Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1 (NCT03560323), a non-randomized phase 1 study. The primary outcome is Cardiac Output (CO).

2. Clinical Question

3. Trial Design

This is a Phase 1 study listed as completed, with a recorded enrollment of 41. The study began on 2019-01-07 and had a primary completion date of 2024-08-30. The sponsor is The University of Texas Health Science Center at San Antonio. The registry identifies the study model as single-group, allocation as non-randomized, and masking as none. These design labels matter: the record does not describe a blinded, randomized comparison with a control group.

Three groups received beta-hydroxy-butyrate infusions at different rates. Groups I and II are described as receiving a 6-h infusion in the primary-outcome population text. The primary endpoint schedule specifies measurements at baseline and 360 minutes after infusion for those groups, but baseline and 180 minutes after infusion for Group III. The record does not explain the reason for the different measurement schedules or describe whether the groups were intended as dose comparisons under a common protocol.

There is an internal inconsistency about assignment. The allocation entry says NON RANDOMIZED, while the population description says participants were randomized in a 1:1:1 ratio. The record does not resolve this conflict. Accordingly, the design should not be interpreted as a confirmed randomized comparison. The registry itself flags that the arms are not a like-for-like control comparison.

The brief summary describes cardiac MRI assessment of left ventricular systolic and diastolic function and PET assessment of myocardial glucose uptake. Secondary outcomes include myocardial glucose uptake and myocardial blood flow. Five outcome measures are listed, but no analysis results are posted. The specific statistical analysis plan, rationale for the sample size, interim analyses, handling of missing observations, and analysis populations are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Patients with diabetes who met entry criteria were randomized (1:1:1 ratio) to receive one of three different infusion rates of b-OH-B ((prime dose was 0.4 mg/kg/min for 20 min followed by constant rate of infusion 0.2 mg/kg/min until study end). Group I and Group II received a 6-h b-OH-B infusion. Group III received a 3-h b-OH-B infusion

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: Participants were recruited from the Heart Failure (HF) clinic of UT Health San Antonio and from the Texas Diabetes Institute. Before the screening visit, patients had an established diagnosis of HF documented by an acceptable imaging modality within 6 months.

6. Primary Endpoint

The registry lists the primary outcome as Cardiac Output (CO), measured over Baseline at 0 minute before B-OH-B infusion and 360 minutes after B-OH-B infusion for Group I & II. For Group III was baseline at 0 minute and 180 minutes after infusion.

Cardiac output is the primary endpoint. It is a continuous measure expressed in mL/min. In general, cardiac output represents the volume of blood pumped by the heart over time. The registry describes measuring blood flow in the ascending aorta with velocity-encoded phase contrast MRI, synchronized to heartbeats using ECG gating. The imaging system uses blood-flow velocity and vessel cross-sectional area to derive flow, then uses flow over the cardiac cycle to obtain stroke volume. The description states that cardiac output is calculated as stroke volume multiplied by heart rate.

This measure is used to characterize overall pumping output, complementing measures focused on particular features of cardiac function. The registry’s broader study aim includes evaluating left ventricular systolic and diastolic function, but the primary endpoint named in the record is cardiac output. This distinction is important: the endpoint is a specific MRI-derived measure, not a general summary of every aspect of cardiac function.

The planned time points are baseline at 0 minute before infusion and follow-up at 360 minutes after infusion for Groups I and II; Group III has baseline at 0 minute and follow-up at 180 minutes after infusion. No group means, standard deviations, changes from baseline, or inferential comparisons for cardiac output are reported in the registry record. Therefore, the endpoint’s measurement method and timing can be described, but its observed results and precision cannot.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is cardiac output?

Cardiac output is a continuous outcome, meaning it can take a range of numerical values rather than belonging to a small set of categories. The registry specifies a mean as the summary parameter and standard deviation as the measure of dispersion. In general, a mean describes the center of observed values, while a standard deviation describes how spread out individual values are around that center. Neither summary is posted for the primary endpoint in the registry record, so no observed distribution can be assessed.

What does the MRI measurement involve?

The registry describes velocity-encoded phase contrast MRI at the ascending aorta. In general, MRI measures can be affected by acquisition and processing choices, and a clear measurement protocol helps readers understand what the endpoint represents. The record describes ECG synchronization, magnitude images for anatomical reference, and phase images that encode blood-flow speed and direction. It also describes deriving flow from velocity and vessel area, integrating flow over the cardiac cycle to obtain stroke volume, and calculating cardiac output using stroke volume and heart rate. The record does not report measurement reproducibility or quality-control results.

