Empagliflozin and ACEi- Effects on Hyperfiltration: BETWEEN Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Empagliflozin and ACEi- Effects on Hyperfiltration: BETWEEN Study (NCT02632747), a randomized phase 2 study. The primary outcome is Glomerular Filtration Rate (GFR) Under Euglycaemic Conditions After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril..

2. Clinical Question

In statistical terms, the question concerns a continuous kidney-function measure under two treatment conditions, in a population selected for elevated GFR at screening. The crossover design means the sequences received both assigned study treatments, rather than different treatments throughout. The posted arm summaries give a mean and standard deviation for each treatment, but do not provide a paired treatment-effect estimate, confidence interval, or p-value. The record therefore describes the intended comparison and provides limited descriptive results, but it does not establish the size or precision of a treatment contrast.

3. Trial Design

The BETWEEN Study is recorded as a phase 2, randomized, double-blind, placebo-controlled crossover trial. Its brief summary also describes a double-dummy design. Empagliflozin or matching placebo was added to open-label ramipril; ramipril was therefore the background treatment rather than the randomized comparison.

Participants were assigned to sequences with opposite treatment orders. Sequence A received empagliflozin, then a wash-out, then matching placebo, while taking ramipril. Sequence B received matching placebo, then a wash-out, then empagliflozin, also while taking ramipril. The registry record does not report the wash-out duration or further details about treatment-period scheduling. It records 31 participants enrolled and the trial status as completed.

A crossover design can allow each participant to contribute observations under both treatment conditions. That feature can make within-participant comparisons informative, but the analysis must account for the paired structure and any relevant sequence or period effects. The registry record does not describe how such effects would have been handled. It also says the pre-specified analysis was not conducted because data were too sparse in the hyperfilterer subgroup. The displayed means and standard deviations should therefore be read as descriptive summaries, not as the result of a completed crossover analysis.

The study began on 2016-05-10, and its primary completion date is recorded as 2017-12-19. Boehringer Ingelheim is listed as the sponsor. The registry record does not report further details about recruitment, allocation concealment, adherence, or the conduct of the wash-out periods.

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: Participants who successfully completed the 4 weeks open-label ramipril run-in period and meet all of the inclusion, and non of the exclusion criteria were randomized into the trial, with no stratification to one of two sequences.

Treatment Period 1

Wash-out Period

Reasons for not completing this period:

Treatment Period 2

Analysis population for the primary outcome, as defined in the registry: Hyperfilterers: Patients before ramipril monotherapy with GFR ≥ 135 mL/min/1.73m², as measured at screening (visit 4).

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: Full Analysis Set (FAS): The FAS consists of all patients who were randomised, treated with at least one dose of empagliflozin/placebo and provided randomisation baseline (visit 8) and at least one post-randomisation glomerular filtration rate (GFR) measurement.

6. Primary Endpoint

The registry lists the primary outcome as Glomerular Filtration Rate (GFR) Under Euglycaemic Conditions After 4 Weeks of Treatment With Either Empagliflozin Added to Ramipril or Placebo Added to Ramipril., measured over At week 4 and at week 12.

The primary endpoint is glomerular filtration rate under euglycaemic conditions after 4 weeks of treatment with empagliflozin plus ramipril or placebo plus ramipril. GFR is a continuous measure of kidney filtration, reported in milliliters per minute per 1.73m² of body surface area. The registry record lists the timeframe as at week 4 and at week 12.

The primary endpoint population is defined by screening GFR >= 135 mL/min/1.73m² before ramipril monotherapy. In general, measuring GFR in this selected group is intended to examine a renal mechanism in people meeting the study’s definition of hyperfiltration. The endpoint is not itself a clinical event or a direct measure of how participants feel or function. It is a physiological measurement that can describe filtration under the specified study conditions.

The posted summaries report a mean and standard deviation for each treatment label. They list 124.0 with a standard deviation of 10.61 for 25 mg empagliflozin, and 132.5 with a standard deviation of 7.78 for placebo; each summary has n=2. No confidence interval or treatment-effect estimate is reported, and the record states that the pre-specified analysis was not conducted because subgroup data were too sparse. Thus, the endpoint definition is clear, but the available results do not provide a precise inferential comparison between treatments.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a randomized, double-blind, crossover trial with a placebo comparator and open-label ramipril as background treatment. Those design features help define the intended statistical comparison, but the record does not provide a completed statistical analysis for the primary endpoint. The values available for interpretation are treatment-specific means and standard deviations in a sparse hyperfilterer subgroup.

What does the mean describe?

For a continuous endpoint such as GFR, the mean is the arithmetic average of the observed measurements in the summarized treatment group. It gives a measure of the group’s central value, but it does not show the full distribution of individual measurements. Here the record reports a mean of 124.0 for 25 mg empagliflozin and 132.5 for placebo. Each summary is based on n=2, so the means are descriptive of the small amount of posted subgroup data rather than stable estimates for a broad population.

What does the standard deviation describe?

