Nutrition Monitoring and Feeding Optimization With the smART+ System - Comparative Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Nutrition Monitoring and Feeding Optimization With the smART+ System - Comparative Study (NCT04098224), a randomized na study. The primary outcome is Nutrition Optimization.

2. Clinical Question

3. Trial Design

NCT04098224, titled Nutrition Monitoring and Feeding Optimization With the smART+ System - Comparative Study, is recorded as a completed randomized parallel-group study. The registry lists an enrollment of 100 and records the phase as NA. It identifies ART Medical Ltd. as the sponsor. The recorded study start was 2020-01-12, and primary completion was 2022-03-10.

Participants were assigned to an interventional device group or a control group. The device group was connected to the investigational smART+ system; the control group was treated according to local standard of care. The registry records no masking. It does not report how the random sequence was generated, whether assignment was concealed, or whether any personnel or outcome assessors were blinded.

The primary endpoint concerned nutrition delivery over Days 2-14. The registry lists mean and standard deviation as the summary measures and percentage of feeding efficiency as the unit. Its fuller endpoint description calls the outcome average feeding deviation over that period and defines it using delivered and intended nutrition volumes. This difference in terminology should be kept in mind when interpreting whether a numerically higher value represents a better outcome.

Primary arm summaries are reported for 48.0 in the device group and 50.0 in the control group. The record does not explain how these counts relate to the listed enrollment. Some secondary outcomes have summaries for 50.0 in each group, while several listed secondary outcomes have no posted numerical results. Participant flow, analysis-population definitions, and reasons for any differences in outcome counts 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

Reasons for not completing this period:

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: ITT population

6. Primary Endpoint

The registry lists the primary outcome as Nutrition Optimization, measured over 2 days-14 days.

The primary endpoint was average feeding deviation between Days 2-14, expressed as a percentage. The registry says the measure compares the volume of nutrition delivered with the volume intended to be delivered. It describes the calculation as the absolute value of 100 multiplied by the ratio of delivered volume to intended volume. The endpoint is presented under the title Nutrition Optimization, with percentage of feeding efficiency also given as the unit.

A measure of this kind is intended to summarize how closely nutrition delivery tracks the intended target over the assessment period. A mean gives a group-level summary across observed measurements, while the standard deviation describes the spread of individual measurements around that mean. These summaries do not show how many patients reached a particular target or how outcomes varied over time.

The registry’s wording leaves an interpretive ambiguity: the title and unit refer to optimization and efficiency, while the endpoint description refers to deviation and gives a ratio-based formula. The record does not clarify whether the formula is the complete deviation calculation or how the direction of the scale should be interpreted. The observed group means can therefore be compared as reported, but a claim that a higher value necessarily means better nutrition delivery would require clarification of the endpoint definition.

7. Results Posted in the Registry

• Interventional Device - Treated: mean 89.50 versus 65.00 on control; difference 24.50 (95% CI 18.30 to 30.70), standardized effect d = 1.56; z-test p = <0.001.

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.

Decrease in Intensive Critical Unit Length of Stay

• 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:
  • Interventional Device - Treated: mean 10.37 versus 13.65 on control; difference -3.28 (95% CI -6.48 to -0.08), standardized effect d = -0.40; z-test p = 0.044.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Interventional Device - Treated than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Reduction of Number of Patients With VAE (Ventilation Associated Events)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Interventional Device - Treated: 2.0% (1/50) versus 10.0% (5/50) on control; risk difference -8.0 percentage points (95% CI -17.2 to 1.2), risk ratio 0.20 (0.02–1.65); unadjusted two-proportion z-test p = 0.092.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Interventional Device - Treated and the control. The interval gives the range of effects that remain compatible with the data.

