Mechanisms of Hypoglycemia Associated Autonomic Failure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Mechanisms of Hypoglycemia Associated Autonomic Failure (NCT00678145), a randomized phase 2 study. The primary outcome is Endogenous Glucose Production (EGP) Response Rate - Morphine Sulfate Study.

2. Clinical Question

The clinical rationale in the registry concerns counterregulatory responses to hypoglycemia in type 1 diabetes. It describes impaired glucagon release, hypoglycemia-associated autonomic failure, exercise-associated autonomic failure, and hypoglycemia unawareness as factors relevant to the body’s response to low glucose. The broader research program listed several interventions, but the primary outcome result available for this analysis is restricted to the morphine sulfate and matched placebo study.

The outcome is endogenous glucose production (EGP) response rate, a measure of glucose produced by the body from substrates. The registry says this outcome was assessed following antecedent morphine administration and that results were reported using descriptive statistics. It also states that EGP response was not assessed following other treatment combinations and parameters because of early study termination. Thus, the posted result addresses a narrow comparison under the specified clamp conditions, not every treatment or physiological question in the broader study.

3. Trial Design

The registry identifies this as a randomized, double-masked, crossover Phase 2 study. The recorded enrollment is 39, and the study status is terminated. The sponsor is Albert Einstein College of Medicine. The registry lists a start date of 2008-03 and a primary completion date of 2018-08. These dates and status do not, by themselves, explain why the study ended or how the study proceeded between those dates.

A crossover study exposes participants to more than one treatment condition, so comparisons can potentially use within-person information. The registry describes the overall study as crossover, and its arm descriptions state that both healthy individuals and people with type 1 diabetes were to receive active drug and placebo comparators. However, the sequence of treatments, washout arrangements, allocation details within the crossover, and whether the reported outcome comparison preserves pairing are not reported in the registry record. That information is important for understanding how the design was implemented and how an analysis should account for repeated observations from the same participant.

The registry lists naloxone, fructose, exercise, morphine sulfate, and epinephrine among the interventions. The primary outcome results available for interpretation concern only morphine sulfate and its matched saline placebo. The reported outcome groups each contain 12 participants, while the overall enrollment is 39. The registry does not provide enough information to reconcile those counts, describe the analysis population, or determine which participants contributed to each treatment-condition summary.

For the morphine study, morphine was administered on Day 1, followed by a stepped hypoglycemia clamp on Day 2. The clamp sequence is described as euglycemia followed by glucose targets of 90 mg/dl, 80 mg/dl, 70 mg/dl, and 60 mg/dl. Measurements were obtained every 15 minutes during the first and third 2-hour hypoglycemic episodes, on Day 1 and Day 2, at crossover visits up to approximately 7 months apart. The reported endpoint is based on the final hour of the third clamp episode. Further visit, sequence, and protocol details 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.

Before assignment: Zero (0) Type 1 Diabetes (T1D) patients were enrolled into the study. All study participants were healthy individuals without diabetes who were not on medication and had no history of hypoglycemia or family history of diabetes. One participant in the Naloxone vs Placebo comparator crossover study consented but was not enrolled. As such, 17 participants were enrolled into that study.

1st Intervention (2 Days)

Washout (~5-19 months)

2nd Intervention (2 Days)

Analysis population for the primary outcome, as defined in the registry: EGP response rate was only assessed following antecedent morphine administration. EGP response was not assessed following other treatment combinations and parameters due to early study termination.

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.

6. Primary Endpoint

The registry lists the primary outcome as Endogenous Glucose Production (EGP) Response Rate - Morphine Sulfate Study, measured over Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~7 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported..

The primary endpoint is the endogenous glucose production response rate, reported as a mean in mg/kg/min with standard deviation. EGP describes glucose produced by the body from substrates, and the registry explains that it is relevant to maintaining blood glucose, particularly during fasting. In this study, the endpoint was used to characterize the glucose-production response during a hypoglycemia clamp after antecedent morphine administration.

Measurements were obtained every 15 minutes during the first and third 2-hour hypoglycemic episodes on Day 1 and Day 2, at crossover visits up to approximately 7 months apart. The registry states that the reported value averages data from the final hour of the third clamp episode. It describes the clamp as progressing through euglycemia and glucose targets of 90 mg/dl, 80 mg/dl, 70 mg/dl, and 60 mg/dl. These details define the physiological setting and the portion of the clamp represented by the reported summary.

