Acute Effects of Exogenous Ketone Ester Administration in Heart Failure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Acute Effects of Exogenous Ketone Ester Administration in Heart Failure (NCT04633460), a randomized phase 2 study. The primary outcome is Maximal Exercise Capacity (Peak VO2) Assessed by Cardiopulmonary Exercise Testing.

2. Clinical Question

The rationale in the registry record is that people with heart failure can be limited during exercise by fatigue and shortness of breath, and that ketones might influence heart or muscle function. The record notes prior evidence concerning ketones in healthy volunteers and intravenous ketones, while identifying the effect of a ketone drink in heart failure as unknown. The use of DeltaG in the study is described as experimental and not approved by the FDA for the use being evaluated. The trial therefore addressed an acute physiological research question, rather than a long-term clinical outcome.

3. Trial Design

This was a Phase 2, randomized, triple-masked, crossover study sponsored by the University of Pennsylvania. Its title was “Acute Effects of Exogenous Ketone Ester Administration in Heart Failure,” and its registry identifier is NCT04633460. The listed condition was heart failure with preserved ejection fraction. The registry record lists enrollment of 26 and status as completed. The recorded study start was 2020-10-06 and primary completion was 2023-10-04.

In a crossover design, participants receive more than one intervention condition, so each participant can contribute measurements under both conditions. The primary outcome description states that all 20 participants contributed data: 10 started with ketone ester and then crossed over to placebo, while 10 started with placebo and then crossed over to ketone ester. The arm summaries list 20 observations for each condition. Those condition-specific counts should be understood in the context of the crossover description, not as two independent groups of participants.

Randomization refers to how treatment order is assigned; masking means that treatment assignment is concealed from designated people involved in the study. The registry labels this study randomized and triple-masked, but does not report the specific masking roles or the randomization method. A crossover design can help account for between-person differences because participants receive both conditions. At the same time, valid analysis may need to address within-participant pairing, period effects, and possible carryover. The statistical plan for those issues is not reported in the registry record.

The ketone ester and placebo were dietary supplements. Outcomes were assessed 60 minutes after the intervention. The record lists six outcome measures and four secondary outcomes as posted. It does not report a detailed protocol description, a washout interval, or a rationale for the enrollment target. These omissions make it important to distinguish the trial’s design labels and posted summaries from assumptions about its conduct or analysis.

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: Out of 26 consented participants, 5 screen failed and 1 participant withdrew, leading to 20 randomized participants.

First Intervention

Washout

Second Intervention

Analysis population for the primary outcome, as defined in the registry: All 20 participants contributed to the data. 10 participants started first in the ketone ester group and then crossed over to placebo, while 10 participants started first in the placebo arm and crossed over the ketone ester.

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.

Population: All 20 randomized participants are included.

6. Primary Endpoint

The registry lists the primary outcome as Maximal Exercise Capacity (Peak VO2) Assessed by Cardiopulmonary Exercise Testing, measured over Assessed 60 minutes after the intervention..

The primary endpoint was maximal exercise capacity measured as peak VO2 during cardiopulmonary exercise testing. VO2 refers to oxygen uptake; peak VO2 is the highest oxygen uptake recorded during the exercise assessment. The registry reports the unit as L/min and identifies the summary measure as a mean with standard deviation. Assessment took place 60 minutes after the intervention.

Peak VO2 is used in exercise research because it provides a quantitative measure of oxygen uptake at maximal effort. During exercise, oxygen delivery and use involve the lungs, circulation, heart, and working muscles. The measure therefore captures integrated exercise performance rather than isolating a single organ or mechanism. That makes it relevant to a study asking whether an acute drink is associated with a change in exercise capacity.

It is still a specific laboratory endpoint, not a direct measure of every aspect of daily functioning or longer-term health. The registry’s posted group means were 1.0 L/min after ketone ester and 1.0 L/min after placebo, with a standard deviation of 0.3 in each condition. The arm means alone do not reveal how each participant’s paired measurements varied, nor do they establish that the conditions are equivalent. The registry record does not report a trial-authored analysis of the primary endpoint.

