This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults 55 Years Old or Older (NCT04421014), a randomized na study. The primary outcome is Change in β-hydroxybutyrate in the Posteromedial Cortex Measured by ¹H-MRS (PRESS).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04421014 |
| Phase | NA |
| Condition | Metabolic Syndrome, Normal Cognition |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Enrollment | 99 |
| Arms in the primary outcome | n/a |
| Lead sponsor | National Institute on Aging (NIA) |
| Results posted | Yes |
2. Clinical Question
Population
The trial concerns cognitively intact adults aged 55 years or older with metabolic syndrome. The primary-outcome analysis population was narrower than everyone randomized: participants had to receive at least one dose and have at least one post-baseline ¹H-MRS PRESS assessment. Measurements with a Cramér-Rao lower bound of 40% or higher were excluded.
Intervention
The intervention was a ketone ester drink. The registry summary describes taking the assigned drink during the study period, with the primary outcome assessed at Week 0 and Week 4.
Comparator
The comparison was an isocaloric dextrose drink described as placebo. The summary says participants were randomly assigned and that neither participants nor researchers knew the assignment. The registry classifies masking as triple; the identities of all masked parties are not reported in the registry record.
Primary question
The primary outcome asks how β-hydroxybutyrate in the posteromedial cortex changes around a drink at Week 0 and Week 4, and how the pre-drink measurement at Week 4 compares with the pre-drink measurement at Week 0. These are acute, acute-on-chronic, and chronic contrasts. Numerical estimates for those contrasts are not reported in the registry record, so the direction and precision of the measured changes cannot be described.
3. Trial Design
This was a randomized, triple-masked, parallel-group trial, listed as completed. The registry records enrollment of 99. The study compared a ketone ester drink with an isocaloric dextrose drink in cognitively intact adults aged 55 years or older with metabolic syndrome. The listed phase is not applicable. The sponsor is the National Institute on Aging.
The study summary describes four visits. Screening included medical history, physical examination, blood and urine tests, and cognitive testing. Later visits included repeat assessments, MRI/MRS, and additional blood and urine tests. Participants were assigned to one of the drinks, and the summary describes a study period of 28 days. The primary outcome specifies measurements at Week 0 and Week 4, including pre-drink and approximately 75-minute post-drink assessments.
The arm descriptions list 25 participants for the ketone ester drink and 25 for placebo. The safety record lists 25 at risk in the ketone ester group and 26 in the placebo group. The registry record does not explain the difference between these arm descriptions and safety denominators, or how they relate to the enrollment figure. These counts should therefore be understood in the context in which each is recorded, not treated as interchangeable.
The registry lists 37 outcome measures and no analysis entries. Numerical primary-outcome results, details of the statistical model, and a fuller statistical analysis plan are not reported in the registry record. Randomization and masking describe features of the design; they do not, by themselves, establish whether the groups were balanced or whether the outcome estimates were precise.
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: 99 participants provided informed consent and underwent screening; 41 were ineligible, 4 withdrew prior to randomization, and 54 participants were randomized, 26 to KE and 28 to Placebo.
Overall Study
| Stage | Ketone Ester Drink | Placebo |
|---|---|---|
| STARTED | 26 | 28 |
| COMPLETED | 25 | 25 |
| NOT COMPLETED | 1 | 3 |
Reasons for not completing this period:
| Reason | Ketone Ester Drink | Placebo |
|---|---|---|
| Physician Decision | 1 | 2 |
| Lost to Follow-up | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: Analysis was performed in a modified intention-to-treat population, which included all randomized participants who received ≥ 1 dose of the intervention and had ≥ 1 post-baseline ¹H-MRS PRESS assessment. BHB estimates with Cramér-Rao lower bounds (CRLB, %SD) ≥ 40% were excluded from analysis.
