Pivotal Study of VNS During Rehab After Stroke (VNS-REHAB): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pivotal Study of VNS During Rehab After Stroke (VNS-REHAB) (NCT03131960), a randomized na study. The primary outcome is Fugl-Meyer Assessment, Upper Limb (FMA-UE) Average Change.

2. Clinical Question

The trial focuses on motor impairment in the upper limb after stroke. The Fugl-Meyer Assessment, Upper Limb (FMA-UE) is described in the registry as a common scale for measuring this impairment. Its recorded range is 0, indicating more impairment, to 66, indicating no impairment. The primary comparison concerns change from baseline, rather than the score at the end of therapy alone.

The registry also reports a later FMA-UE assessment, a response outcome based on that measure, and average change on the Wolf Motor Function Test (WMFT). Those outcomes provide additional information about measurements made 90 days after six weeks of therapy. The primary question remains the between-arm difference in average FMA-UE change at the earlier assessment, one day after the therapy period.

3. Trial Design

The VNS-REHAB study, registered as NCT03131960, is listed as a completed, randomized, parallel-group study. The registry lists quadruple masking and phase as NA. Enrollment is recorded as 108. The study began on 2017-07-01, and primary completion is recorded as 2020-04-30. MicroTransponder Inc. is listed as the sponsor.

All participants were described as receiving implantation of the Vivistim System® before randomization. The study-treatment arm received VNS during rehabilitation. The active-control arm received standard-of-care rehabilitation with only a minimal amount of VNS at the start of each session; the registry says this was intended to support blinding. Randomization was described as stratified by age and baseline FMA-UE. The registry describes the age categories as <30 and >30, and the baseline FMA-UE categories as 20 to <35 and >35 to 50. It does not give further details about the allocation procedure in the record.

The primary endpoint was assessed at V5, one day after six weeks of therapy. Secondary assessments include outcomes at V7, 90 days after six weeks of therapy. The posted outcome groups contain 53 in the VNS-plus-rehabilitation arm and 55 in the control arm for the reported primary and secondary comparisons. These are the outcome denominators shown for those measures; the registry information summarized does not explain whether any participants were excluded from a particular analysis or why the group denominators differ from the overall enrollment figure.

The registry record does not report the original sample-size justification, planned analysis populations, or further details of the masking procedures. Those omissions limit what can be concluded about the design rationale from the record alone.

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 Fugl-Meyer Assessment, Upper Limb (FMA-UE) Average Change, measured over V5, One day after 6-weeks of therapy.

The primary endpoint is average change in FMA-UE score from baseline at V4 to the assessment at V5, one day after six weeks of therapy. The FMA-UE is a scale for upper-limb motor impairment after stroke. The registry describes its range as 0, more impairment, to 66, no impairment. Change in score is used to express how the measured impairment differs from baseline at the specified follow-up, rather than treating the follow-up score as if all participants started at the same level.

The clinical question is whether the average change differs between participants assigned to VNS during rehabilitation and those assigned to active-control rehabilitation. A difference in group averages expresses the contrast between the arms; it does not describe every participant’s change or the range of individual responses. The posted results report arm means and standard deviations, along with a recalculated unadjusted difference and confidence interval. The sponsor’s reported primary analysis used ANCOVA, but the registry record does not give its effect estimate or confidence interval.

The scale’s defined direction helps interpret the measurement: higher scores correspond to less impairment. The endpoint is a measured motor-impairment outcome at a specified time, not a direct measure of every aspect of recovery or daily function.

7. Results Posted in the Registry

• VNS + Rehabilitation (1): mean 5.00 versus 2.40 on control; difference 2.60 (95% CI 1.05 to 4.15), standardized effect d = 0.63; 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.

Fugl-Meyer Assessment, Upper Limb (FMA-UE) Average Change

• 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:
  • VNS + Rehabilitation (1): mean 5.80 versus 2.80 on control; difference 3.00 (95% CI 0.88 to 5.12), standardized effect d = 0.54; z-test p = 0.006.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for VNS + Rehabilitation (1) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Fugl-Meyer Assessment, Upper Limb (FMA-UE) Response

• 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:
  • VNS + Rehabilitation (1): 47.2% (25/53) versus 23.6% (13/55) on control; risk difference 23.5 percentage points (95% CI 6.0 to 41.0), risk ratio 2.00 (1.15–3.47); unadjusted two-proportion z-test p = 0.010.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for VNS + Rehabilitation (1) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Wolf Motor Function Test (WMFT) Average Change

• 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:
  • VNS + Rehabilitation (1): mean 0.46 versus 0.16 on control; difference 0.30 (95% CI 0.17 to 0.43), standardized effect d = 0.85; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for VNS + Rehabilitation (1) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes form a broadly consistent directional pattern: the posted later FMA-UE average change, FMA-UE response, and WMFT average change favor the VNS-plus-rehabilitation arm, and the sponsor analyses are labeled superiority. These findings extend the primary result to a later assessment and to additional measures of upper-limb motor function. They should be interpreted as supporting context rather than as independent confirmation of the primary result.