A standard deviation describes how dispersed measurements are around their mean. The record reports standard deviations of 10.61 for empagliflozin and 7.78 for placebo. In general, dispersion matters because a mean alone cannot show whether participants’ measurements were tightly grouped or widely spread. With very sparse data, however, estimates of spread can themselves be unstable and are not a substitute for an uncertainty interval around the treatment effect.

Why is crossover analysis different?

In a crossover trial, participants receive treatments in sequence, so measurements under different treatments from the same person are generally related. A comparison that accounts for this pairing can differ in precision from a comparison that treats the treatment summaries as independent groups. The posted means and standard deviations do not reveal the within-participant differences. The registry record does not provide paired data or a treatment-effect estimate from a crossover analysis, and it does not state how sequence or period effects were addressed.

The treatment order also matters in principle. A wash-out period is intended to separate treatment periods, but the registry record does not report its duration or whether the analysis evaluated carryover. This is a general methodological consideration, not a claim that carryover occurred in this trial. The trial’s specific approach to assessing or accounting for such issues is not reported in the registry record.

What would a confidence interval add?

In general, a confidence interval gives a range of values compatible with an estimate under the statistical model and communicates its precision. It helps distinguish a precise estimate from one with substantial uncertainty. No confidence interval is reported for the primary endpoint comparison. Nor does the record report a p-value for that comparison. A reader therefore cannot use inferential statistics from the registry record to judge how uncertain the treatment contrast is or whether it is distinguishable from no effect under a specified test.

What does the unperformed analysis mean?

The record states that the pre-specified statistical analysis was not conducted because data were too sparse in the hyperfilterer subgroup. This is distinct from a completed analysis that found no evidence of a difference. It means the planned inferential result is not available in the registry record. The record does not describe whether the analysis was replaced by another model, whether any additional data were considered, or why subgroup observations were sparse.

The registry record does not report a detailed statistical analysis plan, a model specification, a method for handling missing outcome data, or an approach to multiplicity. In general, a model specification would describe how the treatment comparison was estimated and which design features were included. Without that information and without a completed analysis, the summary statistics alone cannot answer the trial’s intended inferential question.

How should planning calculations be read?

In general, sample-size planning calculations explore how many participants per arm might be needed under stated assumptions. The registry record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. Such illustrations are hypothetical planning exercises, not observed power and not the trial’s original design justification. The record does not report the trial’s own sample-size justification. Any planning values should therefore be interpreted as conditional on their stated assumptions, not as evidence about the strength or reliability of the observed treatment effect.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("25 mg Empagliflozin", "Placebo")
n   <- c(2, 2)
m   <- c(124, 132.5)
sp  <- c(10.61, 7.78)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  25 mg Empagliflozin  2  124.000  10.610  28.673  219.327
CARM  Placebo  2  132.500  7.780  62.599  202.401

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary GFR endpoint and a secondary filtration-status outcome. The secondary outcome classifies GFR as < 120 mL/min/1.73m² after 4 weeks of either empagliflozin plus ramipril or placebo plus ramipril. One secondary outcome is posted, but the registry record does not provide a result for it. It reports no registered analyses.

Multiplicity arises when several outcomes, timepoints, subgroups, or statistical tests are considered. In general, testing multiple hypotheses can increase the chance of a nominally notable result arising by chance unless the analysis plan accounts for that multiplicity. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting outcomes. The primary endpoint timeframe is listed as at week 4 and at week 12, but the record does not clarify how those timepoints were incorporated into the planned analysis.

Information about missing outcome data is not reported in the registry record. It does not state whether any GFR measurements were missing, how missing measurements were handled, or whether a sensitivity analysis was conducted. The analysis population is also not fully described: the record defines the hyperfilterer population by screening GFR, but does not report the exact analysis-set rules or how participants with incomplete crossover periods were treated.

The record’s explicit statement that the pre-specified analysis was not conducted because data were too sparse in the hyperfilterer subgroup limits interpretation more than the absence of a p-value alone. It leaves no reported inferential estimate for the primary comparison and no documented alternative analysis to evaluate. Details about outcome availability, analysis populations, multiplicity control, and the statistical plan are not reported in the registry record.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: intestinal obstruction (3.3%), testicular rupture (3.3%).

The registry record reports serious adverse event counts by treatment group. For 25 mg empagliflozin, serious adverse events are listed for 0 of 31 at risk; for placebo, they are listed for 2 of 30 at risk. Deaths are reported as 0 in each group. The record lists intestinal obstruction and testicular rupture as top serious event terms, each at 3.3%.

These figures are descriptive safety counts, not a formal comparison of risk. The record does not provide a statistical test or uncertainty interval for the serious adverse event results. It also does not clarify whether the listed event terms correspond to unique participants, or how events were assigned across periods in the crossover design. The reported at-risk counts may differ between treatment groups, and the record does not explain the reasons.

Other adverse events are listed for 15 of 31 at risk in the empagliflozin group and 13 of 30 at risk in the placebo group. These are separate registry categories from the serious adverse event counts. The figures do not establish that an adverse event was caused by a study treatment. They should be read as reported counts within this trial, with the sparse primary endpoint population and crossover design kept distinct from the safety summaries.