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.
| Characteristic | Unit | Ketone Ester Drink | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 25 | 25 | 50 | |
| Age, Continuous | years | 65.9 (SD 4.9) | 65.8 (SD 7.1) | 65.9 (SD 6.0) |
| Sex: Female, Male: Female | Participants | 12 | 12 | 24 |
| Sex: Female, Male: Male | Participants | 13 | 13 | 26 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 7 | 5 | 12 |
| Race (NIH/OMB): White | Participants | 18 | 20 | 38 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Body Mass Index, Continuous | kg/m^2 | 33.4 (SD 4.7) | 31.9 (SD 3.9) | 32.6 (SD 4.3) |
| Waist Circumference, Continuous | cm | 115.9 (SD 11.1) | 112.3 (SD 8.2) | 114.1 (SD 9.8) |
| Montreal Cognitive Assessment (MoCA) score, Continuous | units on a scale | 28.2 (SD 1.4) | 27.6 (SD 1.2) | 27.9 (SD 1.3) |
6. Primary Endpoint
The registry lists the primary outcome as Change in β-hydroxybutyrate in the Posteromedial Cortex Measured by ¹H-MRS (PRESS), measured over Week 0 and Week 4 (pre-drink and ~75 minutes post-drink).
| Element | Registry entry |
|---|---|
| Result type | Geometric Least Squares Mean |
| Measure of spread | Standard Error |
| Unit | Ratio |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint measures β-hydroxybutyrate (BHB) in the posteromedial cortex using proton magnetic resonance spectroscopy with PRESS acquisition. BHB is the brain-metabolism marker named in the endpoint. The registry describes three within-person ratios: the post-drink value to the pre-drink value at Week 0, the same post/pre contrast at Week 4, and the Week 4 pre-drink value relative to the Week 0 pre-drink value. The first is termed acute, the second acute-on-chronic, and the third chronic.
Ratios express a measurement in relation to another measurement from the same participant, rather than as a simple difference. In general, this can make a relative change the focus when measurements are taken at different times or under different conditions. The endpoint is reported as a geometric least-squares mean with standard error. In general, a geometric mean is used for quantities analyzed on a multiplicative scale; its interpretation is tied to ratios rather than ordinary additive changes.
The outcome was measured at the specified visits to assess both the response around a drink and the pre-drink change across the study period. The registry describes predefined spectral quality criteria and excludes BHB estimates with Cramér-Rao lower bounds of 40% or higher. The numerical estimates for the endpoint’s contrasts are not reported in the registry record. Thus, the measurement approach and intended contrasts are described, but the observed size and precision of the changes cannot be assessed from the record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies the primary outcome and its measurement schedule, but does not report numerical estimates for any of its three contrasts. There is consequently no reported result from which to characterize the direction, magnitude, or precision of the BHB response. The endpoint’s description is not itself evidence of a change: it specifies what was measured and how the contrasts were defined.
The three contrasts address different questions. The Week 0 post/pre ratio describes an acute response around the first measurement visit. The Week 4 post/pre ratio describes an acute response at the later visit after the study period. The Week 4 pre-drink to Week 0 pre-drink ratio describes change between visits before the drink at each visit. Because these contrasts have different reference measurements, they should not be collapsed into one general claim about the endpoint. The registry record does not report estimates or uncertainty for any of them.
The outcome is described as a geometric least-squares mean, with standard error as the dispersion measure. No estimate, standard error, confidence interval, or p-value for the primary outcome is reported in the registry record. Without these quantities, readers cannot judge how close an estimate is to a null ratio, how variable it is, or how compatible it is with a range of possible effects. A standard error, in general, summarizes uncertainty in an estimated mean; it is not a substitute for seeing the estimate itself.
The record also does not report a primary-outcome comparison between randomized groups, an adjusted effect estimate, or a statistical test for the primary endpoint. The endpoint description defines within-visit and across-visit ratios, but does not state how the investigators combined those measurements to estimate a between-group treatment effect. The statistical model and inferential procedure are not reported in the registry record.
Enrollment, arm descriptions, and outcome measurement details help characterize the study, but they do not fill this results gap. Nor can the listed secondary outcomes—such as serum ketone measures, fasting glucose, insulin, or cholesterol—be used as substitutes for the primary outcome. Their numerical results are not reported in the registry record. The appropriate interpretation is therefore limited: the study was designed to examine specified brain BHB contrasts, while the posted registry information does not establish what those contrasts showed or how precisely they were estimated.
