Scrambler Trial for Pain in NMOSD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Scrambler Trial for Pain in NMOSD (NCT03452176), a randomized na study. The primary outcome is Acceptability as Assessed by the Number of Participants Responding Yes to a Question.

2. Clinical Question

The clinical question combines a feasibility concern with an acceptability measure. A participant’s willingness to continue can indicate whether the intervention is acceptable to people taking part, but it does not establish that pain improved or that the intervention is feasible in other settings. The registry describes change in pain level as a secondary outcome, while the posted primary endpoint is the yes response. The available result therefore addresses a narrow, patient-reported question about willingness to continue at the end of the stated treatment period.

3. Trial Design

The registry record describes a randomized, parallel-group comparison of Scrambler Therapy with sham control in people with NMOSD and central neuropathic pain. Enrollment is listed as 22. The trial is marked completed, with a start date of 2018-02-21 and primary completion date of 2019-08-29. Its phase is recorded as NA. Johns Hopkins University is listed as the sponsor.

The study summary describes random assignment in a 1:1 ratio. Both arms involved daily sessions for 10 days, with each session lasting 1 hour. The Scrambler arm received the Scrambler intervention and the comparator arm received Sham-Control. The summary also says that the intervention was added to standardized empiric medications. Details about how those medications were standardized are not reported in the registry record.

There is an inconsistency in the masking descriptions. The registry field records double masking, while the study summary calls the trial single blinded. The available record does not clarify which description applies or who was masked. Randomization is recorded, but the method used to generate or conceal the assignment is not reported in the registry record.

The primary outcome is acceptability, assessed by the number of participants who answered yes to whether they would want to continue treatment if it were available. Its timeframe is 10 days. The registry lists Change in Pain Level as a secondary outcome, with three secondary outcomes posted. Further details about their definitions and assessment timing are not available in the record. The registry does not report an analysis record, although it does post summary results for the primary outcome and a comparison between arms. The planned enrollment and posted outcome counts should be read as registry entries, not as a basis for inferring additional participant flow or analysis populations.

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

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 Acceptability as Assessed by the Number of Participants Responding Yes to a Question, measured over 10 days.

The primary endpoint counts participants who answered yes to a question about wanting to continue the treatment if it were available. The record gives a 10-day timeframe and identifies the response count, rather than a pain-score change, as the primary measure. The posted result is 7 of 11 participants in the Scrambler arm and 5 of 11 in the Sham-Control arm.

Acceptability can be relevant when assessing an intervention that requires repeated treatment sessions. A direct question about willingness to continue captures the participant’s expressed preference at the time it is asked. It can complement outcomes about symptoms or function, but it does not substitute for them: a yes response does not itself demonstrate pain relief, while a no response does not identify why the participant would not continue.

The registry summary describes pain change as a secondary outcome, but the posted primary result is not a pain-change estimate. The exact wording of the acceptability question is described in the record, as is the count-based endpoint. The record does not report additional details about how the question was administered, whether nonresponses were possible, or how missing responses were handled. Those details matter for interpreting a participant count because the endpoint depends on a recorded answer. The result should therefore be read as the posted number answering yes in each arm, not as a comprehensive measure of acceptability, feasibility, or clinical benefit.

7. Results Posted in the Registry

• Scrambler: 63.6% (7/11) versus 45.5% (5/11) on control; risk difference 18.2 percentage points (95% CI -22.7 to 59.1), risk ratio 1.40 (0.64–3.07); unadjusted two-proportion z-test p = 0.392.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary: each participant either answered yes or did not answer yes to the stated willingness-to-continue question. For a binary endpoint, the basic summary is the number of participants with the event and the number assessed in each arm. Here, the event is a yes response. The registry posts 7 of 11 in the Scrambler arm and 5 of 11 in the Sham-Control arm. The word event in this statistical context means the outcome of interest, not necessarily an adverse medical event.

What does the risk difference describe?

The risk difference compares the response proportions by subtracting the Sham-Control proportion from the Scrambler proportion. The posted estimate is 0.182. A value above zero indicates a larger observed proportion answering yes in the Scrambler arm; a value below zero would indicate a larger proportion in Sham-Control. The estimate is an absolute contrast on the proportion scale, which can be easier to interpret than a ratio because it describes the size and direction of the difference in response proportions.

The comparison is unadjusted, meaning the posted summary does not describe adjustment for other variables. That is a description of the reported comparison, not a claim about every analysis conducted by investigators. The registry lists no analysis records. The registry record does not report a covariate-adjusted primary analysis or explain whether any other analytical approach was used.

How should the confidence interval be understood?

