Efficacy and Safety of Metoclopramide Nasal Spray Solution in Diabetic Patients With Gastroparesis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Metoclopramide Nasal Spray Solution in Diabetic Patients With Gastroparesis (NCT00845858), a randomized phase 2 study. The primary outcome is The Primary Efficacy Endpoint is the Change From Baseline to Week 4 of the Treatment Period in the Modified Gastroparesis Cardinal Symptom Index-Daily Diary (mGCSI-DD) Total Score..

2. Clinical Question

The comparison concerns average change over the treatment period, not whether every participant improved or whether a particular participant experienced a meaningful change. The primary endpoint combines four symptom ratings into a daily mean and then averages daily scores over the observation period. The registry says that a mean improvement of >1 category is considered clinically meaningful, but the posted group mean changes are not themselves a direct count of participants who met that criterion.

The record reports separate results for the 10 mg dose, the 14 mg dose, and placebo. It does not report a posted analysis comparing the two active doses directly. The primary question is therefore best read as two comparisons with the shared placebo group, with the estimated average change and its uncertainty considered for each comparison.

3. Trial Design

The registry identifies NCT00845858 as a completed phase 2, randomized, quadruple-masked, parallel-group study sponsored by Evoke Pharma. Its official title describes a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study of metoclopramide nasal spray in diabetic subjects with gastroparesis. The study began in 2009-04, and primary completion was recorded in 2011-12.

The posted groups were metoclopramide nasal spray 10 mg, metoclopramide nasal spray 14 mg, and placebo nasal spray. The registry reports 96 participants in each metoclopramide group and 95 in the placebo group for the primary outcome. The overall enrollment recorded for the trial is 287. No additional arm-level treatment details are reported in the registry record.

The primary efficacy outcome was assessed from baseline to week 4 of the treatment period. The registry labels its primary population ITT and describes the endpoint as a mean change in the mGCSI-DD total score. The available outcome results are group means with standard deviations; posted comparisons give unadjusted mean differences and confidence intervals.

The record reports two outcome measures but no secondary outcomes posted in the results information summarized for this analysis. It also reports no posted analyses beyond the arm-level outcome and the two comparisons with placebo. The original allocation procedure, the detailed masking procedures, the trial’s planned statistical model, and the original sample-size justification are not reported in the registry record. Those details should not be inferred from the randomized and quadruple-masked design labels.

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:

Analysis population for the primary outcome, as defined in the registry: ITT

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: Provides at least 80% power (alpha=0.05 two sided) to detect a mean difference between treatment groups of 0.5, for the GCSI-DD total score. Based on the literature, the standard deviation (SD) of the endpoint is approximately 1.1 resulting in a sample size of 77 per treatment group.

6. Primary Endpoint

The registry lists the primary outcome as The Primary Efficacy Endpoint is the Change From Baseline to Week 4 of the Treatment Period in the Modified Gastroparesis Cardinal Symptom Index-Daily Diary (mGCSI-DD) Total Score., measured over 4 weeks.

The primary endpoint was change from baseline to week 4 in the modified Gastroparesis Cardinal Symptom Index-Daily Diary total score, or mGCSI-DD. It is a patient-reported measure intended to capture the severity of gastroparesis symptoms during the treatment period. The four component symptoms are nausea, early satiety, bloating, and upper abdominal pain. Each symptom is graded from 0 (none) to 5 (very severe).

The daily score is the mean of the four symptom scores, and the total score is the mean of daily scores over the observation period. A change score expresses how the average score at follow-up differs from baseline. In the posted results, negative changes represent a decrease in the score. The mean change was -1.2 in each metoclopramide group and -1.0 in the placebo group.

This endpoint is used to summarize a patient-reported symptom experience across several symptoms and diary days rather than relying on a single symptom rating. The registry states that a mean improvement of >1 category is considered clinically meaningful. That statement provides context for interpreting changes, but it does not establish how many participants achieved a meaningful improvement. The record does not report individual responder counts for that threshold.

7. Results Posted in the Registry

• Metoclopramide Nasal Spray 10 mg: mean -1.20 versus -1.00 on control; difference -0.20 (95% CI -0.50 to 0.10), standardized effect d = -0.19; z-test p = 0.186.
• Metoclopramide Nasal Spray 14 mg: mean -1.20 versus -1.00 on control; difference -0.20 (95% CI -0.46 to 0.06), standardized effect d = -0.22; z-test p = 0.131.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: it is a score measured on a scale, and the registry reports means and standard deviations. The posted treatment comparisons are mean differences between each metoclopramide group and placebo. This is a direct way to describe the average separation in change scores, using the same score and time point for each group.