9. Statistical Methods Explained
The registry provides some information about the endpoint’s measurement and analysis population, but little detail about the inferential methods. The following explanations distinguish those recorded details from general statistical concepts. A full analysis plan and numerical primary-outcome estimates are not reported in the registry record.
What does the endpoint’s ratio scale mean?
The endpoint uses post/pre and Week 4/Week 0 ratios. A ratio compares one measurement with a reference measurement by division. In general, ratios are useful when a relative change is the scientific focus or when changes are naturally interpreted multiplicatively. The registry calls the reported summary a geometric least-squares mean, which is consistent with describing results on a multiplicative scale. No ratio estimate is reported in the registry record, so there is no observed value to interpret.
The three defined ratios are not equivalent. The Week 0 post/pre ratio and Week 4 post/pre ratio compare measurements made within each visit. The chronic ratio compares two pre-drink measurements taken at different visits. A reader would need to keep the timing and reference for each contrast clear when interpreting any estimate. The registry’s definitions identify these contrasts, but not how they were compared between randomized groups.
What does standard error convey?
The endpoint lists standard error as its measure of dispersion. In general, standard error describes the uncertainty of an estimated quantity due to sampling variability. It is distinct from the spread of individual participant measurements. A small standard error relative to an estimate can indicate greater precision, while a larger one indicates less precision, but precision cannot be judged without the actual estimate and standard error. Neither is reported for the primary endpoint in the registry record.
A confidence interval is another common way to express uncertainty. In general, it gives a range of values compatible with the data and a specified inferential procedure. The registry record does not report a confidence interval or state a confidence level for the primary outcome. A p-value and the test used are also not reported in the registry record. No conclusion about statistical significance can be drawn from the endpoint definition alone.
How were BHB measurements screened?
The record says BHB estimates were derived from spectral fitting using predefined quality-control criteria. It also states that estimates with Cramér-Rao lower bounds of 40% or higher were excluded. In general, such quality thresholds define which measurements are considered sufficiently reliable for an analysis. Excluding measurements can reduce the influence of poor-quality readings, while also reducing the data available for estimation. The number of measurements excluded and their distribution across arms or visits are not reported in the registry record.
The registry does not give further details of the spectral-fitting procedure, the full set of quality-control rules, or how measurements that failed other criteria were handled. Those details would help readers assess measurement reliability and the potential effect of exclusions, but are not reported in the registry record.
What analysis population was specified?
The primary-outcome population is described as modified intention-to-treat. It included randomized participants who received at least one dose and had at least one post-baseline ¹H-MRS PRESS assessment, subject to the stated quality exclusion. This is not identical to an analysis that includes every randomized participant regardless of whether they received an intervention or had a usable post-baseline measurement. The number of participants meeting the analysis-population definition is not reported in the registry record.
In general, intention-to-treat analysis aims to preserve the benefits of random assignment by analyzing participants according to their assigned groups. Modified populations may apply additional eligibility or data-availability conditions. Such restrictions can affect how directly the analysis reflects the randomized comparison. Here, the exact analysis population is described, but the number excluded for each reason and any sensitivity analyses are not reported in the registry record.
What can be inferred from the design labels?
Random allocation is intended, in general, to reduce systematic differences between groups at the time of assignment. Masking is intended, in general, to limit the influence of knowledge of assignment on participant behavior, care, measurement, or assessment. The registry labels the study randomized and triple-masked, but does not report the randomization procedure, allocation concealment details, or the identities of the parties included in the triple-masking designation. The labels alone do not establish that masking was maintained or that groups were balanced.
The record lists a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It characterizes the effect to detect as a stated portion of the observed effect and specifies that non-time-to-event illustrations use participants per arm. These are planning assumptions, not observed power. The registry record does not report the underlying numerical effect or the resulting sample-size values in the information available for this interpretation. It also does not report the trial’s own sample-size justification.