The later FMA-UE measurement uses the same scale as the primary endpoint but is taken 90 days after six weeks of therapy rather than one day after therapy. The response measure changes the outcome form from an average score change to a participant classification. The WMFT is another motor-function measure. Because the outcomes differ in timing, scale, and statistical form, a consistent direction does not make their estimates directly comparable or establish that they measure the same aspect of function.

Secondary results generally carry less confirmatory weight when many outcomes or analyses are considered and the record does not state whether multiplicity was controlled. Testing multiple outcomes can increase the chance that at least one result appears statistically persuasive by chance. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting secondary endpoints. Thus, their reported p-values should be read as nominal results unless a prespecified adjustment is documented elsewhere in the record.

The secondary outcomes also do not replace the primary endpoint or remedy uncertainties about missing data, analysis populations, or model specification. The registry does not report the response definition or the adjusted effect estimates and confidence intervals for the sponsor’s secondary analyses. The overall direction is informative, but the record does not support treating the secondary outcomes as a fully specified confirmatory testing program.

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

• Fugl-Meyer Assessment, Upper Limb (FMA-UE) Average Change
• Fugl-Meyer Assessment, Upper Limb (FMA-UE) Response
• Wolf Motor Function Test (WMFT) Average Change

9. Statistical Interpretation

10. Statistical Methods Explained

What does the unadjusted recalculation estimate?

For a continuous outcome such as FMA-UE change, a mean difference compares the average change in the VNS-plus-rehabilitation arm with the average change in the control arm. The recalculation uses the posted group means and sample sizes to estimate that contrast without adjustment for baseline values or other variables. For the primary endpoint, the estimated difference is 2.6 units. The sign indicates that the VNS-plus-rehabilitation group had the higher average change.

This is a descriptive, unadjusted comparison of group summaries. It is not the same as the sponsor’s ANCOVA. ANCOVA is a regression-based method that can compare groups while accounting for specified covariates, often including a baseline measure. The registry reports that ANCOVA was used for the primary analysis, but does not identify the covariates or provide the adjusted estimate and interval. Those details are not reported in the registry record.

What does a standard deviation describe?

A standard deviation describes the spread of individual observations around a group mean. It is not the standard error of the mean and is not a confidence interval for the treatment contrast. The posted primary standard deviations are 4.4 for VNS plus rehabilitation and 3.8 for control. A spread measure helps show that the mean does not represent every participant’s outcome: individual changes can lie above or below the group average. The standard deviation alone does not show the shape of the outcome distribution.

How should the p-value be read?

The unadjusted primary p-value is 0.001. In general, a p-value describes how compatible the observed data are with a specified null model of no group difference, given the analysis assumptions. A small p-value is not the probability that the null hypothesis is true, nor is it a measure of the size or clinical importance of an effect. Interpretation also depends on the analysis plan, outcome selection, data completeness, and whether multiple comparisons were considered. The registry record does not report the multiplicity plan.

Why distinguish the sponsor analysis from the recalculation?

The sponsor’s analysis is reported as ANCOVA and tests superiority, with a reported p-value of 0.001 for the primary outcome. The recalculation is a simple comparison derived from the posted summary statistics and is not a reconstruction of that model. The registry record does not provide the ANCOVA effect estimate, confidence interval, or model specification. Consequently, the two results can be compared in broad terms, but the adjusted effect’s size and precision cannot be independently described from the reported analysis entry. Because no discrepancy is flagged, the sponsor’s own analysis takes precedence as the trial’s reported analysis.

What does superiority mean in this record?

A superiority analysis asks whether the data support a difference favoring one group over the other under the specified analysis. The sponsor’s reported analysis is labeled superiority. That label and its p-value do not by themselves convey how large the difference is, how precisely it is estimated, or whether it is meaningful to patients. For the primary endpoint, the unadjusted estimate and confidence interval add information about magnitude and precision, while the registry does not report the corresponding adjusted effect estimate.

How do the later outcomes fit into the analysis?