7. Results Posted in the Registry

• Ketone Ester: mean 1.00 versus 1.00 on control; difference 0.00 (95% CI -0.19 to 0.19), standardized effect d = 0.00; z-test p = 1.000.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percent Change in Systemic Vascular Resistance With Exercise

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Ketone Ester: mean -21.50 versus -34.20 on control; difference 12.70 (95% CI 2.69 to 22.71), standardized effect d = 0.97; z-test p = 0.013.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Ketone Ester than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Substrate Utilization (Reflected by the Respiratory Exchange Ratio) Assessed by Cardiopulmonary Exercise Testing.

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Ketone Ester: mean 1.09 versus 1.14 on control; difference -0.05 (95% CI -0.13 to 0.03), standardized effect d = -0.37; z-test p = 0.242.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Ketone Ester and the control. The interval gives the range of effects that remain compatible with the data.

VO2 Efficiency (Total Work Performed Over Oxygen Consumed) During Submaximal Cardiopulmonary Exercise Testing.

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Ketone Ester: mean 6.00 versus 6.10 on control; difference -0.10 (95% CI -1.81 to 1.61), standardized effect d = -0.04; z-test p = 0.909.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Ketone Ester and the control. The interval gives the range of effects that remain compatible with the data.

Across the posted secondary outcomes, the pattern is not uniform. The unadjusted summary-statistic comparison for exercise-related systemic vascular resistance gives a difference that is separated from zero by its reported interval, whereas the corresponding comparisons for respiratory exchange ratio and VO2 efficiency are less distinct from zero. This mixed pattern does not provide a single consistent signal across the measured physiological domains.

The secondary outcomes are related to the primary question but measure different aspects of exercise physiology. Systemic vascular resistance concerns the vascular response during exercise; respiratory exchange ratio reflects substrate utilization; and VO2 efficiency relates work performed to oxygen consumed. These measures can add context to an acute exercise study, but none is interchangeable with peak VO2, the primary measure of maximal exercise capacity. The primary and secondary outcomes therefore need not move together.

Secondary results generally carry less weight when several outcomes are examined without a reported multiplicity strategy. Each unadjusted comparison is considered on its own and does not account for the number of opportunities to observe a nominally notable result. The registry record does not report which secondary outcomes, if any, were prioritized in a formal testing sequence. It also does not report sponsor analyses for these outcomes.

The secondary findings should consequently be read as exploratory evidence that may motivate further study, not as confirmation of a broad effect across exercise physiology. Their relationship to the primary outcome is informative at a descriptive level, but the registry record does not provide enough information to conclude that the observed pattern was prespecified, robust to an appropriate crossover analysis, or independent of chance variation.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percent Change in Systemic Vascular Resistance With Exercise
• Substrate Utilization (Reflected by the Respiratory Exchange Ratio) Assessed by Cardiopulmonary Exercise Testing.
• VO2 Efficiency (Total Work Performed Over Oxygen Consumed) During Submaximal Cardiopulmonary Exercise Testing.
• Presence of Exercise-induced Arrhythmias (Significant Atrial or Ventricular Arrhythmias)

9. Statistical Interpretation

10. Statistical Methods Explained

Continuous outcomes can be described by a mean, which locates the center of the measurements, and a standard deviation, which describes their spread around that mean. For peak VO2, the registry reports a mean and standard deviation in each condition. These summaries are useful for understanding the recorded measurements, but in a crossover study they do not show how the two measurements from each participant relate to each other.

What does an unadjusted recalculation represent?

The posted primary comparison is a simple, unadjusted recalculation from the arm-level summary statistics. It compares the mean in the ketone ester condition with the mean in the placebo condition and reports a mean difference, confidence interval, and p-value. Such a calculation provides a transparent descriptive check on the posted summaries. It is not necessarily the analysis used by the investigators, and the registry record does not report the sponsor’s statistical analysis.