How should repeated time points be understood?

The endpoint schedule includes a baseline and a post-infusion measurement. In general, a baseline value can help describe the starting level and can be used in analyses of change or in adjusted comparisons. The record does not report whether the primary analysis used change from baseline, post-infusion values, or another approach. Groups I and II have a follow-up measurement at 360 minutes, while Group III has one at 180 minutes. Because the scheduled times differ, interpretation of between-group comparisons would depend on the analysis and estimand, neither of which is reported.

What does non-randomized allocation imply?

In general, random allocation is intended to reduce systematic differences between groups at the outset. With non-randomized allocation, group differences may reflect characteristics that were not measured or controlled, in addition to any effect associated with the intervention. Here, the registry’s allocation entry says NON RANDOMIZED, but its primary-outcome population text says participants were randomized in a 1:1:1 ratio. The registry does not resolve this inconsistency. The record separately cautions that the arms are not a like-for-like control comparison, so group contrasts should not be treated as a clean causal comparison.

What can be said about statistical testing?

The registry lists zero analyses. It does not report a statistical model, hypothesis test, confidence interval, p-value, covariate adjustment, or approach to repeated measurements. In general, a statistical analysis plan specifies how the endpoint will be summarized and compared, and how uncertainty will be quantified. Without those details and without outcome estimates, the analysis cannot be independently interpreted from the registry record.

How should planning calculations be read?

In general, sample-size calculations describe the number of participants that a hypothetical design would require under stated assumptions; they do not establish what was observed in a completed study. The registry’s planning illustration is described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. It specifies participants per arm for non-time-to-event outcomes. These are planning assumptions, not the study’s reported design justification or observed power. The record does not report the trial’s own sample-size justification, and no numerical planning results are included in the record information.

Why does over-dispersion matter in general?

For count outcomes, over-dispersion means that observed variability exceeds what a simple count model expects. In general, ignoring over-dispersion can make uncertainty appear smaller than it is. Cardiac output is a continuous endpoint rather than a count, and no count-outcome analysis is reported for the primary endpoint. There is no reported model fit or variance assessment to interpret for this endpoint.

10. Multiplicity, Missing Data and Analysis Populations

The record lists five outcome measures, including cardiac output as the primary endpoint and myocardial glucose uptake and myocardial blood flow as secondary outcomes. It does not report how multiple outcomes or repeated measurements were handled statistically. In general, when several outcomes or comparisons are examined, the chance of obtaining at least one apparently notable result can increase. Prespecified priorities or multiplicity adjustments can help clarify how results should be interpreted. The analysis plan and any multiplicity procedure are not reported in the registry record.

Missing-data methods are also not reported. The registry does not state how participants without a post-infusion measurement would be handled, whether any imputation would be used, or what sensitivity analyses were planned. The record does not report the number of participants with evaluable cardiac-output data or the extent of missing outcome data. The enrollment figure alone does not establish the endpoint analysis population.

The record does not define analysis populations, such as whether analyses would include all enrolled participants or only those with measurements at specified visits. It also does not explain how deviations from the infusion or measurement schedule would be treated. These omissions limit the ability to assess whether any eventual estimate reflects the intended study population or is sensitive to exclusions and missing observations.

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.

The registry lists three groups for adverse events. Each group has 12 participants at risk for serious adverse events and 12 at risk for other adverse events. The listed number affected is 0 for serious adverse events and 0 for other adverse events in every group. Deaths are listed as 0 in each group. No top serious-event terms are listed.

These are the counts posted in the registry record, not evidence that no adverse events could occur. In general, an observed count of zero in a study does not establish that the underlying risk is zero, particularly when the number of participants observed is limited. The record does not provide event descriptions, timing, exposure-adjusted rates, or further detail on safety ascertainment. The enrollment is 41, whereas the adverse-event listings show 12 at risk in each group; the record does not explain the relationship between these figures. The safety counts should therefore be read as the registry’s posted group-level counts, without assuming they account for every enrolled participant or establish a broader safety profile.

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

The record documents a study of beta-hydroxy-butyrate infusion and a plan to measure cardiac output by MRI, alongside a broader interest in cardiac function and myocardial energetics. It specifies three infusion regimens and different post-infusion measurement times for Group III compared with Groups I and II. It also lists safety counts with no serious adverse events, other adverse events, or deaths recorded in the group listings.

