity strategy is used. A statistical plan might identify a primary outcome, specify a hierarchy, or adjust inference across tests. The registry record does not report a multiplicity adjustment or an analysis hierarchy beyond identifying the primary endpoint.

The primary endpoint is described for participants who completed the study. The record does not provide a participant flow account explaining how many people completed, why any outcome observations may be absent, or how missing outcomes were handled. It does not report whether the analysis used all available observations, imputed missing values, or applied another approach. Missing-data assumptions and sensitivity analyses are not reported in the registry record.

Enrollment was 10, while the primary outcome records list 8 observations for each treatment. Because this is a crossover design, those treatment-specific counts should not be added together or interpreted as separate groups of participants. The registry does not explain the relationship between enrollment, completion, and the treatment-specific records. Nor does it state whether all randomized participants were included in the analysis or whether the primary outcome population was restricted to completers beyond its description as all participants who completed the study.

These reporting gaps matter because missingness and selection into a completer population can affect how representative the posted results are of all enrolled participants. Without a reported missing-data approach and analysis population details, the direction or size of any such effect cannot be determined.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event records list 8 participants at risk for serious adverse events under ketamine and 8 under midazolam. Serious adverse events affected 0 in each treatment record, and deaths were 0 in each. The record lists no top serious adverse-event terms. For other adverse events, 8 participants were at risk and 8 were affected under each treatment.

These are treatment-specific records in a crossover study, not necessarily independent groups of people. The counts should not be added across treatments to estimate the number of people affected, because participants received both treatments in assigned sequences. The registry does not list the types, severity, timing, or duration of the other adverse events in the registry record reported for these results. It also does not provide a formal comparison of adverse-event rates between treatments.

A zero count for serious adverse events in the posted records means none were recorded in those treatment-specific observations. It does not establish that serious events cannot occur or precisely quantify the frequency of rare harms. Likewise, the other-adverse-event counts describe what was recorded in this study, not a complete safety profile for broader use. These figures are descriptive and should be interpreted alongside the study’s size, crossover structure, and limited reporting detail.

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

The registry results show median reductions in self-reported Fatigue VAS relative to baseline for both treatment records at three days after infusion: -21.0 for ketamine and -12.6 for midazolam. Since higher scores indicate worse fatigue, the negative values represent lower scores than at baseline. These descriptive summaries give readers information about the observed endpoint values in the posted records.

They do not establish the size of a treatment difference. The primary outcome is summarized separately by treatment, and the registry record does not report a formal comparative estimate, p-value, or confidence interval. Because the trial used a crossover design, an appropriate comparison would need to account for the relationship between observations from the same participant and the assigned sequence. The registry does not report how that comparison was analyzed. The medians should not be subtracted to create a new comparative result.

The findings are also specific to the Fatigue VAS measurement and the three-day time point. They do not establish how fatigue changed at other times, what happened on the listed secondary measures, or whether the posted pattern applies to people outside the enrolled study population. The record describes adults aged 18 to 70 with fatigue who were cancer survivors or had chronic illness, and the primary outcome population is described as study completers.

More generally, a result from a proof-of-concept study can help describe observations and inform further study, but its interpretation depends on the quality and completeness of the design and analysis information. Enrollment was 10, the treatment-specific outcome records list 8 observations each, and the registry does not explain their relationship. The record also does not report missing-data procedures, multiplicity handling, or the statistical method for the crossover comparison. These limits make the posted values descriptive rather than a complete basis for a precise treatment-effect conclusion.

The registry record does not establish that either treatment works or does not work. It reports observed summaries and safety counts, with important details of comparative inference absent. The results are best read as limited evidence about the measured outcomes in this study, not as medical advice or a basis for decisions about treatment.