EGP is a continuous measure, so a mean and standard deviation describe the group’s average response and the spread of individual measurements around that average. This summary does not show the full distribution, individual trajectories, or how each participant’s response changed across clamp stages. Those details are not reported in the registry record. The registry also states that EGP response was assessed only following antecedent morphine for this outcome and was not assessed for other treatment combinations and parameters because the study terminated early. The endpoint therefore supports interpretation only for this particular reported morphine-placebo assessment.

7. Results Posted in the Registry

• Morphine Sulfate: mean 1.15 versus 1.29 on control; difference -0.14 (95% CI -0.35 to 0.07), standardized effect d = -0.53; z-test p = 0.197.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous, and the registry reports each treatment-condition summary as a mean with standard deviation. The mean describes the group’s average EGP response rate. The standard deviation describes variability among the observed measurements around that group mean; it is not a confidence interval for the mean and does not indicate how precisely the group mean has been estimated on its own. The posted values are 1.15 mg/kg/min with standard deviation 0.18 for morphine sulfate, and 1.29 mg/kg/min with standard deviation 0.33 for matched placebo.

The comparison is reported as a mean difference of -0.14. A difference is useful because it puts the treatment-condition contrast on the endpoint’s original scale. The negative sign reflects the order of the contrast reported for morphine relative to placebo, with the morphine mean lower than the placebo mean. This is not a percentage change and does not express a change for each individual participant. The registry does not report adjusted estimates, covariates, or a model-based analysis plan for the primary comparison.

What does the p-value describe?

The unadjusted p-value is 0.197. In general, a p-value describes the compatibility of the observed data with a specified null hypothesis, assuming the statistical model and its assumptions are appropriate. It is not a measure of the size or clinical importance of a difference, and it is not the probability that the null hypothesis is true. A p-value alone also does not show whether the data are precise enough to rule out differences that could matter.

The word “unadjusted” matters because it indicates that the reported value is not adjusted for multiple comparisons. The registry lists nine outcome measures but posts no secondary outcome results and no analysis entries. It does not report whether the p-value is from a sponsor’s prespecified analysis or a particular model. Accordingly, it is best read alongside the arm summaries and the reported interval, and not as a complete account of the study’s statistical plan.

How should the interval be understood?

A confidence interval is a range of estimates compatible with the data and the method used to construct it. In general, a wider interval indicates less precision than a narrower interval. For this comparison, the reported interval spans zero, meaning that the posted interval is compatible with no difference as well as with differences in either direction. Its endpoints are not restated because they are recorded with more than three decimal places, and the registry does not state the confidence level or method used to calculate the interval. The interval should not be interpreted as a range containing a fixed proportion of individual participant responses; it concerns uncertainty in the estimated contrast.

What does the crossover design change?

In general, a crossover design can allow participants to serve as their own controls, because each participant can contribute observations under more than one treatment condition. A paired analysis can use the within-participant differences and account for the correlation between repeated observations. The registry identifies the study as crossover, but the participant-level paired data, treatment sequence, within-person covariance, and crossover-specific analysis are not reported in the registry record.

The posted comparison includes a mean difference, interval, and unadjusted p-value, while the arm summaries provide group means and standard deviations. Without the paired data or a stated crossover analysis, it is not possible to determine whether the reported comparison accounts for the pairing inherent in the overall design. A simple comparison based on group summaries can differ from a paired analysis when measurements from the same person are correlated. The analysis population and handling of incomplete pairs are also not reported.

Why does variability matter?

Standard deviations help describe how much responses varied in the two reported groups. They do not reveal the distribution’s shape, outliers, repeated-measure pattern, or whether variability changed across clamp stages. Those features can matter when selecting or checking an analysis. General statistical practice considers whether a method’s assumptions fit the design and data; the registry does not report diagnostic checks or a distributional analysis for this endpoint.

In general, over-dispersion means that observed variability is greater than a model expects. It can make standard errors too small if the model does not account for the extra variability, which can in turn make intervals look more precise than warranted. The registry does not identify an over-dispersion issue or report a model for repeated EGP measurements, so no such issue should be inferred from the summary statistics alone.

