PROTOCOL 3: Role of the Renal Nerves in the Increase in EGP in Response to Glucosuria: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for PROTOCOL 3: Role of the Renal Nerves in the Increase in EGP in Response to Glucosuria (NCT03168295), a randomized phase 4 study. The primary outcome is Change in Endogenous Glucose Production (EGP).

2. Clinical Question

In general, a crossover design can compare conditions within the same participant, which may account for stable differences between participants. That design feature does not by itself establish how the study analyzed the measurements or whether the comparison was statistically precise. The registry record describes measurements on separate days and randomized administration order, but does not report washout details, period-specific estimates, or an analysis of order effects. The study also included non-diabetic transplant subjects and a non-transplant control group; these groups address different descriptive contrasts and should not be mistaken for the placebo-controlled comparison. The primary question is therefore best understood as a measurement question about change in endogenous glucose production under the recorded study conditions, rather than as a reported conclusion about treatment effect.

3. Trial Design

The registry identifies NCT03168295 as a phase 4, randomized, unmasked, crossover study. Its title concerns the role of renal nerves in the increase in endogenous glucose production in response to glucosuria. The stated condition is diabetes mellitus, type 2, and enrollment was 34. The study status is completed. The recorded start was 2016-10, and primary completion was 2018-10. The sponsor was The University of Texas Health Science Center at San Antonio.

The study included renal transplant subjects with intact native kidneys and a control group described as subjects with type 2 diabetes mellitus who had not undergone renal transplant. The record distinguishes diabetic and non-diabetic renal transplant subjects. It describes oral dapagliflozin 10mg and placebo, with the endpoint description stating that transplant subjects received the treatments in randomized order on separate days. The arm descriptions also identify a dapagliflozin-then-placebo sequence for diabetic transplant subjects and a placebo-then-dapagliflozin sequence for non-diabetic transplant subjects. These descriptions are not enough to reconstruct the allocation process for each group.

The endpoint description says the control group had no renal surgery and was administered dapagliflozin, not placebo. Consequently, that group does not supply the same within-subject placebo contrast described for transplant subjects. The record does not report further details about sequence allocation, the interval between study days, adherence, withdrawals, or whether participants completed both treatment periods.

Randomization concerns how treatment order is assigned; masking concerns whether treatment assignment is concealed from participants or study personnel. The registry records randomized allocation and no masking. In general, crossover trials need to account for the repeated measurements from each participant and may need to consider period and sequence effects. The registry record does not report the statistical plan used to address these issues, or a detailed sample-size justification. Its sample-size assumptions are described as a planning illustration based on the observed effect, not as the trial’s own design rationale.

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: Diabetic and non-diabetic subjects were assigned to both interventions after randomization, either dapagliflozin first with placebo second, or placebo first and then dapagliflozin next.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The control group did not have renal surgery and were only administered the dapagliflozin, not the placebo, so no participants show for baseline or 240 to 300 minutes for placebo measurements, only for dapagliflozin.

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: Subjects who underwent renal transplant surgery with intact native kidneys, and a type 2 diabetic control group that did not undergo renal transplant

6. Primary Endpoint

The registry lists the primary outcome as Change in Endogenous Glucose Production (EGP), measured over baseline and 240-300 minutes.

The primary endpoint was change in endogenous glucose production (EGP), a continuous measure reported in mg/kg.min. The registry describes a mean with standard deviation and gives the measurement timeframe as baseline and 240-300 minutes. The measurement protocol involved an 8 hour infusion of 3-3H-glucose on 2 separate days in renal transplant subjects with intact native kidneys. Dapagliflozin 10mg or placebo was administered after 3 hours of tracer equilibration, and the record identifies the measurement at that point as baseline.

EGP is used in this study to assess glucose production by the body. In general, tracking change from a baseline measurement can describe how the measured quantity varies after an intervention, while the tracer method is the stated approach for measuring EGP. The study’s stated rationale links SGLT2 inhibition and glucosuria with possible changes in EGP and plasma glucose, and asks whether a neural pathway may contribute to changes in plasma glucagon and/or insulin. That rationale explains why EGP was selected as the primary outcome; it is not itself evidence that a particular change occurred.

The registry says change in EGP was measured for all subjects, while also noting that the control group received dapagliflozin but not placebo. It does not report numerical EGP values, the estimated change under either condition, a between-condition contrast, or an uncertainty interval. Thus the endpoint definition and measurement schedule can be described, but the magnitude and precision of any treatment contrast cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary outcome as a mean of a continuous measure, with standard deviation as its dispersion measure. In general, a mean summarizes the central value of observations, while a standard deviation describes their spread around that mean. Neither statistic alone conveys the uncertainty of a treatment contrast. To evaluate a contrast, readers would ordinarily need an estimate of the contrast and an uncertainty measure, such as a confidence interval. The registry record does not report those outcome statistics.

What does the crossover design imply?