Decrease in ICU Ventilation Days

• 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:
  • Interventional Device - Treated: mean 9.52 versus 12.78 on control; difference -3.26 (95% CI -6.42 to -0.10), standardized effect d = -0.40; z-test p = 0.043.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Interventional Device - Treated than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Across the secondary outcomes with posted numerical summaries, the group averages for ICU length of stay and ICU ventilation days are lower in the device group, and fewer participants in that group are recorded with ventilation-associated events. The continuous comparisons have unadjusted intervals that lie close to the no-difference boundary. The binary-outcome interval includes no difference. Taken together, these results are compatible with a pattern of lower resource use or fewer events in the device group, but they do not establish a consistent, definitive secondary benefit.

The secondary outcomes relate to the primary question by considering downstream clinical and care-process measures alongside nutrition delivery. Differences in ventilation duration or ICU stay could be relevant to the broader care context, but the registry does not report an analysis demonstrating that any such difference followed from the nutrition endpoint. Nor does it report mediation analyses or a prespecified hierarchy connecting the primary and secondary outcomes. These outcomes should therefore be read as related observations, not as proof of a causal pathway.

The registry lists additional secondary outcomes concerning safety, nursing workload, urine-flow monitoring, and staff convenience. Numerical results for those outcomes are not reported in the registry record. This limits assessment of the broader balance of benefits and burdens and means the posted secondary findings do not cover every outcome named in the study record.

Unadjusted secondary results carry less weight because multiple outcomes create more opportunities for apparently notable findings to arise by chance. The record does not report a multiplicity strategy, such as a hierarchy or correction, and the secondary analyses are not accompanied by reported investigator analyses. The findings are useful as descriptive signals for further evaluation, but they should not be treated as independent confirmation of the primary comparison.

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

• Device Safety According to Occurrence or Absence of Related AE Adverse Event or SAE Serious Adverse Events
• Decrease in Intensive Critical Unit Length of Stay
• Reduction of Number of Patients With VAE (Ventilation Associated Events)
• Decrease in ICU Ventilation Days
• Decrease in Workload Related to Nurse Gastric Residual Volume (GRV) Time
• Assessment of Urine Flow Monitoring Related to Patient Condition
• Convenience of Use of the System and the User Interface (by Subjective Staff Questionnaire)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous, and the registry summarizes each group with a mean and standard deviation. A mean difference expresses how far apart the group means are on the outcome’s original scale. For the primary comparison, the posted estimate is 24.5, with the device-group mean higher than the control-group mean. This is a direct comparison of the displayed averages; it does not adjust for other patient characteristics or site differences.

A confidence interval describes a range of values compatible with the observed data under the statistical model used for the interval. It conveys uncertainty in the estimated mean difference. A narrower interval indicates greater precision, while an interval spanning no difference leaves more uncertainty about the direction and size of the underlying contrast. The primary interval, 18.3 to 30.7, is wholly on the positive side. The secondary continuous-outcome intervals approach or include the no-difference boundary in different ways, so they offer less decisive evidence.

The p-value measures how incompatible the observed data are with a specified no-difference hypothesis, assuming the model and its assumptions are appropriate. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of a result. The primary p-value is reported as < 0.001. The secondary p-values are unadjusted, and the record does not report whether the investigators used additional methods to account for multiple comparisons.

For a binary outcome, such as whether a participant experienced a ventilation-associated event, a risk difference compares the proportions in the groups by subtraction. The reported risk difference is -0.08, with an interval from -0.172 to 0.012. Because that interval includes zero, the data are compatible with no difference as well as with effects in either direction represented by the interval. The registry also posts relative risk and odds ratio summaries for this comparison. These are alternative effect scales: relative risk compares event probabilities, while an odds ratio compares event odds. They can be harder to interpret directly than a difference in probabilities, especially when event numbers are limited.

Standard deviation and standard error describe different forms of variation. A standard deviation reflects variation among observations within a group; a standard error reflects uncertainty in an estimated quantity, such as a group mean. The registry’s primary group standard deviations are 13.0 and 18.0. The comparison summaries include standard errors for the two group means. These measures help explain why group averages and their contrasts are not exact descriptions of every participant’s outcome.