However, the registry record does not report numerical results for cardiac output. It therefore does not show the size or direction of any observed change, how variable the measurements were, or how precisely any estimate was measured. No statistical analyses are listed. The available information cannot establish whether cardiac output changed, whether groups differed, or whether any finding would be statistically distinguishable from chance variation.

The design information also limits interpretation. Allocation is recorded as non-randomized, while the outcome description says participants were randomized in a 1:1:1 ratio. The record does not resolve that conflict and cautions that the arms are not like-for-like control comparisons. The different measurement times further complicate direct comparisons across groups.

These limitations do not negate the value of the study question or the documented measurement protocol. They define what can be concluded from the registry information: the study’s aim, interventions, scheduled endpoint assessments, and posted safety counts can be described, but treatment effects and their uncertainty cannot be evaluated without reported outcome data and analysis details. The results should not be interpreted as evidence for or against a clinical benefit.

13. Why This Trial Matters Statistically

This study is statistically notable because it combines a continuous imaging-derived endpoint with several infusion regimens and repeated measurements. Such a design raises practical questions about the target comparison, the timing of measurements, and how baseline and follow-up values should be analyzed. Clear reporting of these choices is important for assessing both the estimated effect and its uncertainty.

The registry record illustrates why design labels and narrative descriptions need to align. It lists non-randomized allocation but also describes participants as randomized in a 1:1:1 ratio. Since allocation affects how group differences can be interpreted, resolving this discrepancy is central to understanding the strength of any comparative inference. The record itself cautions that the arms are not a like-for-like control comparison.

It also illustrates the distinction between a study’s measurement protocol and its statistical results. The MRI procedure is described in detail, but the primary endpoint estimates and analyses are not reported. Knowing how a measure is obtained is useful, yet readers also need outcome summaries and uncertainty estimates to judge what the data show. Planning illustrations, where available, are not substitutes for observed estimates or evidence about the study’s actual power.

Finally, the safety listings and total enrollment figures do not identify the primary-endpoint analysis population. Reporting participant flow, missing measurements, analysis populations, and methods for repeated outcomes would help readers connect enrollment to the results. These are general reporting considerations, and the registry record does not provide those details.

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 trial-specific limitations affect interpretation of the registry information. First, the record contains conflicting descriptions of allocation: the design entry says non-randomized, whereas the primary-outcome population description says participants were randomized in a 1:1:1 ratio. The actual allocation procedure is not reported in a way that resolves this conflict. The registry also states that the arms are not a like-for-like control comparison.

Second, the study has no described placebo or untreated control group. The three groups are different infusion regimens, but the record does not explain whether they were intended for direct dose comparisons or how potential baseline differences would be addressed. Third, the primary endpoint is scheduled at different post-infusion times for Group III versus Groups I and II. The rationale and analytical handling of this difference are not reported.

Fourth, numerical primary-endpoint results and analyses are absent. The registry does not report group summaries, variability, confidence intervals, statistical tests, or the number of participants contributing endpoint data. It also does not report the statistical plan, missing-data methods, analysis populations, or sample-size justification. The enrollment of 41 and safety listings of 12 at risk per group are not reconciled in the record.

Finally, the registry describes the primary measurement method but does not report reproducibility or measurement-quality information. These limitations apply to interpretation of the record; they do not establish that the corresponding methods or analyses were not performed.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1 — NCT03560323.
• Registry record last updated 2025-09-29; status last verified 2025-09.
• Results first posted 2025-09-29.
• 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

NCT03560323 is a completed Phase 1 study sponsored by The University of Texas Health Science Center at San Antonio, with recorded enrollment of 41. It examined beta-hydroxy-butyrate infusion in people with type 2 diabetes and heart failure. The primary endpoint was cardiac output measured by cardiac MRI, with baseline and post-infusion assessments scheduled at 360 minutes for Groups I and II and 180 minutes for Group III.

The registry describes three infusion regimens and lists five outcome measures. It records non-randomized allocation, although another description says participants were randomized in a 1:1:1 ratio. The record does not resolve this inconsistency. Numerical primary-endpoint results and statistical analyses are not reported. The adverse-event listings show zero serious adverse events, zero other adverse events, and zero deaths in each group, with 12 participants at risk per group.