The comparison treats the displayed condition summaries as its inputs. In a crossover trial, measurements from the same participant are generally related, rather than independent. A paired analysis uses the within-participant differences, and its uncertainty depends on how strongly measurements under the two conditions are associated. That paired information cannot be recovered from the separate means and standard deviations alone. The recalculated comparison should therefore not be interpreted as a substitute for a trial-specific analysis that accounts for the design.

What does the confidence interval convey?

A confidence interval expresses uncertainty around an estimated effect under the assumptions of the method used to calculate it. A narrower interval indicates greater precision under those assumptions; a wider interval indicates less precision. An interval that includes zero is compatible with no difference under the model, but it can also be compatible with differences on either side of zero. It is not proof of equality. The primary recalculated interval includes zero, so the point estimate of 0.0 should be read together with the uncertainty range rather than alone.

For secondary outcomes, the recalculated comparisons also use the posted means and standard deviations. For example, the systemic vascular resistance comparison has a mean difference of 12.7 and an unadjusted p-value of 0.013. A p-value measures how unusual the observed result, or a more extreme one, would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. Interpretation also depends on design, precision, and whether the result was prespecified.

Why does multiplicity matter?

When many outcomes are examined, the chance of seeing an apparently notable result by chance can increase. The registry lists multiple secondary measures, but does not report a multiplicity adjustment or a prespecified testing hierarchy. The p-value for an individual secondary comparison is therefore unadjusted and should not be treated as if it were the sole planned test. The record also does not report whether interim analyses were conducted.

How should the planning illustrations be read?

The planning illustrations use the observed effect as a starting point and show hypothetical participants per arm under stated assumptions: a two-sided significance level of 0.05, equal allocation between arms, a normal approximation, and an effect to detect set as a stated fraction of the observed effect. These are planning illustrations, not the trial’s design justification, and not observed power. The registry record does not report the sample-size justification used when the study was designed. Since this trial used a crossover design, the equal-allocation, two-arm planning framework should not be assumed to represent the trial’s own design or the analysis needed for a future crossover study.

In general, over-dispersion means that observations vary more than a statistical model expects. When that happens, a model that assumes less variability can understate uncertainty and make results look more precise than they are. This is a general statistical point; the registry record does not report an over-dispersion assessment for these continuous outcomes. More broadly, the reported summaries do not establish whether distributional assumptions were checked, how missing observations were handled, or whether any covariate adjustment was planned.

These distinctions separate descriptive summaries, recalculated comparisons, and analyses conducted under a full trial plan. The summaries are useful for seeing the reported means and variation. The recalculations make a simple comparison from those summaries. Neither can supply unreported design details or replace a prespecified analysis that reflects the crossover structure.

11. Confidence Intervals and Precision

Precision describes how tightly the data estimate an effect. The primary recalculated mean difference is 0.0 L/min, but the confidence interval includes zero and allows for differences in either direction. Its bounds are reported in the registry-derived comparison with more than three decimal places, so they are not repeated. The main interpretation is that the point estimate does not identify a direction of difference, while the interval does not rule out a range of effects.

The standard deviation was 0.3 L/min in each condition. Standard deviation describes spread among measurements; it is not the same as the uncertainty in the estimated difference. In a crossover study, precision for the treatment contrast depends in part on the within-participant relationship between measurements. That relationship is not reported in the registry record, so the condition-specific standard deviations cannot by themselves establish the precision of a paired treatment effect.

For the systemic vascular resistance comparison, the recalculated mean difference is 12.7, with a confidence interval from 2.693 to 22.71. That interval lies on one side of zero under the unadjusted summary-statistic calculation. This does not address multiplicity or establish that the comparison was the study’s prespecified analysis. The registry record does not report sponsor analyses that would clarify how uncertainty was modeled for the crossover design.