Over-dispersion is a general issue for count and binary data: observed variability can exceed what a simple model assumes. When that happens, model-based standard errors and intervals may be too narrow if the extra variability is ignored. The record does not report a model for the binary outcome, a check for over-dispersion, or details of any robust variance method. It is therefore not possible to assess those modeling choices from the registry entry.

The comparison estimates and intervals described as recalculated are simple, unadjusted calculations from the posted summary statistics. They should not be confused with a trial analysis adjusted for baseline factors or with a model that uses participant-level observations. The registry lists no reported analyses for the posted secondary outcomes. For the primary comparison, no detailed investigator analysis method is reported in the record. The registry does not state whether the reported summaries follow an intention-to-treat population, a per-protocol population, or another definition.

The planning illustrations use the observed effect as a reference and show participant requirements under specified hypothetical assumptions. They are not a reconstruction of the trial’s design. The trial’s own sample-size justification, statistical analysis plan, interim-analysis approach, and assumptions about outcome variability are not reported in the registry record. General statistical concepts explain what the displayed estimates mean, but they cannot fill in those missing protocol details.

11. Confidence Intervals and Precision

The primary mean difference is 24.5, and its 95% confidence interval extends from 18.3 to 30.7. The interval excludes no difference and stays on the positive side, which indicates that the direction of the observed numerical contrast is relatively clear under the unadjusted comparison. The interval still allows a range of possible underlying differences; it does not identify one exact effect. Whether values within that range are meaningfully important cannot be judged without a clinically meaningful threshold, which is not reported in the registry record.

The continuous secondary estimates are less precise in relation to their scale and include values near the no-difference boundary. For ICU length of stay, the mean difference is -3.28, with a 95% confidence interval from -6.477 to -0.083. For ICU ventilation days, the mean difference is -3.26, with a 95% confidence interval from -6.42 to -0.1. Although these intervals are on the negative side, their proximity to zero means small differences remain compatible with the estimates. The record does not report adjusted intervals or analyses accounting for multiple secondary comparisons.

For ventilation-associated events, the risk difference is -0.08, with a 95% confidence interval from -0.172 to 0.012. This interval includes zero and is compatible with no difference. It also spans differences in either direction, so the estimate is imprecise as evidence about the direction of the underlying group contrast.

Confidence intervals quantify statistical uncertainty under their calculation assumptions; they do not account for every possible source of uncertainty. In this study, the endpoint’s wording, unreported analysis-population details, and absence of documented missing-data methods add interpretive uncertainty that the intervals do not capture. The posted results are therefore most informative when the numerical precision is considered alongside these limitations.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for the continuous and binary comparisons in this study. They are not total event counts. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The trial’s own original design assumptions are not reported in the registry record.

The 80% power column describes the number of participants per arm that the planning calculation estimates would be needed for an 80% chance of detecting the chosen effect if that effect and the planning assumptions were correct. The 90% power column uses a higher chance of detection, so its corresponding participant requirement is larger. These percentages describe hypothetical design performance, not the probability that the reported finding is true.

Planning for 100% of the observed effect uses the full observed contrast as the target. Planning for 75% of the observed effect uses a smaller target, and planning for 50% uses a smaller target still. Smaller effects are generally harder to distinguish from random variation, so detecting them requires more participants per arm. The figures are illustrations based on the observed effect rather than evidence about the study’s original planning process. They are not observed power and should not be read as a retrospective measure of whether the completed study was adequately powered.

These calculations also rely on assumptions that may not match a future study, including the assumed allocation and approximation. They do not account for factors not included in the stated planning method. The planning figures therefore show how estimated requirements change under the listed assumptions, not a guaranteed enrollment target or a forecast of future results.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 24.500; pooled standard deviation σ = 15.752.
2. n = 2 × (1.96 + 0.842)² × 15.752² / 24.500² = 6.5, rounded up to 7 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 24.5                      # observed difference in means
sigma <- 15.7516533523733                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(4098224)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 7 (80% power), 9 (90% power)
 75% of observed effect: n per arm = 12 (80% power), 16 (90% power)
 50% of observed effect: n per arm = 26 (80% power), 35 (90% power)
power.t.test: 7.6 
Simulated power at n = 7 per arm: 0.764 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and multiple secondary outcomes. When several outcomes are examined, the chance of encountering at least one apparently notable result by chance can increase. Statistical approaches can address this issue through a prespecified hierarchy, an adjustment to significance thresholds, or other methods. Whether any such approach was planned or used is not reported in the registry record. The secondary p-values should consequently be regarded as unadjusted evidence rather than as results that account for the full set of comparisons.