The endpoint description says measurements were made repeatedly during clamp episodes, but the reported result averages the final hour of the third episode. Repeated measurements from one person are generally not independent observations. An analysis of all repeated measurements would ordinarily need to account for their dependence, whereas a summary of an endpoint averaged over a specified period has a different analytic structure. The registry does not report the aggregation details beyond the stated final-hour average, nor does it provide participant-level data or the exact statistical method.

Finally, a statistically detectable contrast and a clinically meaningful contrast are different concepts. Statistical evidence depends on the estimate, its uncertainty, the method, and the analysis plan. Clinical importance requires context about meaningful response differences, which is not specified in the registry record. The posted result therefore supports a statistical description of the observed means and their uncertainty, but does not establish a clinical threshold or a treatment implication.

10. Confidence Intervals and Precision

The mean difference is reported as -0.14, and the interval associated with it extends from a negative value to a positive value. Because zero lies within that interval, the data do not precisely distinguish the observed contrast from no difference under the interval’s calculation. The interval also leaves room for a difference in the opposite direction from the point estimate. Its exact endpoints are not repeated because they have more than three decimal places; the registry record does not state the confidence level or interval method.

The arm means are 1.15 mg/kg/min for morphine sulfate and 1.29 mg/kg/min for matched placebo. Their standard deviations are 0.18 and 0.33, respectively. These describe observed variability, not the precision of the treatment contrast by themselves. The reported outcome groups each contain 12 participants. With a limited outcome sample, estimates can remain uncertain, although the registry does not provide enough information to quantify how much each design feature contributed to the interval width.

Precision also depends on the analysis matching the crossover design. If the same participants contributed outcomes under both conditions, the correlation between their responses can affect the uncertainty of the paired difference. The registry does not report participant-level paired data or state whether the interval accounts for that structure. The reported interval is therefore the uncertainty statement attached to the posted comparison, not a basis for reconstructing an unreported crossover analysis.

The absence of a confidence level, interval method, and detailed analysis population information limits further assessment. The interval should be read as evidence of uncertainty around the estimated contrast, not as proof of equivalence or as a range of likely individual responses. The p-value of 0.197 is also unadjusted and cannot substitute for a precision assessment. Overall, the point estimate is modest relative to the uncertainty expressed by an interval spanning zero, and the registry does not establish a definitive direction or size of difference.

11. 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 sample-size figures are planning illustrations based on the observed morphine-versus-placebo effect, not the original design assumptions for the trial. For continuous outcomes, the figures are participants per arm, not total events. The 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 80% power column gives the illustrative number of participants per arm for a design that would have an 80% chance of detecting the specified effect under those assumptions, if that effect and the assumed statistical model were true. The 90% power column gives the corresponding planning number for a 90% chance. These are prospective planning quantities, not descriptions of the achieved chance that this completed study detected an effect. The figures are not observed power.

The rows scale the assumed effect to 100%, 75%, and 50% of the observed effect. As the effect targeted for detection becomes smaller, the planning requirement increases: the listed participants per arm rise from 57 to 101 to 227 for the 80% power illustrations, and from 76 to 135 to 303 for the 90% illustrations. These are planning values generated under the stated assumptions, not sample sizes observed in the trial. The displayed curve expresses the same general relationship between smaller target effects and larger required samples.

The registry’s own sample-size justification, original target, and design assumptions are not reported in the registry record. These illustrations should not be taken as evidence that the trial was designed around the observed estimate or that it had a particular probability of finding a result. They are sensitive to the observed effect used as their starting point, and an uncertain observed estimate can make such planning illustrations unstable. They also do not resolve the unreported crossover analysis details or account for any unreported missing outcome data.

12. 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 = -0.140; pooled standard deviation σ = 0.266.
2. n = 2 × (1.96 + 0.842)² × 0.266² / -0.140² = 56.6, rounded up to 57 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 <- -0.14                      # observed difference in means
sigma <- 0.26580067720004                     # 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(678145)
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 = 57 (80% power), 76 (90% power)
 75% of observed effect: n per arm = 101 (80% power), 135 (90% power)
 50% of observed effect: n per arm = 227 (80% power), 303 (90% power)
power.t.test: 57.6 
Simulated power at n = 57 per arm: 0.795 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists nine outcome measures, identifies the EGP response rate after morphine as the primary outcome considered in this analysis, and posts no secondary outcome results. It also records zero analysis entries. The statistical plan for handling multiple outcomes, treatment comparisons, time points, or clamp measurements is not reported in the registry record. In particular, it is not reported whether a multiplicity adjustment was planned or whether any outcome hierarchy was prespecified. The reported p-value is unadjusted, so it does not account for a family of comparisons.

