Botulinum Toxin Effects on Plantar Ulcer Recurrence: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Botulinum Toxin Effects on Plantar Ulcer Recurrence (NCT00845897), a randomized na study. The primary outcome is Plantar Flexor Muscle Strength.

2. Clinical Question

Accordingly, the main statistical question addressed by the posted primary outcome is how the reported muscle-strength measurements were distributed across the treatment arms and assessment times. The record describes assessments before treatment, 2 weeks after injection, upon ulcer healing, and 3 months and 6 months after ulcer healing. It does not identify clearly which of these assessment times corresponds to the arm summaries reported in the results. Nor does it provide a statistical comparison, confidence interval, or analysis result for the primary outcome.

The study also lists barefoot plantar pressure as a secondary outcome. That outcome is consistent with the proposed pathway in the study summary, but the record does not provide a numerical result for it in the registry record for this analysis. The clinical rationale therefore gives context for why muscle strength and plantar pressure were of interest, but does not establish whether either changed in a particular way or whether ulcer recurrence differed between groups.

3. Trial Design

The registry identifies this as a randomized, parallel-group trial with quadruple masking. It lists three arms: placebo saline, botulinum toxin 200 units, and botulinum toxin 300 units. The placebo injections were given at 6 calf-muscle sites; each active dose was also injected across 6 sites. The record does not define the four roles or parties covered by the term quadruple masking.

Enrollment is reported as 17. The arm-level primary-outcome summaries list 5 participants for placebo, 7 for botulinum toxin 200 units, and 5 for botulinum toxin 300 units. The registry lists the trial as completed. Its recorded start is 2005-03 and its primary completion is 2010-03. The phase is listed as NA, and the sponsor is Washington University School of Medicine.

The study summary describes the project as pilot data collection intended to assess how much botulinum toxin should be injected into calf muscles to decrease muscle strength. It gives a proposed sequence from reduced plantar flexor strength to temporarily reduced plantar pressure, with potential protection for healing tissue and a longer-term interest in ulcer recurrence. This is the stated rationale, not a report that these changes occurred.

The registry record does not report the allocation procedure, concealment details, masking procedures, eligibility criteria, baseline participant characteristics, or the planned statistical analysis. It also does not state how participants were assigned among all three arms or whether treatment adherence was assessed. These omissions limit how fully the conduct and comparability of the groups can be evaluated from the registry record alone. No inference about the success of masking or the balance of prognostic features can be made from the arm summaries.

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.

6. Primary Endpoint

The registry lists the primary outcome as Plantar Flexor Muscle Strength, measured over Pre-treatment, 2 weeks after injection, upon ulcer healing, 3 months and 6 months after ulcer healing.

The primary endpoint is plantar flexor muscle strength, expressed as plantar flexor torque in Nm. The registry describes measuring concentric plantar flexor torque with the Biodex System 3 Pro Orthopedic Testing & Rehabilitation dynamometer. Peak torque was assessed at 60 deg/sec, a speed the record says is comparable to ankle-joint angular velocity during the stance phase of walking. Three trials of each foot were completed; peak torque was calculated as the average of the two highest torque values across trials.

The record states that a positive value represents an increase in torque and a negative value represents a decrease. It specifies assessment before treatment, 2 weeks after injection, upon ulcer healing, and 3 months and 6 months after ulcer healing. The registry does not clarify which assessment or summary time is represented by the arm-level values posted with the primary outcome.

Muscle strength is relevant to the study's stated hypothesis because the investigators proposed that temporarily reducing plantar flexor strength could reduce plantar pressure. The endpoint therefore measures a proposed intermediate physiological change, rather than ulcer recurrence itself. Barefoot plantar pressure is listed as a secondary outcome. A strength measurement can describe the intended physiological target, but by itself does not show that pressure changed or that ulcers recurred less often.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What do the reported summaries describe?

The primary outcome is a continuous measure: plantar flexor torque in Nm. For a continuous measure, a mean gives a location summary, while a standard deviation describes how dispersed observations are around that mean. The registry lists the endpoint parameter as a mean and the dispersion as a standard deviation. These summaries describe the arm-level observations, but they do not by themselves estimate the uncertainty in a difference between arms. A standard deviation is about variation among observations; a confidence interval is about uncertainty in an estimated quantity.