A confidence interval communicates the uncertainty around an estimate under the method’s assumptions. For the risk difference, the posted interval runs from -0.227 to 0.591. The interval spans both negative and positive values, so the observed result does not narrowly locate the underlying contrast on one side of no difference. The interval is not a range in which the individual participant responses lie. It is an estimate of uncertainty about the comparative effect in the population represented by the study, subject to the statistical model and study conduct.

A confidence interval is also not a probability statement about the particular effect after observing the data. Its practical value is to show which effect sizes are reasonably compatible with the data and method. In this study, the wide interval signals substantial uncertainty. A point estimate alone would conceal that uncertainty; the interval makes clear that the posted estimate should not be interpreted as precise.

What do the risk ratio and odds ratio add?

The risk ratio compares the response proportions as a ratio, and the odds ratio compares the odds of a yes response between arms. The posted risk ratio is 1.4, with a confidence interval from 0.638 to 3.074. The posted odds ratio is 2.1, with a confidence interval from 0.381 to 11.59. A ratio of one represents no relative difference. Both intervals include one, and each covers a broad range of possible relative effects. They do not provide a more definitive result than the risk-difference analysis.

The odds ratio and risk ratio are not interchangeable. They use different scales and can differ in size, especially when the outcome is not rare. In general, ratios describe relative contrast, while the risk difference describes absolute contrast. No one scale can compensate for limited information in the observed data. The direction and magnitude should be considered alongside the interval and the endpoint’s clinical meaning.

What does the p-value say?

The unadjusted p-value is 0.392. In general, a p-value measures how compatible the observed data are with a specified null model, under the test’s assumptions. It does not measure the size or importance of an effect, the probability that the null hypothesis is true, or the probability that the result will be reproduced. The value should be read with the point estimate, confidence interval, sample size, endpoint definition, and trial conduct. It is not a standalone verdict.

A failure to meet a conventional threshold would not establish that two interventions have the same acceptability. Demonstrating equivalence or non-inferiority requires a prespecified margin and an appropriate design and analysis; such details are not reported in the registry record. The posted comparison is therefore best described as an uncertain estimate, not evidence of equivalence.

Why do the endpoint and design matter?

Random allocation is intended to make the arms comparable on average, reducing systematic differences in treatment assignment. It does not guarantee balance in a small trial, nor does it address missing data or measurement problems. The record gives randomization and parallel assignment but does not report the specific sequence-generation or concealment methods. It also contains conflicting masking descriptions: double masking in a registry field and single blinding in the narrative. The record does not resolve that inconsistency.

Finally, the endpoint measures a stated intention to continue after the intervention period. That is meaningful as an acceptability response, but it is not a measure of symptom change. The registry’s mention of pain change as a secondary outcome does not provide a posted pain-effect estimate. Statistical interpretation must stay tied to the outcome actually reported: the number answering yes.

10. Confidence Intervals and Precision

The comparative estimate is not precise. The posted risk difference is 0.182, and its confidence interval extends from -0.227 to 0.591. This interval includes no difference and also includes effects in either direction. It therefore leaves uncertainty not only about the size of the contrast, but also about which arm would have a higher yes-response proportion in the wider population represented by the trial.

The ratio estimates tell a similar story. The risk ratio is 1.4, with an interval from 0.638 to 3.074; the odds ratio is 2.1, with an interval from 0.381 to 11.59. The no-relative-difference value is included in both intervals. Their breadth indicates that the posted results do not tightly constrain the relative comparison. Changing the effect measure does not make the estimate more precise.

These intervals should not be read as proving there is no difference. Rather, the study’s observed information is compatible with a range of possible effects. Conversely, the positive point estimate alone should not be treated as a reliable indication that Scrambler participants were more willing to continue in the target population. A point estimate summarizes the observed contrast; the interval conveys how uncertain that summary is.

Precision is distinct from whether a result is statistically significant and from whether an effect would matter to participants. The registry does not report a clinically meaningful threshold for this acceptability endpoint. It also does not report a prespecified equivalence margin. The wide interval and modest arm counts mean that firm claims about the size or direction of a population difference are not supported by this result. The confidence intervals are uncertainty measures for the comparative estimates, not intervals for individual responses.

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 planning display gives illustrative participants per arm, not total events. Its assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect used for planning is a stated fraction of the observed effect. These are planning illustrations computed from the observed estimate; they are not the trial’s original design calculation. The trial’s own sample-size assumptions and justification are not reported in the registry record.

The column for 80% power gives the illustrative number of participants per arm for 80% power under the stated assumptions and effect size. In plain language, power is the probability that a specified statistical procedure would identify an effect of the assumed size if that effect were the true one and the assumptions held. The 90% power column gives the corresponding planning number per arm for 90% power. Greater planned power generally requires more participants for the same assumed effect.