What does a mean change represent?

A group mean is the arithmetic average of participants’ recorded changes. It describes the group’s central tendency, not the experience of every participant. In this trial, the reported mean change was -1.2 in each active-treatment group and -1.0 in placebo. The mean difference was -0.2 for each comparison. Because the endpoint is a change score, these values describe movement from baseline to week 4 rather than the absolute symptom score at week 4.

A standard deviation describes how spread out the participant-level values are around their group mean. The registry reports standard deviations of 1.18 for 10 mg, 0.94 for 14 mg, and 0.89 for placebo. Greater spread means individual changes varied more around the average. A standard deviation is not the uncertainty interval for a mean; the confidence interval for a comparison addresses uncertainty in the estimated difference between group averages.

What does the confidence interval add?

A confidence interval gives a range of values compatible with the observed data under the calculation method. It conveys precision as well as direction: a narrower interval indicates a more precise estimate, while a wider interval leaves more uncertainty about the size and direction of the difference. Both posted intervals for the mean differences include zero. Zero represents no difference between the average changes. The intervals therefore do not rule out no average difference, and they also allow for effects in either direction within their bounds.

The posted p-values are unadjusted: 0.186 for 10 mg versus placebo and 0.131 for 14 mg versus placebo. A p-value describes how unusual data at least as discrepant as those observed would be under a statistical model in which there is no difference. It does not give the probability that the null hypothesis is true, the probability that the result will replicate, or the size of any treatment effect. The registry record does not report the model or significance threshold used in the trial’s original analysis, so these posted values should not be treated as a full substitute for the original analysis plan.

Why does variability matter?

When participant outcomes vary, a group mean is estimated less precisely than it would be with less variation, all else being equal. The observed standard deviations show that changes differed among participants. The precision of the comparison also depends on the number of participants contributing data and on the analysis method. The registry gives the outcome group sizes, but does not report the detailed handling of missing values or the full analysis model. General statistical principle: variability and sample size jointly affect the uncertainty around a group comparison.

The displayed comparisons are unadjusted recalculations from posted summary statistics. They are not reported as adjusted models. The record does not describe baseline adjustment, stratification, repeated-measures modeling, or another approach for accounting for participant-level factors. General statistical principle: adjustment can change an estimate or its precision when relevant factors are included, but whether that occurred in the trial’s own analysis is not reported in the registry record.

How should the two dose comparisons be understood?

Each dose is compared with the same placebo group. The two estimates answer separate questions about 10 mg versus placebo and 14 mg versus placebo; they do not by themselves test whether the doses differ from each other. Because there are multiple comparisons, the overall interpretation can depend on how multiplicity was handled. The registry record does not report a multiplicity adjustment or an analysis plan specifying how these comparisons were prioritized. The unadjusted values should therefore be described as individual posted comparisons.

General statistical principle: over-dispersion is a concern when outcome variability is greater than assumed by a statistical model, because an underestimated variance can make uncertainty look too small. The posted outcome is a continuous score and the record supplies standard deviations, but it does not report an over-dispersion assessment or a model for this endpoint. No conclusion about whether such an issue arose in the trial can be drawn from the registry information.

What can summary statistics not show?

Means, standard deviations, confidence intervals, and p-values do not reveal the full distribution of participant outcomes. They do not show whether score changes were symmetric, whether a small number of values were unusually influential, or how many participants had a change that met the registry’s meaningful-change criterion. Individual-level results and responder analyses are not reported in the registry record. The posted summary statistics are useful for describing the average contrast and its precision, but they cannot answer those individual-level questions.

10. Confidence Intervals and Precision

The mean difference was -0.2 for both dose comparisons. The confidence interval for 10 mg extends from -0.496 to 0.096; for 14 mg, it extends from -0.460 to 0.060. Both intervals include zero, so neither interval excludes the possibility of no average difference. Each also spans values on both sides of zero, leaving uncertainty about the direction and size of the underlying difference.

The interval for the 14 mg comparison is somewhat narrower than the interval for 10 mg, but both have substantial overlap and both include zero. The posted standard deviations are 1.18 for the 10 mg group, 0.94 for 14 mg, and 0.89 for placebo. These describe participant-to-participant spread in change scores, not the precision of a treatment comparison by themselves.