Over-dispersion is a general concern when observed variability exceeds what a simple statistical model assumes. It can make standard errors too small if not accounted for. The registry record does not report whether over-dispersion was relevant to this endpoint or how the analysis addressed it. More broadly, the model, covariates, handling of repeated measures, and any robust variance methods are not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 37 outcome measures, including a primary BHB outcome with three defined contrasts and secondary measures covering serum ketones, non-esterified fatty acids, body mass index, waist circumference, fasting glucose, fasting insulin, and total cholesterol. Considering multiple outcomes or contrasts can increase the chance of at least one apparently unusual result when many tests are conducted. In general, multiplicity procedures can control that risk, but they may also change the interpretation of individual tests.
A multiplicity strategy, including whether any adjustment or prespecified hierarchy was used, is not reported in the registry record. The record does not identify which outcome contrasts were treated as confirmatory, how the three primary-outcome contrasts were handled together, or whether secondary outcomes were exploratory. No numerical tests or estimates are reported to assess.
For missing data, the primary analysis population required at least one dose and at least one post-baseline ¹H-MRS PRESS assessment, and excluded estimates with Cramér-Rao lower bounds of 40% or higher. The registry does not report the number of missing or excluded measurements, reasons for missingness, or whether missing-data methods beyond these eligibility rules were used. Imputation, sensitivity analyses, and assumptions about missingness are not reported in the registry record.
The analysis population is described as modified intention-to-treat, with the inclusion requirements stated in the endpoint record. The number analyzed, participant flow by arm, and any differences between the randomized, treated, and analyzed populations are not reported in the registry record. These omissions limit assessment of whether exclusions or missing measurements could have affected the estimated comparison.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Ketone Ester Drink | 0 | 25 | 0.0% |
| Placebo | 0 | 26 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Ketone Ester Drink | 0 of 25 |
| Placebo | 0 of 26 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Ketone Ester Drink | 1 of 25 |
| Placebo | 3 of 26 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Ketone Ester Drink | Placebo |
|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | 0 of 25 | 1 of 26 |
| Abdominal bloating | Gastrointestinal disorders | 0 of 25 | 1 of 26 |
| Dizziness postural | General disorders | 0 of 25 | 1 of 26 |
| ALT and AST elevation (~3× ULN) | Investigations | 1 of 25 | 0 of 26 |
The safety record lists zero serious adverse events among 25 participants at risk in the ketone ester drink group and zero among 26 at risk in the placebo group. It lists zero deaths in each group. The registry lists no top serious adverse-event terms.
For other adverse events, the record lists one affected participant among 25 at risk in the ketone ester group and three among 26 at risk in the placebo group. These are counts as recorded, not estimates of a causal effect. The record does not provide event descriptions, severity details, timing, or a statistical comparison for these other events. It also does not explain why the safety denominators differ from the arm descriptions, which list 25 participants in each arm.
In general, a zero count in a study does not establish that an event cannot occur, and small counts can be imprecise. The serious-event figures describe what was recorded in this trial; they do not, on their own, establish a comparative safety profile. Further safety details are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The registry record supports a description of the trial’s purpose and design: it was a randomized, triple-masked, parallel-group study of a ketone ester drink versus an isocaloric dextrose drink in cognitively intact adults aged 55 years or older with metabolic syndrome. It specifies a brain BHB endpoint, the measurement method, three timing-based contrasts, and a modified intention-to-treat analysis population with a measurement-quality exclusion.
The record does not report numerical results for the primary outcome. It therefore cannot establish whether the measured BHB ratios increased, decreased, or remained similar, nor how large or precise any change was. The record also does not report numerical results for the listed secondary outcomes. Describing what the study set out to measure is different from reporting what the data showed.
The design features should not be mistaken for evidence of an outcome. Randomization and masking can help limit certain biases in general, but the registry labels alone do not show how well those procedures were implemented. Enrollment and the arm descriptions indicate study scale, but they do not reveal the precision of an estimate. The absence of a numerical effect estimate and uncertainty measure prevents an assessment of the strength of evidence for the primary contrast.
Similarly, the safety counts are limited observations within the recorded at-risk groups. They do not establish that no serious adverse events can occur, and they do not provide a complete comparison of adverse effects. The record lists counts but not detailed event descriptions or inferential analyses.