The registry reports three secondary outcome categories: later FMA-UE average change, FMA-UE response, and WMFT average change. Continuous outcomes are reported with group means and standard deviations; the response outcome is reported as participant counts. The sponsor analyses use ANCOVA for the continuous outcomes and logistic regression for the response outcome. These methods are suited to different outcome forms: ANCOVA models a continuous measurement, while logistic regression models a binary outcome. Their p-values are not directly interchangeable measures of effect size, and neither method removes the need to consider missing data, model assumptions, or multiplicity.

For a binary endpoint, a risk difference expresses a contrast between the proportions meeting the response definition. The registry does not give the response definition in the outcome description, so its clinical threshold cannot be inferred. The recalculated comparison is unadjusted; the sponsor’s reported logistic regression is the trial’s own analysis. The registry does not provide the regression effect estimate or interval. Across outcome types, the key statistical distinction is between a raw contrast calculated from posted summaries and the trial’s reported model-based analysis.

In general, model-based results depend on the variables included and the assumptions used. The registry does not report enough detail to evaluate those specifications fully. The recalculated results are useful as transparent comparisons of the posted group summaries, but they should not be presented as if they reproduce the sponsor’s adjusted analyses.

11. Confidence Intervals and Precision

The primary unadjusted mean difference is 2.6 FMA-UE units, with a 95% confidence interval from 1.047 to 4.153. A confidence interval describes a range of values compatible with the observed data and the method’s assumptions. It conveys uncertainty about the estimated average contrast; it is not a range containing every participant’s individual change. The interval lies above zero, consistent with the positive estimated difference and the unadjusted p-value of 0.001.

The interval’s endpoints also show why the point estimate should not be read as exact. The data are compatible with a range of average differences, rather than only the estimate of 2.6. The interval does not account for uncertainties that are not represented in the simple calculation, such as possible bias from missing outcomes, departures from model assumptions, or selective reporting. The registry does not report enough information to evaluate those issues fully.

The sponsor’s ANCOVA result does not include an effect estimate or confidence interval in the registry record. Its p-value indicates the reported test result, but does not supply the missing estimate or quantify precision in the same way an interval would. No adjusted interval should be inferred from the unadjusted interval.

For the secondary outcomes, recalculated intervals are also available in the posted results, but the appropriate interpretation depends on the outcome and analysis. The registry’s failure to report a multiplicity procedure means the nominal intervals and p-values should not be treated as if they account for all secondary testing. Precision is therefore only one part of interpretation: the endpoint, analysis method, trial design, completeness of data, and multiplicity context also matter.

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 sample-size figures are planning illustrations based on the observed effects, not the trial’s original design assumptions. For these continuous and binary outcomes, the figures refer to participants per arm, not total events. The calculation assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The planned effect to detect is expressed as a stated fraction of the observed effect. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions, if that effect and the assumptions were correct. The 90% power column uses a higher target chance of detection and therefore generally calls for more participants for the same assumed effect. These are design-planning quantities, not descriptions of the chance that this completed trial found a real effect.

Rows for 100%, 75%, and 50% of the observed effect show how planning requirements change when the target effect is smaller than the observed estimate. Smaller effects need more participants to detect under otherwise unchanged assumptions. The observed effect can be an unstable basis for planning, particularly when estimated in a modest study, so these figures should be read as sensitivity illustrations rather than a recommendation for a future design. This is not observed power.

Different outcomes have different planning figures because their observed effects and variability differ. The calculation does not reproduce the trial’s ANCOVA or logistic-regression analysis, and it does not include an adjustment for multiplicity, attrition, or other design features not specified in the stated assumptions. No such adjustment should be assumed from these illustrations.

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 = 2.600; pooled standard deviation σ = 4.105.
2. n = 2 × (1.96 + 0.842)² × 4.105² / 2.600² = 39.1, rounded up to 40 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 <- 2.6                      # observed difference in means
sigma <- 4.10531179152819                     # 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(3131960)
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 = 40 (80% power), 53 (90% power)
 75% of observed effect: n per arm = 70 (80% power), 94 (90% power)
 50% of observed effect: n per arm = 157 (80% power), 210 (90% power)
power.t.test: 40.1 
Simulated power at n = 40 per arm: 0.800 (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. Analyses Reported by the Sponsor

The registry reports that the sponsor analyzed the primary endpoint with ANCOVA and classified the comparison as superiority. Its reported p-value is 0.001. The registry does not report the ANCOVA effect estimate, confidence interval, adjustment variables, or further model details. The sponsor analysis therefore identifies the trial’s own reported inferential result, but the size and precision of its adjusted contrast cannot be described from the analysis entry.

