Ketamine for Treatment of MS Fatigue: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ketamine for Treatment of MS Fatigue (NCT03500289), a randomized phase 1, phase 2 study. The primary outcome is Change in Daily Fatigue Severity Score.

2. Clinical Question

The trial was registered as “Ketamine for Treatment of MS Fatigue” and is marked completed. It was sponsored by Johns Hopkins University. Its stated focus is a symptom of multiple sclerosis rather than a disease-modifying outcome. The registry background describes fatigue as common and burdensome, while noting that its biological mechanisms and treatment targets are not clearly established. These contextual points explain the research question; they do not establish what the trial found.

3. Trial Design

The registry describes a randomized, double-masked, parallel-group trial in phase 1 and phase 2. Participants were assigned to ketamine or midazolam. The posted group sizes are 12 for ketamine and 6 for midazolam, and the listed enrollment is 18. Random allocation can help balance baseline characteristics on average, while masking is intended to reduce the influence of treatment knowledge on participant reports and study conduct. Those design features do not guarantee balance or eliminate bias, particularly in a small trial.

The listed study start date is 2018-08-10, and the primary completion date is 2019-08-30. The registry status is completed. The registry record does not report the randomization sequence, allocation concealment, masking procedures, treatment dose, infusion details, or whether masking was assessed. It also does not give a detailed account of eligibility criteria or the setting in which participants were recruited.

The primary outcome is continuous: change in daily fatigue severity, reported as a mean point-per-day score change. The measurement period runs from baseline at the infusion visit through day 7. The registry describes the reported change as the last-day measure minus baseline, divided by the number of days in the study. The record lists five secondary outcomes, covering fatigue-related quality of life, fatigue impact, sleepiness, depression, and fatigue severity on other named instruments. Numerical results for those secondary outcomes are not included in the posted results described by the registry record.

The primary comparison is between the two randomized groups. The posted results give a mean estimate and a 95% confidence interval for each arm, but no direct between-group estimate, confidence interval, or p-value is reported. The registry record does not report the planned statistical analysis, analysis population, handling of missing measurements, or a sample-size justification. As a result, the design can be described from the registration, but key details needed to assess its implementation and analysis remain unavailable.

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

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 Change in Daily Fatigue Severity Score, measured over Baseline (infusion visit) through day 7.

The primary endpoint is change in daily fatigue severity. Each daily rating asks how much fatigue—described as tiredness, weariness, or difficulty thinking clearly—the participant felt that day. Responses range from 0, “None at all,” to 10, “Extreme Fatigue.” The registry reports an average point-per-day change, calculated from the last-day measure and baseline, divided by the number of days in the study. The specified interval begins at baseline on the infusion visit and ends on day 7.

A repeated daily symptom rating can represent the course of a subjective symptom over a short follow-up interval rather than relying on a single assessment. The change score expresses movement relative to a participant’s baseline, while the mean summarizes the group’s reported change. This is a general statistical description of these measures, not evidence that the scale captures every aspect of fatigue or that the scoring procedure was validated for this particular study.

The registry identifies fatigue as the target symptom because it is a major concern in multiple sclerosis and can affect daily activity. A single-item score is brief, but it may not capture different dimensions of fatigue, day-to-day variation, or the impact on functioning. Other measures are listed as secondary outcomes, including the NeuroQol Fatigue Item Bank and Modified Fatigue Impact Scale. Their posted numerical results are not reported in the registry record.

The endpoint is a symptom score, not a measure of multiple sclerosis disease activity or disability progression. The primary estimate also does not, by itself, show whether the groups differed: an arm-specific mean and its confidence interval are not equivalent to a direct estimate of the contrast between arms.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous, and the registry reports a mean for each arm. A mean is a measure of the center of the observed values: it combines the scores into an average and can be useful for describing a group-level change. It does not show the distribution of individual responses. Participants may have had different experiences even when the arm means are the same. The registry record does not report a measure of spread such as a standard deviation for the primary endpoint.

What does a confidence interval convey?

A confidence interval expresses uncertainty in an estimated quantity. In general, a 95% confidence interval is generated by a procedure that, under its assumptions, would cover the target quantity in 95% of repeated applications. It is not a statement that there is a 95% probability that this particular interval contains the fixed true value. Here, the intervals are reported separately for the two arm means: -0.19 to 0.08 for ketamine and -0.14 to 0.24 for midazolam. They show that the arm estimates are uncertain, but they do not directly answer how much the arms differ.

Why is the between-group estimate important?

A randomized trial’s comparative question concerns the contrast between assigned groups. Estimating that contrast requires a direct comparison and an uncertainty estimate for the comparison. The registry record lists the arm means but does not report a primary between-group estimate, its confidence interval, or a p-value. Separate arm-level confidence intervals cannot be treated as a replacement for those quantities. A formal comparison may account for the relationship between the arm estimates and may use an analysis plan not described in the record.