A confidence interval is not a guarantee that the true effect lies within its bounds. Its interpretation depends on the assumptions of the method, including the way observations are treated and the model used. Here, the recalculated primary interval is based on posted summaries rather than a reported paired analysis. It is therefore more appropriate to regard it as an unadjusted descriptive estimate than as the definitive precision statement for this trial.

12. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint and several secondary outcomes, but does not report a detailed statistical analysis plan, a multiplicity adjustment, or a testing hierarchy. When multiple outcomes are tested, the chance of at least one result appearing notable by chance can increase. Without a stated strategy for handling this issue, unadjusted secondary p-values should be interpreted cautiously and should not be treated as confirmatory evidence on their own.

The record lists zero reported analyses. It does not describe the sponsor’s primary or secondary inferential analyses, the model used, or how the randomized order and crossover structure were incorporated. It also does not report whether period effects or carryover were assessed. These details matter because repeated measurements on the same participant are related, and a crossover contrast is not fully described by separate condition means and standard deviations.

The primary endpoint description says all 20 participants contributed data and identifies how many started in each treatment sequence. The arm summaries likewise list 20 observations per condition. The registry does not report the number of missing observations for each secondary endpoint in a way that explains their causes, or the methods used to address missing data. The systemic vascular resistance summaries have 13 observations in the ketone ester condition and 14 in placebo, whereas the other posted secondary summaries list 20 in each condition. The record does not explain these differences.

The analysis population is also not described in detail beyond the primary outcome statement. The registry record does not report whether analyses followed an intention-to-treat principle, used a per-protocol population, or applied other inclusion rules. Nor does it report interim analyses. Without these details, the recalculated comparisons can be read as simple summaries, but not as a complete reconstruction of the trial’s analysis or data handling.

13. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: laryngeal inflammation (5.0%).

The registry lists serious adverse event figures separately for the ketone ester and placebo conditions. One serious event is recorded for the ketone ester condition and none for placebo; the corresponding at-risk counts are 20 in each condition. Deaths are listed as 0 in both. The most frequent serious-event term listed is laryngeal inflammation, reported as 5.0%.

These figures are descriptive. They do not establish that an event was caused by a study drink, and they do not allow a firm comparison of safety between conditions. In a crossover study, participants may contribute information under both conditions, and the registry’s group summaries do not describe event timing, participant-level overlap, or the investigators’ attribution of causality. The record also lists other adverse events affecting 7 in the ketone ester condition and 6 in placebo, but does not provide enough detail to assess their nature or severity.

A small study with short-term assessment cannot characterize uncommon or delayed harms reliably. The record’s safety counts should therefore be understood as the events recorded during this study, not as a complete estimate of risk. The registry describes the study use of DeltaG as experimental and not FDA-approved for the use being evaluated.

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

The primary result is a comparison of acute peak VO2 measurements after ketone ester and placebo in a randomized crossover study. The reported means were 1.0 L/min in both conditions, and the simple unadjusted recalculation gives a mean difference of 0.0. This is evidence about the displayed summaries in this study; it is not a demonstration that the interventions are exactly equivalent.

A result that does not show a difference clearly is not the same as proof that no meaningful difference exists. Such a conclusion would require an appropriate analysis and a prespecified definition of what range of differences counts as equivalent or acceptably similar. The registry record does not report an equivalence or noninferiority framework. The confidence interval includes zero, but also permits differences in either direction, and the unreported paired-data relationship limits interpretation of the recalculated uncertainty.

The unadjusted secondary comparison for systemic vascular resistance is distinct from the primary endpoint and should be interpreted in light of the multiple outcomes and absent analysis plan. It does not change what the primary outcome measures, nor does it establish a consistent effect across all exercise-related measures. Other posted secondary comparisons do not show the same degree of separation in their unadjusted recalculations.