The arm values are -8.0 with standard deviation 11.0 for botulinum toxin 200 units, 3.0 with standard deviation 4.0 for placebo, and 6.0 with standard deviation 10.0 for botulinum toxin 300 units. The endpoint description says positive values represent increased torque and negative values represent decreased torque. However, the registry record does not specify which of its several listed assessment times these reported values represent. The summaries therefore do not allow a clear assessment of change at a particular visit or change from baseline.

Why are comparisons and confidence intervals important?

A comparison between groups targets a difference in the outcome, rather than describing each group separately. A confidence interval expresses the range of values compatible with the observed estimate under the statistical model and conveys its precision. A narrow interval indicates greater precision than a wide interval, while an interval spanning values on both sides of no difference would leave the direction of the contrast uncertain. This is general statistical interpretation; the registry record does not post a confidence interval or a primary-outcome comparison for this trial.

Although simple calculations can sometimes be made from means, standard deviations, and group sizes, a recalculated comparison is not reported for this outcome. The registry record says values are missing or not estimable for a two-arm comparison of the continuous endpoint. A calculation from incomplete or ambiguously aligned summaries could misrepresent the intended outcome or time point, so the group means should not be turned into a claim about a treatment contrast.

How does the three-arm design affect interpretation?

The parallel design has placebo, botulinum toxin 200 units, and botulinum toxin 300 units arms. Each arm can be described separately, but a treatment question still requires a defined contrast. For example, a dose-versus-placebo comparison asks a different question from a comparison of the two active doses or an overall test across all arms. The registry record does not report which contrast was prespecified, whether an overall test was planned, or how multiple comparisons were to be handled.

Randomization is intended, in general, to support fair group comparisons by making assignment independent of participants' measured and unmeasured characteristics on average. In a small pilot study, chance differences in characteristics can nevertheless occur, and the registry record does not provide baseline characteristics with which to assess group balance. The record identifies quadruple masking but does not explain who was masked or how masking was maintained. No conclusions about successful implementation can be drawn from the label alone.

What does repeated measurement require?

The registry lists assessments before treatment, 2 weeks after injection, upon ulcer healing, and 3 months and 6 months after ulcer healing. Repeated measurements from the same participant are related, so a longitudinal analysis generally needs to account for within-participant correlation. This is a general principle, not a description of the trial's analysis. The registry record does not report whether the intended analysis compared a single visit, change from baseline, or a pattern across visits. It also does not report the statistical model used for repeated measurements.

Timing relative to ulcer healing may vary from participant to participant. Interpreting observations taken at such stages generally requires clarity about when each participant reached the relevant stage and which measurements were available. The registry record does not state how timing was handled, whether all participants contributed observations at every visit, or how missing measurements were treated.

What can be said about planning calculations?

Any planning illustrations based on an observed effect are hypothetical design calculations, not observed power and not a report of the trial's original design rationale. The stated assumptions for those illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. Such illustrations answer a conditional planning question: what sample size would be associated with those assumptions and target effect. They do not establish that the original trial had that power, that the assumptions hold, or that an effect was confirmed.

The registry record describes this project as pilot data collection, but does not report a formal sample-size justification, a target effect, or a planned analysis that can be linked to the posted arm values. The displayed arm summaries also do not support a two-arm recalculation. Planning assumptions should therefore be kept separate from the observed results and from any conclusion about the treatment comparison.