Precision should be considered alongside the estimate, not inferred from the p-value alone. A confidence interval helps distinguish a relatively precise estimate from one that remains compatible with a broad range of effects. Here, the point estimates are small relative to the uncertainty represented by the intervals. The registry does not report confidence intervals for the individual group means, and the posted comparisons are not described as adjusted analyses.

The registry states that a mean improvement of >1 category is considered clinically meaningful. That benchmark concerns the symptom score and should not be confused with the mean difference between active treatment and placebo. The intervals address uncertainty around that difference, not the proportion of participants who reached the stated benchmark. Such responder proportions are not reported in the registry record.

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 effect, not the trial’s original design assumptions. They give participants per arm for 80% power and participants per arm for 90% power; they are not total event counts. The 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 the stated fraction of the observed effect.

For the 10 mg comparison, planning for 100% of the observed effect gives 430 participants per arm for 80% power and 575 participants per arm for 90% power. Planning for 75% of the observed effect gives 764 participants per arm for 80% power and 1,022 participants per arm for 90% power. Planning for 50% of the observed effect gives 1,718 participants per arm for 80% power and 2,299 participants per arm for 90% power.

For the 14 mg comparison, planning for 100% of the observed effect gives 329 participants per arm for 80% power and 441 participants per arm for 90% power. Planning for 75% of the observed effect gives 585 participants per arm for 80% power and 783 participants per arm for 90% power. Planning for 50% of the observed effect gives 1,316 participants per arm for 80% power and 1,762 participants per arm for 90% power.

The 80% and 90% columns describe the planned probability of detecting the assumed effect under the stated assumptions if that effect is real. Smaller effects require more participants to achieve the same target power, which is why the figures rise when the planned effect is a smaller fraction of the observed one. These figures are not observed power, and they should not be read as the trial’s original enrollment target. The trial’s own sample-size justification and original design assumptions are not reported in the registry record.

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 = -0.200; pooled standard deviation σ = 1.046.
2. n = 2 × (1.96 + 0.842)² × 1.046² / -0.200² = 429.3, rounded up to 430 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 <- -0.2                      # observed difference in means
sigma <- 1.04586714989911                     # 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(845858)
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 = 430 (80% power), 575 (90% power)
 75% of observed effect: n per arm = 764 (80% power), 1,022 (90% power)
 50% of observed effect: n per arm = 1,718 (80% power), 2,299 (90% power)
power.t.test: 430.2 
Simulated power at n = 430 per arm: 0.797 (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 reports two posted primary comparisons: 10 mg versus placebo and 14 mg versus placebo. Both use the same placebo group. The record gives unadjusted p-values and confidence intervals, but does not report a multiplicity adjustment, a hierarchy of comparisons, or a prespecified strategy for controlling the chance of false-positive findings across comparisons. The two p-values should therefore be interpreted as unadjusted results rather than as multiplicity-adjusted evidence.

The registry identifies the primary efficacy population as ITT, but does not define in detail which participants were included in that population or how the analysis handled participants without a week 4 score. The amount and pattern of missing primary outcome data, the method used to address missingness, and any sensitivity analyses are not reported in the registry record. Missing outcome data can affect both the estimate and its uncertainty, particularly if the availability of a measurement is related to participants’ outcomes; that is a general statistical concern, not a claim about what occurred in this trial.

The record reports two outcome measures but no secondary outcome results in the posted results summarized for this analysis. It also reports zero posted analyses beyond the outcome results described. There is no reported statistical analysis plan, no account of interim analyses, and no explanation of whether any analysis populations other than ITT were used. The registry’s trial design labels do not resolve these analytical details.

Accordingly, the reported estimates support a description of the posted group means and unadjusted comparisons, but they do not establish how all planned analyses were handled. The original methods for multiplicity, missing data, and analysis populations are not reported in the registry record.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: non cardiac chest pain (1.1%), cholelithiasis (1.1%), kidney infection (1.1%), diabetic ketoacidosis (1.1%), chronic obstructive pulmonary disease (1.1%).

The registry reports serious adverse events for 0 participants in the metoclopramide 10 mg group, 2 in the 14 mg group, and 3 in the placebo group. The number at risk for serious adverse events was 95 in each group. Other adverse events were reported for 53 participants in the 10 mg group, 57 in the 14 mg group, and 53 in the placebo group; the number at risk was also 95 in each group.