The rows use the full observed effect and smaller fractions of it: planning for 100% of the observed effect, planning for 75% of the observed effect, and planning for 50% of the observed effect. As the assumed effect becomes smaller, more participants are needed to distinguish it from no difference with the same target power. The listed figures make that relationship visible: for 80% power, the entries are 117, 210, and 474 participants per arm; for 90% power, they are 156, 280, and 634 participants per arm.

These are prospective planning illustrations, not a description of the trial’s actual enrollment or a measure of the probability that the completed trial detected an effect. This is not observed power. The calculations inherit uncertainty from using an effect estimated in a small study, so they should not be treated as a definitive enrollment recommendation. The registry does not report the assumptions behind the trial’s original design.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.455; treatment proportion p₁ = 0.636; average p̄ = 0.545.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7042 = 1.3802.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6923 = 0.5827.
4. n = (1.3802 + 0.5827)² / (0.1818)² = 116.5, rounded up to 117 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
p0 <- 0.454545454545455                          # control proportion
p1 <- 0.636363636363636                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(3452176)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 117 (80% power), 156 (90% power)
 75% of observed effect: n per arm = 210 (80% power), 280 (90% power)
 50% of observed effect: n per arm = 474 (80% power), 634 (90% power)
power.prop.test: 116.5 
Simulated power at n = 117 per arm: 0.815 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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 identifies one primary acceptability outcome and lists Change in Pain Level as a secondary outcome, with three secondary outcomes posted. The available record does not explain whether the secondary outcomes were prespecified in this form, how their measures were defined, or how their assessment times were chosen. Further secondary outcome results are not reported in the registry record.

Multiplicity arises when several outcomes, time points, subgroups, or statistical comparisons are examined. If many comparisons are tested, the chance of at least one apparently unusual result can increase. Statistical methods can address this concern through prespecified outcome hierarchies or adjustments, but the registry does not report a multiplicity strategy. The posted primary comparison is therefore interpreted as presented, without claiming that it was adjusted for other tests.

Missing-data handling is also not reported in the registry record. The primary results list 11 participants in each arm and show a yes-response count for each, but the record does not state how nonresponses, withdrawals, or incomplete assessments were handled. It does not specify whether the displayed denominators represent all randomized participants, participants who completed treatment, or participants with an available endpoint response. No missing responses should be inferred from the counts alone.

The analysis population is not reported in the registry record. In particular, the record does not say whether the primary analysis followed intention-to-treat principles or used another population definition. The registry lists no analysis records, although it posts summary outcome counts and a comparison. These limitations leave uncertainty about the analysis process and the handling of participants with unavailable outcomes. They do not change the reported values, but they constrain interpretation of how the estimates were produced.

There is also a masking inconsistency: one registry field records double masking, while the narrative calls the trial single blinded. The record does not identify who was masked or reconcile the descriptions. Masking is relevant to participant-reported outcomes because expectations can affect responses, but the available information is insufficient to determine whether or how masking influenced this endpoint.

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 1% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures list zero affected participants in the Scrambler arm among 11 at risk and zero in the Sham-Control arm among 11 at risk. The registry also lists zero deaths in each arm. For other adverse events, the figures are 3 participants among 11 at risk in each arm.

These counts describe what the registry reports for the stated groups; they are not evidence that no adverse events of any kind occurred. The record does not provide serious adverse event terms, and no top serious-event terms are listed. It also does not give additional detail about the other adverse events, their severity, timing, or relationship to the intervention. The summary therefore supports only a narrow reading of the posted counts.

With small groups, the absence of a recorded serious adverse event in the posted figures cannot rule out uncommon harms or establish a comparative safety profile. Likewise, equal counts for other adverse events do not show that the events were identical or caused by the same factors. These registry figures should be interpreted as descriptive reporting, not as a complete safety evaluation or a basis for medical advice.

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

The result does mean that the registry reports a yes response to the willingness-to-continue question from 7 of 11 participants in the Scrambler arm and 5 of 11 in the Sham-Control arm. The unadjusted risk-difference estimate is 0.182, with a confidence interval from -0.227 to 0.591. That interval indicates substantial uncertainty about the direction and size of the comparative difference.

The result does not establish that Scrambler Therapy improved pain. The primary endpoint was acceptability, not change in pain. Although the record names pain change as a secondary outcome, detailed secondary effect estimates are not reported in the registry record. The posted acceptability comparison also does not establish that participants experienced improved quality of life or neurologic function.

The result does not establish equivalence between the arms. The confidence interval includes no difference, but it also includes effects in either direction. A non-significant or uncertain comparison is not proof that two interventions have identical outcomes. The registry does not report a prespecified equivalence margin or an analysis designed to establish equivalence.