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

The registry record documents a randomized, double-blind crossover comparison of empagliflozin and matching placebo, each added to open-label ramipril. The primary endpoint was GFR under euglycaemic conditions after 4 weeks of treatment in participants meeting the screening definition for hyperfiltration. The posted descriptive summaries report mean GFR values and standard deviations for each treatment label.

The record also states that the pre-specified statistical analysis was not conducted because data were too sparse in the hyperfilterer subgroup. Consequently, the posted means do not provide a completed estimate of the treatment effect, and no confidence interval or p-value is reported for the primary comparison. They cannot establish the precision of the contrast or show how it would be interpreted in a paired crossover analysis.

This does not mean that the treatments were equivalent, or that the study demonstrated no effect. An unperformed analysis cannot be read as a finding of no difference. Conversely, the descriptive means do not establish that one treatment changes GFR relative to the other. A numerical contrast between the summaries, without the paired data and inferential analysis, would not resolve that question.

The result is also specific to the endpoint and population described in the record. It concerns a physiological GFR measure under euglycaemic conditions in hyperfilterers defined by their screening measurement before ramipril monotherapy. It does not directly describe other patient groups, other kidney outcomes, or clinical events. The record’s listed conditions do not provide enough detail to infer how the sparse endpoint summaries relate to participants with particular diagnoses.

In short, the registry record describes the trial question and reports limited endpoint and safety summaries, but does not report an inferential primary result. The statistical evidence available in the record is insufficient to determine the magnitude or precision of the treatment comparison. That is a limitation of what is reported, not a conclusion about the underlying biological effect.

14. Why This Trial Matters Statistically

This trial is statistically notable because its randomized crossover design was intended to compare two treatment conditions within a study where ramipril was maintained as background therapy. In general, a crossover design can use within-participant comparisons, which may be informative when measurements from the same participant are related. To interpret such a design, however, the analysis needs to use the pairing and account appropriately for treatment order and period.

The registry record reports only sparse endpoint summaries for the hyperfilterer subgroup and states that the pre-specified analysis was not conducted. Each treatment summary has n=2. That makes the difference between a planned comparison and the available descriptive data especially clear: the record defines a focused mechanistic question, but does not report the inferential result needed to assess its size and precision.

The trial also illustrates why a reported mean is not equivalent to a treatment-effect estimate. A mean describes the observed values in a group, while an effect estimate for a crossover comparison should reflect the relation between each participant’s measurements under the treatment conditions. Without paired results, an uncertainty interval, or a reported model, the displayed summaries cannot show how the crossover structure affects the comparison.

Finally, the record distinguishes study design from planning illustrations. Planning calculations based on an observed effect are conditional exercises and do not show the trial’s observed power or establish the original sample-size rationale. The trial’s own sample-size justification is not reported in the registry record. These points make transparent reporting of the analysis population, missing data, model, and planned comparisons important for interpreting a small mechanistic study.

15. 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 central limitation is the sparse primary endpoint subgroup: the registry record reports n=2 for each treatment summary and says the pre-specified analysis was not conducted. This leaves the main randomized comparison without a reported effect estimate, confidence interval, or p-value. The means and standard deviations are descriptive and cannot replace an analysis that accounts for the crossover structure.

Although the record identifies a crossover design and gives the order of treatments, it does not report paired observations, the wash-out duration, or an analysis of sequence, period, or carryover effects. These details matter in general when interpreting measurements taken under successive treatments. Their absence from the registry record does not show that a design problem occurred; it means that the relevant methods cannot be assessed from the record.

The timing information is also limited. The primary endpoint timeframe is listed as at week 4 and at week 12, while the outcome description refers to 4 weeks of treatment. The registry record does not explain how the two stated timepoints relate to the treatment periods or the analysis. It does not report missing-data handling, detailed analysis-population rules, or multiplicity procedures. The secondary filtration-status outcome is listed, but no result is reported for it.

Finally, the endpoint population is defined by screening GFR, but further characteristics of the participants contributing to the sparse summaries are not reported. Safety counts are also descriptive and do not include inferential comparisons. The result should therefore be interpreted within the narrow scope of the registry record and its stated reporting gaps.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Empagliflozin and ACEi- Effects on Hyperfiltration: BETWEEN Study — NCT02632747.
• Registry record last updated 2020-07-24; status last verified 2020-07.
• Results first posted 2020-07-24.
• 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.

19. Record Summary

The BETWEEN Study is recorded as a completed phase 2 randomized, double-blind, placebo-controlled crossover trial sponsored by Boehringer Ingelheim. It enrolled 31 participants and compared empagliflozin with matching placebo, each added to open-label ramipril. The study began on 2016-05-10, with primary completion on 2017-12-19.

The primary endpoint was GFR under euglycaemic conditions after 4 weeks of treatment, in hyperfilterers defined by screening GFR >= 135 mL/min/1.73m² before ramipril monotherapy. The registry record reports treatment-specific means and standard deviations based on n=2 for each group, and states that the pre-specified analysis was not conducted because the subgroup data were too sparse. No inferential primary comparison is reported. One secondary outcome is listed without a result in the registry record.