10. Confidence Intervals for Each Arm

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

R code and output

arm <- c("Botulinum Toxin 200 Units", "Placebo", "Botulinum Toxin 300 Units")
n   <- c(7, 5, 5)
m   <- c(-8, 3, 6)
sp  <- c(11, 4, 10)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Botulinum Toxin 200 Units  7  -8.000  11.000  -18.173  2.173
CARM  Placebo  5  3.000  4.000  -1.967  7.967
CARM  Botulinum Toxin 300 Units  5  6.000  10.000  -6.417  18.417

11. Multiplicity, Missing Data and Analysis Populations

The primary outcome has multiple listed assessment times: before treatment, 2 weeks after injection, upon ulcer healing, and 3 months and 6 months after ulcer healing. The registry record does not identify which time point was designated for the primary comparison or whether the repeated measurements were intended to be analyzed together. Nor does it report a hierarchy of outcomes, a multiplicity adjustment, or a plan for interpreting several time-specific comparisons. When many outcomes, time points, or group contrasts are examined, the chance of a nominally notable finding can increase; methods for controlling or contextualizing that issue are general statistical considerations, not methods documented for this trial.

The registry lists barefoot plantar pressure as a secondary outcome and reports 2 outcome measures, but the available record does not give a numerical result for the secondary outcome. It does not report whether ulcer recurrence was analyzed as an outcome, despite the study summary's stated long-term interest in recurrence. The registry also reports 0 analyses. This means that the registry record does not provide an analysis result to evaluate; it does not establish that no analyses were conducted outside the posted record.

Missing-data methods and analysis populations are not reported in the registry record. It does not say whether the primary analysis was intention-to-treat, per protocol, or based on another population, nor how participants with incomplete follow-up were handled. The number contributing to each scheduled assessment is not specified. The arm-level counts listed with the outcome should not be assumed to describe attendance at every visit.

These omissions matter because the interpretation of repeated measurements depends on which participants contributed data, when they were measured, and what assumptions were used for unavailable observations. Without those details, the extent to which missingness or selective reporting could affect interpretation cannot be assessed from the registry record.

12. 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 0% reporting threshold.

The registry lists serious adverse events and other adverse events separately for the placebo, 200 units, and 300 units arms. It reports 0 affected participants for serious events and 0 for other events in each listed group. The corresponding numbers at risk are 5 for placebo, 7 for botulinum toxin 200 units, and 5 for botulinum toxin 300 units.

These figures describe what is recorded in the registry, not proof that no events occurred in any broader sense. The record does not report the period over which adverse events were collected, the definitions used, or details of event ascertainment. It also does not list serious-event terms. Death counts are not reported in the registry record.

Zero affected participants in the posted categories means no affected participants are recorded for those categories and groups. It does not establish that the underlying risk is zero. In general, when few participants are observed, a zero count can coexist with substantial uncertainty about the frequency of uncommon events. The figures are therefore best read as a limited descriptive safety record for the trial, not as a precise estimate of event risk or a comparison establishing that one arm is safer than another.

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

The registry record documents a randomized, parallel-group pilot trial comparing saline with botulinum toxin at 200 units and 300 units. Its primary outcome is plantar flexor torque, a continuous measure of muscle strength. The posted arm summaries give means and standard deviations, and the endpoint description explains the direction of positive and negative values. The record does not clearly connect the reported arm summaries to a specific assessment time.

What these results do mean is limited to the descriptive information recorded: the reported arm-level values differ in direction and magnitude, and observations within each arm show variation as expressed by their standard deviations. The record does not provide an inferential comparison, a confidence interval, or a p-value for the primary outcome. It also indicates that a two-arm recalculation is not estimable from the available continuous-outcome values. No conclusion about a treatment effect follows from the summaries alone.

The result does not establish whether botulinum toxin changed plantar flexor strength relative to saline at a defined visit or across follow-up. The record does not provide a usable analysis of the repeated assessments, and it does not report how missing observations or analysis populations were handled. It also does not show whether plantar pressure changed. Although pressure and ulcer recurrence feature in the study rationale, the record does not report a numerical secondary-outcome result for barefoot plantar pressure or a primary analysis of recurrence.

Nor do the summaries establish that a biological pathway from muscle strength to pressure, tissue tolerance, and recurrence occurred. The study summary presents that pathway as a hypothesis and research motivation. The posted results do not quantify each link or demonstrate that an intermediate measurement translates to a longer-term clinical outcome.