The recalculated primary comparison uses the posted group means and standard deviations. It is unadjusted and estimates a mean difference of 2.6 units, with a 95% confidence interval from 1.047 to 4.153 and p = 0.001. It is a transparent calculation from the posted summaries, not a substitute for the sponsor’s model. The record does not flag a discrepancy between the posted result and the recalculation.

The two analyses have different roles. The recalculation helps readers understand the direction and approximate magnitude of the raw group contrast. The sponsor’s ANCOVA is the reported trial analysis and takes precedence for the trial’s own inferential conclusion. Without the model details and adjusted estimate, the sponsor result cannot be checked or compared with the unadjusted estimate in detail. The same distinction applies to the reported secondary analyses: the registry names ANCOVA or logistic regression and gives p-values, while the recalculated comparisons are based on summary statistics.

15. Multiplicity, Missing Data and Analysis Populations

The registry record does not report whether the primary and secondary analyses were adjusted for multiple comparisons. The primary endpoint is clearly identified, but the record also includes three secondary outcome categories and reports analyses for them. In general, when several outcomes or statistical tests are examined, the chance of at least one apparently notable result can increase. A prespecified testing hierarchy or multiplicity adjustment can address that issue. Neither is described in the registry information, so no adjustment should be assumed.

Missing-data handling is also not reported in the registry record. The outcome groups show 53 participants for VNS plus rehabilitation and 55 for control, while overall enrollment is recorded as 108. The record does not explain whether all randomized participants contributed to each outcome, whether any outcome values were missing, or how missing values were handled. It does not identify an imputation method, a sensitivity analysis, or the assumptions made about missingness. The listed outcome denominators alone do not establish the reason for any difference from enrollment.

The analysis populations are not reported in the registry record. In particular, the record does not specify whether the posted results use an intention-to-treat population, a per-protocol population, or another defined group. It also does not describe participant exclusions, protocol deviations, or whether participants were analyzed according to randomized assignment.

The registry reports ANCOVA for the primary and continuous secondary analyses, and logistic regression for the response outcome, but does not provide the covariates, model diagnostics, or full specifications. Interim analyses and stopping rules are not reported. These omissions do not negate the posted comparisons, but they limit assessment of how analyses were selected and implemented, and how robust the findings are to alternative assumptions.

16. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fall (3.8%), seizure (1.9%), urinary tract infection (uti) (1.9%), colinic diverticular abscess (1.9%), acute kidney injury (aki)/ chronic kidney disease (ckd) (1.8%).

The registry reports serious adverse events in both arms. In the VNS-plus-rehabilitation group, 5 of 53 participants are recorded as affected; in the control group, 3 of 55 are recorded as affected. Other adverse events are recorded for 43 of 53 participants in the VNS-plus-rehabilitation group and 42 of 55 in the control group. Deaths are recorded as 0 in each arm.

These are descriptive counts within the reported groups. The registry record does not provide a formal statistical comparison of adverse-event counts, time at risk, or further detail on how events were collected and adjudicated. Counts alone do not establish that event risks differ between arms. The serious-event terms listed include Fall (3.8%), Seizure (1.9%), Urinary Tract Infection (UTI) (1.9%), Colinic Diverticular Abscess (1.9%), Acute Kidney Injury (AKI)/ chronic kidney disease (CKD) (1.8%), and Dysphonia (1.8%). The record’s listing does not provide enough context to infer event severity beyond the serious-event classification or to compare each term across arms.

The absence of recorded deaths is a statement about the registry outcome entries, not a broad conclusion about safety. These figures should be read alongside the limits in event definitions, follow-up, and analysis details that are not reported in the registry record.

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

The primary posted results show a higher average FMA-UE change in the VNS-plus-rehabilitation arm than in the active-control arm at one day after six weeks of therapy. The unadjusted difference is 2.6 units, and its 95% confidence interval ranges from 1.047 to 4.153. The sponsor’s reported ANCOVA analysis is labeled superiority. Together, these results describe a between-arm difference in the measured outcome under the reported trial conditions.

They do not show that every participant experienced the same change, or that an individual participant can expect the group average. They do not establish the clinical importance of the score difference, because the registry record does not report a threshold for meaningful change. A group-level scale result is also not a complete account of recovery, daily activities, or quality of life. Those broader outcomes are not described as the primary endpoint in the registry information.

The result applies to the trial’s comparison: VNS delivered during rehabilitation versus rehabilitation with a minimal amount of VNS at the start of each session, in a randomized, parallel-group study. It does not isolate the effect of VNS from every other element of the rehabilitation context, and it should not be generalized automatically to other populations, treatment schedules, or settings. Details needed to judge those extensions are not reported in the registry record.