The record does not report a statistical analysis plan, details of interim analyses, or a prespecified hierarchy among the secondary outcomes. It also does not describe which analysis populations were used. In particular, there is no registry description confirming whether participants were analyzed according to randomized assignment, according to treatment received, or under another rule. These omissions limit the ability to determine how closely the posted summaries correspond to the original analysis plan.

Missing-data handling is also not reported in the registry record. The primary arm summaries list 48.0 and 50.0, while the study enrollment is listed as 100. The registry does not explain the relationship between these values or report why outcome data may be unavailable for any participants. Secondary summaries use different reported group counts from the primary summaries. Without participant flow and missingness details, it is not possible to assess whether missing outcomes could have influenced the estimates or whether the analyzed groups remained comparable.

The absence of these details does not show that the investigators failed to use appropriate methods; it means the registry entry does not document them. A complete interpretation would benefit from the prespecified analysis plan, participant-flow information, definitions of analysis populations, and a description of how missing outcomes and multiple comparisons were handled.

15. 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: post covid 19 (2.0%), desaturation (2.0%), respiratory and hemodynamic deterioration (2.0%), septic shock deterioration (2.0%), severe progressive hypoxemic and hemodynamic disorder (2.0%).

The registry reports serious adverse events for 3 participants in each group, with 50 at risk in each group. It also reports other adverse events for 35 participants in the device group and 39 in the control group, with 50 at risk in each group. Deaths are listed for 3 participants in each group. These are registry counts and should be read separately for each outcome category; they should not be added together because the record does not state whether categories overlap.

The serious-event terms listed include Post COVID 19, Desaturation, Respiratory and hemodynamic deterioration, Septic shock deterioration, and Severe progressive hypoxemic and hemodynamic disorder. Each is reported as 2.0%. The registry does not clarify whether these terms represent mutually exclusive events or participants, nor does it provide enough detail to determine whether each event was considered related to the device. Definitions, timing, severity criteria, and the relationship between serious events and deaths are not reported in the registry record.

These figures describe reported safety events; they do not establish that the device caused or prevented an event. The record’s safety data should be considered alongside its limited detail on event attribution and the absence of posted numerical results for the listed device-safety secondary outcome.

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

The primary result shows a higher posted mean in the smART+ group than in the control group, with an estimated mean difference of 24.5 and a 95% confidence interval from 18.3 to 30.7. The unadjusted p-value is < 0.001. Statistically, this is evidence of a difference in the reported primary measure under the assumptions of the comparison. The result does not by itself explain the clinical importance of that difference or establish the direction of benefit, because the registry describes the endpoint with both feeding-efficiency and feeding-deviation language.

The secondary comparisons offer a more tentative picture. The posted means for ICU length of stay and ICU ventilation days are lower in the device group, while the ventilation-associated-event count is also lower. The binary comparison’s interval includes no difference, and the continuous comparisons are close to the no-difference boundary. These patterns may be of interest, but they are unadjusted and are not enough to establish that the device changed those outcomes.

The findings do not demonstrate that every feature of the system contributed to the primary contrast, nor do they identify which feature might be responsible. The registry does not report patient-level data, details of adherence, a full analysis plan, or explanations of missing outcome information. It also does not establish how the endpoint’s numerical scale maps onto a clinically meaningful level of nutrition delivery.

Statistical evidence should not be equated with clinical importance or generalizability. The registry does not report a threshold for a meaningful feeding change, detailed participant characteristics, or the specific local standard-of-care practices used in the control group. The study concerns ICU patients, but the posted results alone cannot determine how well the findings apply to other settings or patient groups.