The adverse-event figures are similarly descriptive. The registry records zero affected participants for serious and other adverse-event categories in each arm, but does not provide enough detail to estimate uncommon-event risks precisely or compare safety between treatments. Overall, the record offers a small pilot-study description, not a definitive estimate of efficacy, recurrence, or safety.

14. Why This Trial Matters Statistically

This trial is statistically instructive because it combines a three-arm randomized design with a continuous physiological outcome and repeated assessment times. Each feature raises a distinct interpretive question: which treatment contrast is of interest, which visit defines the primary result, and how observations from the same participant are handled over time. The registry identifies the arms and visits but does not report the analysis plan needed to resolve those questions.

The record also illustrates why descriptive summaries and inferential results are not interchangeable. Means and standard deviations convey the scale and variability of the posted observations, but they do not state the precision of a between-arm contrast. Without a reported confidence interval or test, the reader cannot judge how compatible the data are with different possible treatment effects. The unavailable two-arm recalculation reinforces that the arm summaries should not be treated as a substitute for a defined comparison.

The trial's stated rationale separates a mechanistic endpoint from a longer-term clinical question. Plantar flexor torque is a measure of strength; barefoot plantar pressure is listed separately; ulcer recurrence is described as a potential long-term outcome of interest. Keeping these outcomes distinct prevents a change in a proposed intermediate measure from being mistaken for evidence about recurrence.

Finally, the record is a reminder that a completed trial and a completed registry entry are not the same as a fully reported statistical analysis. Key details about analysis populations, missing measurements, multiplicity, and the selected time point are not reported. For researchers, these distinctions clarify what additional reporting is needed to make results reproducible and interpretable. For readers, they help keep the conclusions proportional to the information actually recorded.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several trial-specific omissions constrain interpretation. The registry lists multiple assessment times for plantar flexor torque but does not identify the time point represented by the posted arm-level summaries. Because values at different stages could answer different questions, this ambiguity limits the meaning that can be assigned to the reported means and standard deviations.

The outcome description gives a measurement procedure, including the device, testing speed, and calculation of peak torque, but the registry does not report baseline participant characteristics or the distribution of observations at each follow-up. It is therefore not possible to assess comparability of the arms at baseline, describe the observed trajectory, or determine how complete follow-up was at the scheduled visits from the record alone.

The registry does not report a statistical analysis plan, a prespecified treatment contrast, confidence intervals, p-values, or methods for repeated measurements. It also does not report a sample-size justification. The study summary calls the project pilot data collection, but does not specify what precision or effect size was intended. Planning illustrations based on observed effects should not be confused with the original design rationale or with observed power.

Although barefoot plantar pressure is listed as a secondary outcome and ulcer recurrence is central to the stated longer-term rationale, numerical results for those outcomes are not reported in the registry entries. The record also does not report how adverse events were defined, the collection period, or analysis populations. These gaps mean that the registry record cannot support a comprehensive assessment of outcome reporting, missingness, safety precision, or the proposed pathway from muscle strength to recurrence.

These limitations concern what can be concluded from the registry record. They do not establish that the unreported information was absent from study conduct or other reporting.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Botulinum Toxin Effects on Plantar Ulcer Recurrence — NCT00845897.
• Registry record last updated 2012-02-03; status last verified 2012-02.
• Results first posted 2012-02-02.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT00845897, titled “Botulinum Toxin Effects on Plantar Ulcer Recurrence,” is listed as a completed randomized, quadruple-masked, parallel-group trial sponsored by Washington University School of Medicine. Enrollment is reported as 17. The arms were placebo saline, botulinum toxin 200 units, and botulinum toxin 300 units.

The primary outcome was plantar flexor muscle strength, measured as torque in Nm at multiple specified stages. The record also lists barefoot plantar pressure as a secondary outcome. Posted primary-outcome summaries include arm means and standard deviations, but the registry does not clearly identify their assessment time or report an inferential comparison. It reports 0 analyses and does not provide a numerical secondary-outcome result in the available record.

The study summary describes a pilot-data rationale linking muscle strength, plantar pressure, and possible ulcer recurrence. The registry does not report a primary analysis of recurrence, a statistical plan, or methods for missing data and analysis populations.