The registry states that EGP response was not assessed following other treatment combinations and parameters because of early study termination. It does not explain whether those outcomes were omitted from collection, were not analyzed, or were not posted. The reason for termination, any decision process related to the results, and whether outcome reporting changed after termination are not reported in the registry record. The status alone does not establish why the study ended.

Missing-data handling and analysis populations are also not reported. The record gives overall enrollment of 39, while the two reported outcome groups each contain 12 participants. It does not provide a participant flow, number completing each crossover period, reasons for missing assessments, or information about withdrawals. It is not possible to determine whether the primary result represents all randomized participants, participants with complete outcome data, or another analysis population. No imputation method or sensitivity analysis is reported.

For a crossover study, missing data can affect the availability of paired observations, while period and sequence effects may also be relevant to analysis. The registry does not report whether these factors were evaluated or how incomplete treatment sequences were handled. It likewise does not describe an intention-to-treat, per-protocol, or other analysis population. These omissions limit assessment of potential bias and make it difficult to judge whether the reported estimate fully reflects the randomized design.

The registry provides adverse-event group counts for the listed treatment conditions, but it does not provide a fuller account of missing safety assessments or the methods used to collect or summarize adverse events. These limitations should be kept distinct from the numerical outcome result: an unadjusted estimate can be described as posted, while the missing analysis and data-handling details remain unresolved.

14. 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 reports no serious adverse events and no deaths for any of the listed treatment-condition groups. For morphine sulfate, 12 participants were at risk and zero serious adverse events were reported; the matched placebo group also had 12 at risk and zero serious adverse events. For epinephrine and its matched placebo, each group had 10 at risk and zero serious adverse events. For naloxone and its matched placebo, each group had 17 at risk and zero serious adverse events. The registry also reports zero other adverse events for each listed group.

These are counts from the registry’s adverse-event reporting, not estimates of the probability of an event. A reported count of zero means that no event was recorded in that group in the posted results; it does not establish that an event is impossible or that the treatments have identical safety profiles. The counts should be interpreted in light of the numbers at risk and the limited outcome reporting. The registry does not provide event terms, additional detail about collection or follow-up, or an explanation of how the adverse-event groups relate to the crossover periods and overall enrollment.

Safety counts also do not answer the efficacy question about EGP response. They describe a separate set of reported outcomes. Because the study was terminated and details of follow-up and missing safety data are not reported in the registry record, these zero counts should be read as the posted observations rather than as a comprehensive characterization of risk.

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

The result is a descriptive comparison of mean EGP response rates under morphine sulfate and matched placebo during the specified hypoglycemia clamp assessment. The reported means were 1.15 mg/kg/min and 1.29 mg/kg/min, respectively, with a mean difference of -0.14. The interval crosses zero, and the unadjusted p-value is 0.197. These statistics describe the observed treatment-condition summaries and the uncertainty attached to their comparison.

The result does not establish that the treatment conditions produce identical responses. A nonsignificant or uncertain comparison is not the same as evidence of equivalence. Equivalence requires a defined margin and an analysis designed to assess whether the plausible differences are sufficiently small; no such margin or framework is reported in the registry record. Nor does the point estimate alone show that one condition produces a reliably lower response in the broader population.

The inference is restricted to the participants and assessment represented by the posted outcome groups. The study includes healthy individuals and people with type 1 diabetes in its descriptions, but the registry does not state the composition of the 12-person outcome groups. The available result concerns the final hour of the third clamp episode after antecedent morphine, rather than every point in the clamp or every treatment condition. Results for other treatment combinations and parameters were not assessed according to the registry because of early termination.

The endpoint is a physiological measure of glucose production; it is not, on its own, a direct measure of symptoms, hypoglycemia awareness, long-term glycemic control, or a clinical outcome. The registry’s rationale discusses counterregulatory responses and hypoglycemia-associated autonomic failure, but this result does not by itself resolve those broader mechanisms. The available summaries also do not establish whether the comparison fully accounts for the paired nature of a crossover design.