In a crossover study, participants can receive more than one condition, so measurements under different conditions may be linked within the same participant. In general, an analysis can use that pairing rather than treat every measurement as if it came from a different person. This can be useful when participants differ in their usual level of the measured outcome. The registry says the transplant subjects underwent measurements on 2 separate days and received dapagliflozin or placebo in randomized order. It does not say whether the reported or intended analysis used paired differences, a repeated-measures model, or another method. No analysis is reported in the registry record.

Period effects are differences associated with when a measurement occurs, rather than with the assigned treatment itself. Carryover refers to an effect of an earlier treatment that remains during a later period. In general, crossover analyses may consider these possibilities, as well as treatment sequence. The registry record does not report a washout interval, period-effect assessment, carryover assessment, or model terms for sequence and period. These are considerations for evaluating the design, not claims that such effects occurred.

How should the outcome scale be read?

EGP is recorded in mg/kg.min, and the stated summary is a mean with standard deviation. The endpoint is change from baseline, with baseline measured after 3 hours of tracer equilibration and the later timeframe listed as 240-300 minutes. In general, a change score represents the difference between measurements for a participant or group, but the registry does not clarify the exact calculation used for the displayed outcome or provide the resulting values. The protocol description says an 8 hour infusion of 3-3H-glucose was used on 2 separate days. This identifies the measurement procedure, not the statistical estimator.

Why can dispersion and uncertainty differ?

Standard deviation describes variation among observations. A confidence interval instead describes uncertainty around an estimated quantity, such as a mean or treatment contrast. In general, an interval depends on the estimator, the amount of information, and the statistical assumptions. A crossover comparison also depends on the within-participant relationship between measurements. Since no estimate, interval, or analysis details are reported, the precision of the primary outcome cannot be assessed. It is not possible to substitute the standard deviation alone for an interval around a treatment effect.

What do the sample-size assumptions describe?

The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustration considers an effect set as a stated fraction of the observed effect. It is explicitly characterized as a planning illustration, not the trial’s own design. The registry entries contain no sample-size justification from the investigators, and no numerical planning results are included in the record details used for this explanation. Such calculations are not observed power and do not show whether an outcome effect was present. They are hypothetical planning quantities dependent on their stated assumptions.

More generally, a normal approximation simplifies the sampling distribution used in a calculation. Its suitability depends on the data and design. Equal allocation is an assumption for the planning illustration; it does not establish that actual groups were equally sized. The trial is described as a crossover study with an additional control group that did not receive placebo, so a simple two-arm planning framework should not be treated as a complete description of the study design. No investigator-authored statistical analysis plan or inferential results are reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and identifies change in EGP as the primary outcome. It also lists change in fasting plasma glucose and change in fasting plasma insulin as secondary outcomes. Multiple outcomes can raise a multiplicity question: when several hypotheses are tested, the chance of obtaining at least one apparently unusual result may differ from the chance associated with a single prespecified test. In general, trial protocols may address this through an outcome hierarchy or a statistical adjustment. The registry record does not report a multiplicity strategy, a testing hierarchy beyond the primary and secondary labels, or results for the listed measures.

The record lists 0 analyses. It does not report a statistical analysis plan, model specification, hypothesis tests, or adjusted estimates. The registry’s skip note says the primary outcome has several categories or time points and was not reduced to one comparison. Accordingly, a single numerical primary-outcome contrast cannot be recovered from the information recorded here, and the analysis of multiple time points should not be inferred.

Missing-data methods and analysis populations are also not reported in the registry record. There is no account of missing endpoint measurements, participant exclusions, completion of both treatment periods, imputation, or whether analyses followed an intention-to-treat or per-protocol approach. In general, missing observations can affect the population represented by an estimate, especially when reasons for missingness relate to outcomes or treatment periods. Without a participant flow or analysis-population description, the extent and handling of missing data cannot be evaluated.

The completed status indicates that the trial is recorded as completed; it does not supply the missing outcome or analysis details. No conclusion about multiplicity control, missing-data bias, or the population included in an analysis is supported by the registry record.

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 safety record lists five groups: diabetic subjects receiving dapagliflozin, diabetic subjects receiving placebo, non-diabetic subjects receiving dapagliflozin, non-diabetic subjects receiving placebo, and the control group. The numbers at risk for serious adverse events were 6, 6, 8, 8, and 20, respectively. Serious adverse events affected 0 participants in each listed group, and deaths were 0 in each group.

The numbers at risk for other adverse events were also 6, 6, 8, 8, and 20, respectively. Other adverse events affected 0 participants in each listed group. No top serious adverse-event terms are listed. These figures describe the adverse-event reporting recorded for the named groups; they do not establish that no unrecorded events occurred or that the treatments have no safety risks.

In general, an adverse-event count is interpreted alongside the group definition, number at risk, event definitions, observation period, and completeness of reporting. The registry record does not report the safety observation window, event-collection procedures, or additional detail about what was counted. The control group also differs in treatment exposure, as it received dapagliflozin and not placebo. These group counts should therefore be read as registry safety entries, not as a direct comparative safety analysis. No comparative estimate or uncertainty measure for adverse events is reported.