Nor does the result show how acceptability would compare in a larger or different population. The trial is described as involving adults with NMOSD and chronic neuropathic pain despite empiric treatment, but the posted counts come from this trial’s arms. The record does not report enough detail about missing outcome handling, analysis populations, or the masking inconsistency to resolve all sources of uncertainty.

The most defensible interpretation is therefore descriptive and limited: a somewhat larger observed count answered yes in the Scrambler arm, while the comparative estimate remains imprecise. The safety entries similarly report no serious adverse events or deaths in either arm and 3 participants with other adverse events in each arm, but they do not establish a full safety profile. These results are statistical summaries of the registry record, not individualized medical guidance.

16. Why This Trial Matters Statistically

This trial is statistically useful because it makes a distinction that is easy to overlook: an intervention’s acceptability is not the same outcome as its effect on pain. The primary endpoint asks whether participants wanted to continue, while pain change is listed as a secondary outcome. Interpreting the result according to the endpoint prevents a willingness response from being treated as evidence of symptom improvement.

The randomized sham-controlled design is also relevant to interpretation of patient-reported outcomes. A sham comparator can support a more structured comparison than an uncontrolled report, because both arms receive a scheduled intervention. However, the registry’s descriptions of masking do not agree: the field says double masking, and the narrative says single blinded. Without clarification, readers cannot determine who was masked or how the sham condition was implemented.

The posted confidence interval emphasizes why the estimate should be read with caution. The point estimate favors a higher yes-response proportion in the Scrambler arm, but the interval includes negative and positive contrasts. This illustrates the difference between an observed direction and a precise conclusion about a population effect. The unadjusted p-value alone cannot convey that full uncertainty.

The record also gives planning illustrations based on fractions of the observed effect. These make clear that smaller target effects require larger planned sample sizes under the stated assumptions. Because the illustrations use an effect observed in this trial, they are not a substitute for an original design justification or independent planning assumptions.

Finally, the registry exposes important reporting gaps: detailed secondary outcome results, missing-data procedures, analysis populations, multiplicity handling, and the original sample-size rationale are not reported. Recognizing those gaps is part of statistical interpretation. It helps distinguish what the posted summaries directly establish from what remains unresolved.

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 study’s planned enrollment is listed as 22, with 11 participants in each arm for the posted primary result. The resulting comparative estimate is imprecise, as reflected in the wide confidence interval. The registry record does not provide a rationale for the planned enrollment or the assumptions used in the original design. The separate planning illustrations are based on the observed effect and should not be mistaken for the trial’s original design analysis.

The primary endpoint is a single acceptability question at the stated 10-day timeframe. It provides a direct response about willingness to continue, but it does not explain why participants answered as they did or quantify changes in pain. The record does not report further details about administering the question or handling missing responses.

Secondary outcomes are only partly described in the registry record. Change in Pain Level is listed, and three secondary outcomes are posted, but detailed results and definitions are not available. The record therefore does not allow a full assessment of the trial’s symptom-related findings or the relationship between acceptability and pain outcomes.

Important methods details are also absent or inconsistent. The registry records double masking, while the narrative says single blinded. Allocation concealment, sequence generation, missing-data methods, analysis population, and multiplicity procedures are not reported in the registry record. These gaps limit assessment of potential bias and the robustness of the comparison.

Safety information is brief: the record lists no serious adverse events or deaths in either arm and 3 participants with other adverse events in each arm. Event descriptions and further context are not reported. These results should not be generalized beyond the reported groups or treated as a complete accounting of safety.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Scrambler Trial for Pain in NMOSD — NCT03452176.
• Registry record last updated 2020-05-05; status last verified 2020-04.
• Results first posted 2020-04-17.
• 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

NCT03452176, titled Scrambler Trial for Pain in NMOSD, is recorded as a completed randomized parallel-group sham-controlled study sponsored by Johns Hopkins University. The registry lists enrollment of 22 and dates the study from 2018-02-21 to primary completion on 2019-08-29. The phase is recorded as NA.

The study compares Scrambler Therapy with Sham-Control, with both arms described as daily 1-hour sessions for 10 days. The primary endpoint is the number answering yes to whether they would want to continue treatment if it were available. The posted counts are 7 of 11 in the Scrambler arm and 5 of 11 in the Sham-Control arm. The unadjusted risk difference is 0.182, with a confidence interval from -0.227 to 0.591 and p-value 0.392.

The record lists Change in Pain Level as a secondary outcome but does not report detailed secondary results. Its masking descriptions conflict, and details about missing data, analysis populations, multiplicity, and the original sample-size rationale are not reported in the registry record. The posted safety figures list zero serious adverse events and zero deaths in each arm, with 3 participants experiencing other adverse events in each arm.