How should the change score be understood?

The registry describes the outcome as the last-day measure minus baseline, divided by the number of days in the study. It labels the result an average point-per-day score change. This expresses change relative to baseline on the fatigue item’s 0-to-10 scale. The sign gives the direction of the reported change according to that calculation: negative values correspond to a lower last-day score than baseline under the stated formula. The registry record does not explain how the calculation was applied when daily observations were missing, or whether all participants had measurements at both time points.

In general, a mean change can be sensitive to unusually high or low observations, especially in a small sample. A confidence interval can communicate uncertainty about the mean but does not, by itself, reveal the shape of the individual data or show whether model assumptions fit. The registry record does not report diagnostic checks, the distribution of scores, or a method for handling skewness or outliers.

What do randomization and masking contribute?

Random allocation is a design method intended to make assigned groups comparable at baseline on average, including with respect to factors that are not measured. It does not ensure that a small set of groups will be balanced on every characteristic. Masking is intended to limit changes in behavior, care, or reporting that could arise from knowing the assigned treatment. These are general purposes of the methods; the registry record does not describe sequence generation, concealment, masking procedures, or whether participants and assessors remained unaware of assignment.

The study is described as parallel-group, meaning each randomized participant is assigned to one group rather than crossing between treatments, as a general design concept. The record identifies the two groups as ketamine and midazolam. It does not provide a protocol-level account of treatment delivery or confirm that all randomized participants contributed to the primary analysis.

What can be said about planning calculations?

The registry describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. The registry record does not report the resulting participant counts or identify a planning value for that fraction in the information available for this interpretation. The illustration is not the trial’s design justification and should not be read as observed power. A sample-size calculation is a planning exercise under assumptions; it does not measure the probability that a completed study’s result is correct or prove that the study could detect a particular effect.

Finally, the registry record lists 0 analyses and indicates that values for a two-arm comparison of the continuous endpoint are missing or not estimable. This is consistent with the absence of a posted direct comparison. It does not explain why the comparison is unavailable. The sponsor’s own analysis does not take precedence on the basis of a reported discrepancy, because the registry record does not flag one. The inferential interpretation must therefore remain bounded by the posted arm summaries and the lack of a direct comparative result.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and five secondary outcomes. The secondary outcomes concern NeuroQol Fatigue Item Bank score, Modified Fatigue Impact Scale score, Epworth Sleepiness Scale score, Beck Depression Inventory score, and Fatigue Severity Scale score. The registry record reports no numerical results for these secondary measures. Their presence indicates that several outcomes were planned or tracked, but the record does not describe how their analyses were prioritized or interpreted.

When multiple outcomes are tested, the chance of at least one apparently unusual result can increase if each is assessed separately. General approaches to this issue include prespecifying a primary outcome, controlling a family-wise error rate, or treating secondary analyses as exploratory. The statistical plan and any multiplicity adjustment are not reported in the registry record, so it is not possible to determine how this issue was handled.

The record also does not report the analysis population, the number of participants with observed primary measurements, or the handling of missing daily ratings. It does not specify whether the analysis followed randomized assignment, used only participants who completed treatment, or applied another population definition. The enrollment and arm counts do not establish how many observations contributed to the primary estimates.

Missing outcome data can affect an estimate when availability is related to symptoms, treatment, or other factors. In general, complete-case analyses, imputation, and model-based approaches make different assumptions. The registry record does not identify an approach or describe sensitivity analyses. These omissions limit assessment of potential bias and reproducibility. They do not establish that data were missing; they mean that the registry record does not report whether or how missingness was addressed.

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 registry reports zero serious adverse events among the 12 participants listed as at risk in the ketamine arm and zero among the 6 listed as at risk in the midazolam arm. It also reports zero deaths in each group. These are the serious-event counts recorded for the trial; they should not be interpreted as proof that serious harms cannot occur. A small study and limited observation can provide little information about uncommon events.

For other adverse events, the registry lists 7 affected in the ketamine arm, among 12 at risk, and 0 affected in the midazolam arm, among 6 at risk. These are posted counts, not a measure of severity or a direct causal comparison. The registry record does not list the specific non-serious event terms, their timing, duration, or relationship to treatment. It also does not report a statistical comparison of adverse events.

In general, safety counts are best read alongside how events were defined, collected, and followed. Those details are not reported in the registry record. The figures describe what was entered in this record and cannot establish the full safety profile of either drug.

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

The posted result is a pair of arm-specific mean estimates for change in daily fatigue severity: -0.05 points per day in both the ketamine and midazolam groups. The 95% confidence intervals extend from -0.19 to 0.08 for ketamine and from -0.14 to 0.24 for midazolam. The intervals show uncertainty around the mean change in each group, and both include zero. This does not prove no change occurred, nor does it indicate whether the groups differ.