Statistical evidence and clinical interpretation are related but distinct. The p-value addresses compatibility with a null model under analysis assumptions; the estimate describes the observed contrast; and the confidence interval expresses uncertainty around that estimate. None alone determines whether the difference matters to patients. Missing-data procedures, analysis populations, multiplicity handling, and the adjusted effect estimate are also not reported in enough detail to remove those interpretive limits.

The secondary outcomes show a generally favorable direction, but their multiplicity context is unspecified. Safety entries describe adverse events in both groups and no recorded deaths. Neither the efficacy summaries nor the safety counts alone support a comprehensive judgment about benefits and harms.

18. Why This Trial Matters Statistically

This trial is statistically informative because it uses random allocation to compare two rehabilitation approaches while keeping an active-control procedure. Randomization is intended, in general, to make treatment groups comparable on average, although it cannot guarantee balance in every characteristic. The registry also reports quadruple masking and stratification by age and baseline FMA-UE, design features relevant to bias control and allocation. The record does not give enough detail to evaluate how these procedures were implemented.

The primary outcome is a continuous measure with a stated scale direction and a defined assessment time. That makes it possible to interpret the result as an average change contrast rather than relying only on a significance test. Reporting the group means, standard deviations, and an unadjusted confidence interval allows readers to see magnitude and uncertainty. The sponsor’s ANCOVA analysis adds the trial’s own model-based test, although the missing adjusted estimate and model specification prevent a full comparison of adjusted and unadjusted results.

The study also illustrates why outcome timing and endpoint hierarchy matter. A measurement one day after therapy addresses a different time point from measurements 90 days after therapy. Later outcomes can inform whether the pattern persists, but they do not replace the primary endpoint. The absence of reported multiplicity handling means secondary p-values require particular caution.

Finally, the registry’s gaps are statistically consequential. Sample-size justification, missing-data methods, analysis populations, interim analyses, and model details are not reported. Readers can describe the posted comparisons, but cannot fully reconstruct the original analysis plan or assess all assumptions. Distinguishing the reported sponsor analysis from the transparent summary-statistic recalculation is therefore essential to a balanced interpretation.

19. 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.

Important design and analysis details are not reported in the registry record. The original sample-size justification and assumptions are not stated, so the planning illustrations based on the observed effects should not be mistaken for the trial’s original design rationale. The record does not report the prespecified handling of multiplicity across the primary and secondary outcomes or any outcome hierarchy beyond identifying the primary endpoint.

The registry does not describe missing-data methods, analysis populations, or reasons that outcome denominators may differ from overall enrollment. Without those details, the extent to which the analyses include all randomized participants, and the sensitivity of results to missing outcomes, cannot be assessed. The record also does not provide the ANCOVA covariates, adjusted effect estimates, confidence intervals, or full model specifications. It gives no further details about interim analyses or stopping rules.

The primary comparison is reported as average FMA-UE change at one day after six weeks of therapy. The registry does not state a threshold for a clinically meaningful change, so the statistical difference cannot by itself establish practical importance. The secondary response outcome’s definition is not reported in the outcome description. The registry also does not give further information about the generalizability of the study population or the details of rehabilitation delivery across sites.

Safety information is presented as counts and selected serious-event terms, without event-level timing, exposure time, or a formal comparative analysis in the record. The study is listed as completed, but the summarized registry information is not a complete account of all trial conduct or subsequent evidence. These limits do not change the reported figures; they define what can and cannot be concluded from them.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Pivotal Study of VNS During Rehab After Stroke (VNS-REHAB) — NCT03131960.
• Registry record last updated 2022-07-20; status last verified 2022-07.
• Results first posted 2021-06-14.
• 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.

23. Record Summary

NCT03131960 is a completed, randomized, quadruple-masked, parallel-group study sponsored by MicroTransponder Inc. Enrollment is recorded as 108. It compares VNS delivered during rehabilitation with active-control rehabilitation that includes a minimal amount of VNS at the start of each session.

The primary outcome is average FMA-UE change from baseline to one day after six weeks of therapy. The posted means are 5.0 for VNS plus rehabilitation and 2.4 for control; the unadjusted mean difference is 2.6, with a 95% confidence interval from 1.047 to 4.153. The sponsor reports an ANCOVA superiority analysis with p = 0.001, but the adjusted estimate and interval are not reported.

Later secondary outcomes show a generally favorable direction for VNS plus rehabilitation. The registry does not report multiplicity handling, missing-data methods, analysis populations, or the original sample-size justification. Serious adverse events are recorded in both arms, and deaths are recorded as 0 in each arm.