In short, the registry supports a difference in the posted primary mean and describes secondary patterns that merit cautious interpretation. It does not, on its own, settle the endpoint-direction ambiguity, establish causal explanations for secondary outcomes, or provide a complete account of safety, missingness, and analysis methods.

17. Why This Trial Matters Statistically

This trial is statistically informative because it pairs a randomized comparison with a continuous nutrition-delivery endpoint and several secondary outcomes that reflect ICU care. The primary estimate is accompanied by a confidence interval and an unadjusted p-value, allowing readers to assess both the direction of the posted contrast and the uncertainty around its size rather than relying on a single significance label.

At the same time, the case illustrates why endpoint definition matters as much as the choice of statistical test. The registry labels the outcome as nutrition optimization and percentage of feeding efficiency, but describes it as feeding deviation and gives a ratio-based formula. A clear scale definition is necessary to know whether larger values are desirable, how the measurement relates to the intended nutritional target, and what a difference of 24.5 represents in practice.

The secondary results also show why a pattern of estimates should not be treated as a collection of independent confirmations. Several outcomes are listed, but analysis methods and multiplicity handling are not documented. Some secondary comparisons appear more suggestive than others, and some listed outcomes have no numerical results. A cautious synthesis recognizes the pattern without assigning it more certainty than the record supports.

Finally, the registry’s reporting gaps are part of the statistical interpretation. The absence of analysis-population definitions, missing-data handling, and a documented statistical plan constrains assessment of possible bias and reproducibility. These are not merely administrative details: they affect how confidently the estimates can be connected to the randomized comparison and how well another study could plan a confirmatory analysis.

18. 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 registry record affect interpretation. First, the primary endpoint is described using potentially inconsistent terms: its title and unit refer to nutrition optimization and feeding efficiency, while the detailed definition calls it feeding deviation and gives a ratio-based calculation. The record does not resolve how to interpret the direction of the scale, so the higher device-group mean should not automatically be described as better.

Second, the primary arm summaries report 48.0 in the device group and 50.0 in the control group, while enrollment is listed as 100. The record does not explain this relationship, and it does not provide participant flow or reasons for unavailable outcomes. The secondary summaries report different group counts for some outcomes. Missingness and analysis-population effects cannot be assessed from these entries.

Third, the control condition is local standard of care, but the registry does not describe the care practices across sites. That makes the comparator less precisely specified for readers seeking to understand what the device was compared against. Details such as site structure, participant characteristics, adherence, and intervention exposure are not reported in the record.

Finally, several secondary outcomes are listed without numerical results, and the registry does not document multiplicity adjustment, missing-data methods, detailed analysis methods, or a sample-size justification for the trial itself. The safety entries do not clarify attribution or possible overlap among event categories. These limitations do not invalidate the posted summaries, but they restrict conclusions about robustness, clinical meaning, and reproducibility.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Nutrition Monitoring and Feeding Optimization With the smART+ System - Comparative Study — NCT04098224.
• Registry record last updated 2025-05-29; status last verified 2025-05.
• Results first posted 2025-05-29.
• 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.

22. Record Summary

NCT04098224 is recorded as a completed randomized, unmasked, parallel-group comparison of the smART+ system with local standard of care in ICU patients. The registry lists enrollment of 100 and identifies nutrition optimization as the primary outcome, assessed between Days 2-14.

The posted primary means are 89.5 for the device group and 65.0 for control, with an unadjusted mean difference of 24.5, a 95% confidence interval from 18.3 to 30.7, and p < 0.001. The endpoint’s wording makes the direction of clinical benefit unclear despite the numerical difference. Secondary findings include lower posted means for ICU length of stay and ventilation days in the device group, while the ventilation-associated-event interval includes no difference. Several listed secondary outcomes have no numerical results in the registry record.

Interpretation is limited by unreported analysis populations, missing-data methods, multiplicity handling, and trial-design assumptions, as well as ambiguity in the primary endpoint definition.