Overall, the registry information describes a study framework and endpoint definitions, rather than a set of interpretable efficacy results. It does not support a conclusion about whether the intervention changed brain metabolism or cognitive performance. Cognitive performance is part of the study’s stated objective, but numerical cognitive results are not reported in the registry record. It also does not support conclusions about effects in people outside the stated study population.
13. Why This Trial Matters Statistically
This trial is statistically notable for defining several biologically timed contrasts within one primary measurement. The Week 0 post/pre ratio, Week 4 post/pre ratio, and Week 4 pre-drink/Week 0 pre-drink ratio address acute response, response after the study period, and change across visits. Keeping these questions distinct matters because each contrast has a different reference and interpretation.
The endpoint also illustrates the role of measurement quality in an analysis. BHB values were derived from spectral fitting, and estimates with Cramér-Rao lower bounds of 40% or higher were excluded. This rule makes the analyzed data dependent not only on randomization and follow-up, but also on whether measurements met the stated quality threshold. Without counts of excluded readings, readers cannot judge how much data were affected or whether exclusions differed across visits or groups.
The study’s registry information further distinguishes a planned comparison from a reported result. It describes randomization, masking, the endpoint, and an analysis-population definition, but gives no numerical outcome estimates or analysis entries. This is a useful reminder that a detailed outcome definition does not replace the estimates and uncertainty needed to interpret evidence.
The record also identifies 37 outcome measures, making transparent reporting of multiplicity and outcome-selection decisions important in general. Those methods are not reported in the registry record. Because results and analysis details are absent, the statistical importance of this trial lies chiefly in the measurement and design questions it raises, rather than in a quantifiable treatment effect available for evaluation.
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 principal limitation for interpreting this trial is that numerical results for the primary and secondary outcomes are not reported in the registry record. Without estimates and measures of uncertainty, the direction, magnitude, and precision of the outcomes cannot be evaluated. The registry lists 37 outcome measures but no analysis entries, leaving the relationship between the specified outcomes and completed analyses unclear.
The primary outcome involves three distinct ratios, but the registry does not report how these were incorporated into a between-group analysis or how multiplicity was addressed. The statistical model, covariate adjustment, treatment of repeated measurements, and planned inferential procedures are not reported in the registry record. A sample-size justification for the trial is also not reported; the planning illustration is described as based on an observed effect, but it is not the trial’s own design justification.
The analysis population excludes randomized participants who did not receive at least one dose or did not have at least one post-baseline assessment, and excludes BHB estimates meeting the stated quality threshold. Counts and reasons for these exclusions are not reported. Missing-data assumptions and sensitivity analyses are also not reported in the registry record.
There is an unresolved difference in the recorded group counts: arm descriptions list 25 participants in each group, while the safety record lists 25 and 26 at risk. The registry does not explain this difference. The safety information is limited to counts and does not include event descriptions or comparative analyses. Finally, the study population is specified as cognitively intact adults aged 55 years or older with metabolic syndrome; the record does not establish how findings would apply outside that population.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults 55 Years Old or Older — NCT04421014.
- Registry record last updated 2026-04-02; status last verified 2026-03.
- Results first posted 2026-04-02.
- 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.
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18. Record Summary
The registry record describes a completed, randomized, triple-masked, parallel-group trial of a ketone ester drink and an isocaloric dextrose drink in cognitively intact adults aged 55 years or older with metabolic syndrome. Enrollment is listed as 99. The primary outcome measures posteromedial cortex BHB by ¹H-MRS PRESS and defines acute, acute-on-chronic, and chronic ratios across Week 0 and Week 4.
The primary analysis population required at least one dose and at least one post-baseline assessment, with BHB estimates having Cramér-Rao lower bounds of 40% or higher excluded. The record lists 37 outcome measures and no analysis entries. Numerical primary and secondary outcome results, the statistical model, multiplicity procedures, and missing-data methods are not reported in the registry record. Safety counts include zero serious adverse events and zero deaths in either group; other adverse events are listed for one participant in the ketone ester group and three in placebo.