The direct comparative result is not reported in the registry record. Without a between-group estimate and its uncertainty, the posted arm summaries do not establish the size or precision of a ketamine-versus-midazolam contrast. No claim that one treatment was better or worse follows from the matching point estimates alone. The registry record also does not state a threshold for a clinically important change, so the clinical importance of the reported values cannot be assessed from the record.

The endpoint is a subjective fatigue rating followed through day 7. It offers information about reported symptom change over that interval, not about longer-term fatigue, functioning, disease progression, or other outcomes. Five secondary outcomes are listed, but their numerical results are not reported in the registry record. The adverse-event entries describe recorded counts, but do not provide enough detail to characterize event types or establish causation.

In general, a completed randomized trial can contribute evidence even when its estimates are uncertain. The extent of that contribution depends on the quality of the measurements, conduct, and analysis, as well as the precision of the results. Several relevant details—including the analysis population, missing-data methods, and statistical plan—are not reported in the registry record. The appropriate reading is therefore limited: the registry provides arm-level primary estimates and safety counts, but not a complete comparative analysis or a basis for broad conclusions about treatment effects.

13. Why This Trial Matters Statistically

This trial is statistically notable for the difference between having randomized groups and having a reported comparative estimate. Randomization is intended to support a fair comparison, but the primary results posted in the registry are arm-specific means. The central treatment question concerns the contrast between those means, and that contrast with its uncertainty is not reported. The distinction is important: descriptive summaries do not automatically provide the inferential result of a randomized comparison.

The reported means are equal at -0.05 points per day, while their confidence intervals are not identical. That combination illustrates why point estimates and uncertainty both matter. An estimate is not exact, and uncertainty around separate group means cannot be read as the uncertainty of the difference. The broad overlap and inclusion of zero in both arm intervals are not a formal test of whether the groups differ.

The study’s listed enrollment is 18, with unequal arm sizes of 12 and 6. In general, limited sample size can constrain precision, and unequal allocation can leave estimates with different uncertainty. The posted intervals make uncertainty visible, but the registry record does not report a direct contrast interval or a sample-size justification to contextualize the study’s ability to estimate an effect.

The outcome also raises a measurement question relevant to clinical research: a brief daily score is practical and symptom-focused, but it may not capture the full experience or consequences of fatigue. The registry lists broader secondary measures, yet does not report their numerical results. Together, the missing comparative analysis and secondary results mean the record offers a narrow view of the trial’s statistical evidence, even though it identifies a clear primary symptom outcome and randomized design.

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 leaves important details unavailable for assessing the trial’s conduct and analysis. It does not report eligibility criteria in detail, baseline characteristics, the randomization method, allocation concealment, or how masking was implemented. It also does not describe ketamine or midazolam administration. These omissions make it difficult to judge how comparable the groups were in practice and how the interventions were delivered.

The primary outcome is summarized by arm, but the record does not report the between-group estimate, its confidence interval, or a p-value. It gives no measure of spread beyond the confidence intervals and does not describe the statistical model or assumptions used to produce them. The analyzed population and the number of participants with usable primary data are not reported. Neither missing daily ratings nor their handling is described.

The registry lists five secondary outcomes without numerical results. It does not report a multiplicity strategy, protocol deviations, or sensitivity analyses. The endpoint covers baseline through day 7, and longer-term results are not reported. The single-item fatigue score may also capture a narrower aspect of the symptom than the broader instruments listed as secondary outcomes; how well it represented the intended patient experience is not reported in the registry record.

Safety information is limited to counts for serious events, deaths, and other adverse events. Specific non-serious event terms and further collection details are not reported. Finally, the enrollment is small, and the arm sizes are unequal. These features constrain how precisely results can be estimated, while the missing direct comparison prevents a clear quantitative account of the primary treatment contrast.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Ketamine for Treatment of MS Fatigue — NCT03500289.
• Registry record last updated 2020-08-18; status last verified 2020-07.
• Results first posted 2020-08-04.
• 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

The registry record describes a completed, randomized, double-masked, parallel-group phase 1 and phase 2 trial sponsored by Johns Hopkins University. The study began on 2018-08-10, and primary completion is listed as 2019-08-30. Enrollment is listed as 18, with 12 in the ketamine arm and 6 in the midazolam arm.

The primary outcome was change in daily fatigue severity from baseline at the infusion visit through day 7. The reported mean was -0.05 points per day in each arm. The 95% confidence interval was -0.19 to 0.08 for ketamine and -0.14 to 0.24 for midazolam. A direct between-group estimate is not reported in the registry record.

The record lists five secondary outcomes but no numerical results for them. It reports zero serious adverse events and zero deaths in either arm, alongside other adverse events affecting 7 in the ketamine arm and 0 in the midazolam arm. Analysis details, missing-data methods, and the statistical plan are not reported in the registry record.