13. Why This Trial Matters Statistically

This trial is statistically notable because it uses a randomized, double-masked crossover design to compare two intravenous treatments for fatigue. In a crossover study, each participant receives both treatments in an assigned order, allowing observations to be made under both conditions. That structure can make within-participant comparisons informative, but it also means the analysis must reflect the dependence between observations and consider treatment period and sequence.

The registry provides treatment-specific medians for the primary fatigue measure, but it does not report a formal treatment contrast or explain the statistical method used. That distinction is important: descriptive summaries can communicate what was observed under each treatment, while a comparative estimate is needed to quantify the difference between conditions with appropriate uncertainty. The posted medians alone do not supply that inference.

The study also illustrates why complete reporting matters in small proof-of-concept research. Enrollment was 10, while each treatment record lists 8 outcome observations. Without participant flow information, analysis-population details, or missing-data methods, readers cannot determine how the outcome records relate to all enrolled participants. Likewise, the registry lists several secondary outcomes but does not report a multiplicity strategy.

The primary endpoint is a self-reported percentage change at a defined follow-up time. That makes its scale and timing central to interpretation: it is not a raw VAS-point change, a measure of all dimensions of fatigue, or evidence about longer-term outcomes. The registry describes the VAS direction, median summary, and treatment regimens, but the lack of a reported comparative analysis limits what can be concluded statistically.

For researchers, this record shows the value of reporting the analysis method, paired treatment estimate, uncertainty, participant flow, and handling of multiple outcomes alongside descriptive results. Those details allow a crossover result to be evaluated on its design-specific terms.

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.

Several limitations specific to this trial affect interpretation. The registry reports a small enrollment of 10 and treatment-specific primary outcome records of 8 observations each. It does not explain the relationship between those counts, provide a participant flow account, or report reasons for missing observations. The endpoint population is described as participants who completed the study, which may not be the same as every randomized participant; further detail is not reported in the registry record.

The study is a crossover trial, but the statistical method for comparing the treatments is not reported. The record does not state how within-participant dependence, treatment period, sequence, or possible carryover was addressed. Although the sequence descriptions specify a two week washout, the record does not provide analysis details that would show how the crossover features were handled statistically.

The registry presents medians and bounds for the primary outcome but does not identify the bounds as confidence intervals or provide a comparative confidence interval, p-value, or treatment-effect estimate. The stated inter-quartile range is not explicitly linked to the posted bounds. Without those details, the precision and inferential meaning of the results cannot be fully assessed.

The outcome is self-reported fatigue measured at baseline and three days after infusion. This captures a specific symptom measure and time point; it does not alone describe longer-term effects or the full range of outcomes listed in the registry. The record lists multiple secondary measures but does not report a multiplicity strategy. Sample-size justification, missing-data methods, and the detailed statistical plan are not reported in the registry record.

Finally, adverse-event reporting is limited to counts. The registry does not provide the types or timing of other adverse events or a formal comparison between treatments. These reporting limitations do not invalidate the posted summaries, but they constrain how far those summaries can be interpreted.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Proof-of-Concept Trial on the Effect of Ketamine on Fatigue — NCT04141696.
• Registry record last updated 2025-04-15; status last verified 2025-02-11.
• Results first posted 2025-04-15.
• 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

NCT04141696 is a completed, randomized, double-masked phase 1 and phase 2 crossover trial sponsored by the National Institute of Nursing Research (NINR). It enrolled 10 adults with fatigue who were cancer survivors or had a chronic illness, and compared ketamine with midazolam in two treatment sequences. The registry lists the study start as 2021-07-26 and the primary completion as 2024-03-21.

The primary endpoint was percentage change in self-reported Fatigue VAS from baseline to three days after infusion. The posted medians were -21.0 for ketamine and -12.6 for midazolam, with 8 outcome observations listed for each treatment. The registry record does not report a formal comparative analysis, a confidence interval or p-value for the treatment contrast, or details of missing-data handling. Serious adverse events and deaths were recorded as 0 for each treatment; other adverse events affected 8 in each treatment record.