Accordingly, the posted data support a cautious description: the observed mean response was lower in the morphine group, but the interval and unadjusted test leave substantial uncertainty about the direction and size of the underlying difference. The result should not be generalized to other drugs, populations, outcomes, or treatment strategies that are not represented by this specific comparison.

16. Why This Trial Matters Statistically

This trial is statistically instructive because its registered crossover design and its posted summaries raise different questions about analysis. In a crossover study, the relationship between a participant’s responses under different treatment conditions can contribute useful information. Evaluating whether that pairing was incorporated requires information about sequence, repeated observations, and within-person differences. Those analysis details are not reported in the registry record, so the reader must distinguish the overall design label from the analysis that can be verified from the posted summaries.

The comparison also illustrates why an estimate and its uncertainty should be read together. The mean difference of -0.14 gives a direction and scale for the observed contrast, while the interval spanning zero shows that the estimate is not precise enough to separate the contrast clearly from no difference. The unadjusted p-value of 0.197 adds a test-based summary but does not measure clinical importance or establish equivalence.

Another statistical issue is the difference between enrollment and the outcome sample. Overall enrollment is 39, but each reported treatment-condition group has 12 participants. Without a participant flow, analysis-population definition, or missing-data account, it is difficult to assess how the outcome summaries relate to the randomized cohort. This is especially relevant for crossover studies, where complete observations across treatment conditions can affect which participants contribute to a paired comparison.

Finally, the study is marked terminated, and the registry says that other treatment combinations and parameters were not assessed because of early termination. That makes the limited scope of the posted result central to interpretation. The record offers an example of why transparency about outcome availability, planned analysis, multiplicity, and missing data is important: these details affect how confidently a statistical estimate can be connected to the study’s broader research questions.

17. 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 primary limitation is the narrow outcome coverage. Although the registry lists multiple interventions and nine outcome measures, the posted primary result is restricted to EGP response after antecedent morphine. The registry states that EGP response was not assessed following other treatment combinations and parameters because of early termination. Results for those other conditions are therefore not available for comparison in this outcome.

The reported outcome groups contain 12 participants each, while enrollment is 39. The registry does not explain the relationship between these counts, identify the outcome analysis population, or report participant flow and reasons for missing observations. It is not possible to establish from the record whether the outcome groups include all eligible participants or only those with particular data available.

The crossover label raises an additional interpretive limitation. The sequence, period structure, washout details, paired observations, and crossover-specific analysis are not reported in the registry record. The posted arm summaries do not show the within-participant relationship between treatment-condition responses. That prevents independent assessment of whether the reported interval and unadjusted p-value appropriately reflect the design.

The record does not report the original sample-size justification, prespecified statistical plan, interval method or confidence level, multiplicity procedure, or missing-data method. It also does not provide participant-level data or detailed distributions for the continuous endpoint. These omissions limit evaluation of assumptions and robustness. The terminated status is recorded, but the reason for termination and its implications for the planned analyses are not reported.

Finally, the EGP summary describes the final hour of the third clamp episode and does not represent the complete time course of response. The registry’s rationale is broader than this single physiological endpoint, but no conclusion about other counterregulatory outcomes can be drawn from this result. These limitations call for a narrow reading of the observed estimate rather than broad generalization.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Mechanisms of Hypoglycemia Associated Autonomic Failure — NCT00678145.
• Registry record last updated 2026-05-19; status last verified 2026-04.
• Results first posted 2026-05-19.
• 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.

21. Record Summary

The registry describes a randomized, double-masked, crossover Phase 2 study with enrollment of 39 and status listed as terminated. The primary result analyzed is the mean EGP response rate after antecedent morphine sulfate compared with matched placebo during the specified hypoglycemia clamp assessment. The reported means were 1.15 mg/kg/min for morphine sulfate and 1.29 mg/kg/min for placebo, with a mean difference of -0.14 and an unadjusted p-value of 0.197. The reported interval spans zero.

The two outcome groups each contain 12 participants, but their composition and relationship to total enrollment are not reported in the registry record. The registry says other treatment combinations and parameters were not assessed because of early termination. It posts no secondary outcome results and no analysis entries. Serious adverse events, other adverse events, and deaths are recorded as zero in each listed safety group. The original sample-size justification, detailed crossover analysis, missing-data methods, and multiplicity plan are not reported.