These are descriptive counts of participants affected, not estimates of comparative risk adjusted for other factors. The record lists serious-event terms including non cardiac chest pain, cholelithiasis, kidney infection, diabetic ketoacidosis, chronic obstructive pulmonary disease, and condition aggravated, each at 1.1%. The registry does not report death counts in the displayed safety information. The figures do not establish that an intervention caused or prevented an event, and comparisons should be interpreted in the context of the trial’s size and the limited posted safety detail.

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

The posted efficacy results show mean symptom-score changes of -1.2 in both metoclopramide groups and -1.0 in the placebo group from baseline to week 4. The mean difference against placebo was -0.2 for each dose. The confidence intervals for both comparisons include zero, and the unadjusted p-values were 0.186 and 0.131. Thus, the registry results describe a modest estimated separation in group averages with uncertainty that includes no difference.

These results do not establish that every participant had the average change, or that individual participants experienced the same effect. Group means can conceal a range of responses. The record does not report the number of participants who improved by the registry’s stated clinically meaningful threshold of >1 category, nor does it report symptom-specific changes that would show which component contributed most to the total.

The results also do not, on their own, settle whether a difference is clinically important or how the original trial analysis evaluated the comparisons. The registry does not report the original statistical analysis plan, missing-data handling, multiplicity strategy, or sample-size justification. The posted p-values are unadjusted and should be understood in that context. No direct comparison between the two metoclopramide doses is reported.

Safety counts are also descriptive. The posted serious adverse event counts were 0, 2, and 3 across the 10 mg, 14 mg, and placebo groups, while other adverse event counts were 53, 57, and 53. These numbers do not establish a causal safety difference. Taken together, the registry record allows a focused reading of the reported week 4 average symptom changes and adverse event counts, but it does not support conclusions beyond those posted results.

16. Why This Trial Matters Statistically

This trial illustrates why a treatment comparison should be read through both its estimated effect and its precision. The two active groups had the same posted mean change, and each mean difference versus placebo was -0.2. Yet the confidence intervals include zero, so the estimates remain compatible with no mean separation as well as with differences in either direction. A point estimate alone gives an incomplete account of the data.

The endpoint also highlights the distinction between an average change and a clinically meaningful response. The mGCSI-DD combines four patient-reported symptoms and averages scores over the observation period. The registry gives a benchmark for meaningful mean improvement, but does not report the proportion of participants reaching that benchmark. A group mean cannot substitute for individual responder information.

Finally, the record makes visible how interpretation depends on reporting of analysis decisions. Two dose comparisons share a placebo group, yet a multiplicity procedure is not reported. Missing-data handling, the original analysis plan, and the trial’s sample-size justification are also not reported. These gaps do not change the posted numerical results, but they limit what can be inferred about the broader planned analysis. The trial is a useful example of reading registry outcomes cautiously: identify the estimand, describe the group contrast, inspect uncertainty, and distinguish posted results from methodological details that are not reported.

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 result is reported as group means and standard deviations, with two unadjusted comparisons against placebo. The registry does not report a detailed statistical analysis plan, including the original model, whether baseline values were incorporated into the analysis, or how multiple comparisons were addressed. The record also does not describe the handling or extent of missing week 4 outcome data, despite identifying the primary population as ITT.

The registry does not report individual-level score distributions, responder counts for the stated >1-category meaningful-change benchmark, or separate results for the four symptom components. The group-level mean therefore cannot show how consistently participants changed or whether a subset experienced larger changes. No direct comparison of the two metoclopramide doses is posted.

The posted safety information gives participant counts for serious and other adverse events, but does not report death counts in the displayed information or provide detail sufficient to establish causal relationships. The original sample-size justification and design assumptions are not reported; the available planning illustrations use the observed effect and should not be confused with the trial’s original planning. These limitations restrict interpretation to the posted group summaries and comparisons.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy and Safety of Metoclopramide Nasal Spray Solution in Diabetic Patients With Gastroparesis — NCT00845858.
• Registry record last updated 2014-06-27; status last verified 2013-11.
• Results first posted 2014-06-17.
• 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

NCT00845858 was a completed, randomized, quadruple-masked, parallel-group phase 2 study sponsored by Evoke Pharma. It compared metoclopramide nasal spray 10 mg and 14 mg with placebo in diabetic gastroparesis. The primary outcome was change from baseline to week 4 in the mGCSI-DD total score, reported for an ITT population.

Mean changes were -1.2 in both metoclopramide groups and -1.0 with placebo. The mean difference versus placebo was -0.2 for each dose; both confidence intervals included zero. The registry also reports serious and other adverse event counts by group. The original statistical plan, missing-data methods, multiplicity handling, and sample-size justification are not reported in the registry record.