The study addresses an acute physiological response measured 60 minutes after a drink. It does not establish effects on long-term exercise capacity, symptoms over time, hospitalization, survival, or quality of life. Those outcomes are not reported as results in the registry record. The findings also do not establish that the experimental use is approved for clinical care. Overall, the record supports a careful description of the posted measurements, with substantial limits on claims about efficacy, equivalence, mechanism, or longer-term outcomes.

15. Why This Trial Matters Statistically

This study illustrates why design and analysis must be read together. A crossover trial allows each participant to receive both conditions, which can make within-person comparisons informative. But the advantage depends on analyzing the paired measurements and considering period and carryover effects. Separate means and standard deviations do not show the participant-level relationship needed to understand the precision of that paired contrast.

The distinction between an observed mean difference and the uncertainty around it is also important. The primary point estimate is 0.0, but an estimate alone does not establish equivalence. The interval conveys uncertainty under the recalculation’s assumptions, and the unreported paired structure means that interval is not necessarily the trial-specific answer. This is a practical example of why a confidence interval and a p-value should be interpreted alongside the design and analysis plan.

The secondary outcome pattern also highlights multiplicity. A notable unadjusted result among several outcomes may be hypothesis-generating, but its evidential weight depends on whether it was prespecified and how multiple testing was addressed. The registry record does not report those details. A transparent distinction between recalculation and sponsor analysis prevents summary data from being mistaken for a complete trial report.

Finally, the enrollment count and the number contributing to the primary outcome are not interchangeable descriptions. The registry lists enrollment of 26, while the primary outcome description reports data from 20 participants. Understanding why those figures differ would require information about participant flow and analysis populations that is not reported in the registry record. These gaps matter for assessing precision, generalizability, and reproducibility.

16. 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 record constrain interpretation. First, the study is described as a crossover trial, but the registry does not report a trial-specific statistical analysis accounting for paired measurements. The simple recalculations from condition summaries cannot recover the within-participant covariance or show whether period and carryover effects were considered.

Second, the registry lists enrollment of 26, while the primary outcome description says all 20 participants contributed data. It does not explain the difference or provide a participant flow account. The secondary outcomes also have varying numbers of observations, and the record does not explain the missing measurements or how they were handled.

Third, the record does not report the sample-size rationale, detailed analysis plan, multiplicity strategy, interim analyses, or the sponsor’s inferential results. Planning illustrations based on observed effects do not fill these gaps and should not be mistaken for the original design justification. The lack of reported analysis details also limits assessment of whether the secondary findings were prespecified or exploratory.

Finally, the outcomes concern acute physiological measurements, assessed 60 minutes after an intervention. The registry record does not report longer-term outcomes or establish how these measurements relate to sustained functioning. The sample and setting also limit how broadly the results can be generalized. These limitations do not invalidate the posted summaries, but they narrow the conclusions that can be drawn from them.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Acute Effects of Exogenous Ketone Ester Administration in Heart Failure — NCT04633460.
• Registry record last updated 2024-11-27; status last verified 2024-11.
• Results first posted 2024-11-27.
• 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.

20. Record Summary

NCT04633460 is a completed Phase 2 randomized, triple-masked crossover study sponsored by the University of Pennsylvania. It enrolled people with heart failure with preserved ejection fraction and compared a ketone ester drink with a placebo drink. The primary outcome was peak VO2 during cardiopulmonary exercise testing, assessed 60 minutes after intervention.

The primary outcome description reports that 20 participants contributed data, with the treatment order split between the two sequences. Mean peak VO2 was 1.0 L/min in each condition, with a standard deviation of 0.3. The registry record lists several secondary outcomes, but does not report the sponsor’s statistical analyses or a detailed analysis plan. Unadjusted recalculations from posted summaries are descriptive, particularly because the crossover pairing is not available in those summaries.

The results describe acute measurements and do not establish equivalence, longer-term effects, or a treatment recommendation. The registry record also describes the study use of DeltaG as experimental and not FDA-approved for the use evaluated.