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

The trial record identifies a randomized, unmasked crossover study intended to measure change in EGP after dapagliflozin or placebo in renal transplant subjects with intact native kidneys. It describes measurements on separate days, randomized treatment order, and a control group that received dapagliflozin without placebo. It also records fasting plasma glucose and fasting plasma insulin as secondary outcomes. These details establish the study question and measurement framework, but not the findings.

The registry record does not report the numerical primary outcome, the estimated contrast between dapagliflozin and placebo, or a confidence interval or p-value. It does not report the secondary outcome results either. Therefore, the direction and magnitude of any observed change, and the precision with which treatment conditions might be distinguished, are not known from this record. The biological rationale involving glucosuria, renal nerves, and possible changes in glucagon or insulin is a motivation for the study, not a demonstrated mechanism or result.

In general, the meaning of a trial result depends on the outcome estimate, its uncertainty, the design, the analysis, and the population studied. Because the analysis details and results are absent, the registry record cannot establish whether an observed difference was small or large, precise or uncertain, or consistent with the study’s proposed explanation. The control group cannot be treated as a placebo-controlled comparison because it did not receive placebo.

The adverse-event entries report 0 serious adverse events, 0 other adverse events, and 0 deaths in each listed group. Those entries describe the recorded safety counts; they do not prove that a treatment is risk-free. Overall, the record supports a description of the intended experiment and its recorded safety counts, but not a conclusion about efficacy, mechanism, or comparative clinical benefit.

13. Why This Trial Matters Statistically

This study is statistically notable for combining a crossover comparison with a separate control group. In general, a crossover design can make use of within-participant comparisons, while a separate control group offers a different descriptive reference. Those structures answer different questions. The record says transplant subjects received dapagliflozin and placebo in randomized order, whereas the control group received dapagliflozin but not placebo. Treating all groups as if they contributed to the same randomized comparison would obscure that distinction.

The endpoint also emphasizes the importance of specifying measurement timing. The record identifies baseline after 3 hours of tracer equilibration and describes a later measurement timeframe of 240-300 minutes. A continuous outcome measured over time can lead to multiple possible summaries, such as a change at a defined time or a pattern across measurements. The registry record notes that the primary outcome has several categories or time points and was not reduced to one comparison. Without the analysis specification, readers cannot determine which time contrast or summary should represent the primary result.

In general, repeated measurements from the same participant are statistically dependent. Analyses that account for this dependence can differ from approaches that treat each measurement as independent. The registry does not report the model or inferential analysis, so there is no basis to assess how within-participant correlation, treatment order, or measurement timing was handled.

The record is also a reminder to separate protocol description from evidence about outcomes. The primary and secondary endpoints are identified, but no estimates are reported, and the registry lists 0 analyses. The sample-size assumptions are described as an illustrative planning exercise rather than the trial’s design justification. A clearly described design can still leave the central statistical question unanswered when results and analysis methods are absent.

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.

A central limitation of interpreting this trial from the registry record is the absence of primary and secondary outcome results. There are no EGP estimates, standard deviations, treatment contrasts, uncertainty intervals, or test results recorded in the registry record for this analysis. The record lists 0 analyses, so the direction, magnitude, and precision of any outcome difference cannot be evaluated.

The treatment sequence descriptions do not fully explain allocation across participants. The endpoint description says dapagliflozin or placebo was administered in random order on separate days, while the arm descriptions identify different sequences for diabetic and non-diabetic transplant subjects. The registry record does not provide enough detail to resolve how those descriptions relate to the randomized allocation. It also does not report washout, adherence, period effects, carryover, or completion of both periods.

The control group is not a placebo comparator: the record says it had no renal surgery and received dapagliflozin, not placebo. Consequently, contrasts involving that group may reflect differences in group composition or study condition in addition to any treatment-related difference. No adjusted comparisons are reported.

Further limitations are that eligibility criteria, participant characteristics, missing-data handling, analysis populations, and statistical models are not reported in the registry record. The record identifies multiple outcome measures and notes several primary-outcome categories or time points, but does not give an analysis plan or multiplicity approach. The safety entries lack a reported observation window and event-collection details. These omissions limit assessment of both the study’s statistical evidence and the completeness of the recorded safety information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: PROTOCOL 3: Role of the Renal Nerves in the Increase in EGP in Response to Glucosuria — NCT03168295.
• Registry record last updated 2020-09-17; status last verified 2020-09.
• Results first posted 2020-01-14.
• 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

NCT03168295 is recorded as a completed phase 4, randomized, unmasked crossover study sponsored by The University of Texas Health Science Center at San Antonio. Enrollment was 34. The study concerned type 2 diabetes mellitus and the role of renal nerves in the increase in EGP in response to glucosuria.

The primary outcome was change in EGP, measured in mg/kg.min, with baseline and 240-300 minutes identified as the timeframe. The record describes dapagliflozin 10mg and placebo for renal transplant subjects with intact native kidneys, and a control group without renal surgery that received dapagliflozin but not placebo. Secondary outcomes were change in fasting plasma glucose and change in fasting plasma insulin.

The registry record does not report outcome estimates, inferential analyses, missing-data methods, or a statistical analysis plan. It lists 0 analyses. Safety entries show 0 serious adverse events, 0 other adverse events, and 0 deaths in each listed group.