Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy (NCT03627416), a randomized na study. The primary outcome is Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Directly After rTMS.

2. Clinical Question

The clinical question concerns a short-term change in a timed walking task, rather than a broad measure of daily function or long-term disease progression. Participants walked barefoot over 10 meters at maximal speed while remaining safe. The registry also describes assessments of lower-extremity strength and spasticity, as well as follow-up measurement two weeks after rTMS.

The comparison is relevant because the registry summary describes limited or absent established therapeutic options for these conditions and identifies gait disturbance as a central problem. The trial asks whether the active stimulation condition is associated with a different change in walking time than the sham condition. It does not, by itself, answer whether any observed difference is durable, meaningful to participants in everyday settings, or applicable beyond the enrolled study population.

3. Trial Design

The registry record describes a completed, randomized, double-masked crossover pilot study of rTMS for gait improvement in hereditary spastic paraplegia and adrenomyeloneuropathy. The planned enrollment was 15. The posted primary outcome summaries contain 14 observations for active rTMS and 14 for sham rTMS. Because the design is crossover, participants were assigned to receive treatment conditions in a sequence; however, the registry record does not report the sequence details, treatment periods, or any washout interval.

Active treatment consisted of stimulation over bilateral primary motor areas for lower-extremity muscles. The intervention description specifies five daily sessions on consecutive weekdays. Each session involved 3000 magnetic pulses at 90% of resting motor threshold intensity. Sham stimulation was intended to resemble active treatment, with the coil held perpendicular to the scalp to prevent a significant magnetic field from reaching brain tissue.

The primary endpoint was the change from baseline in time to walk 10 meters, measured directly after rTMS on the same day. The registry also lists a measurement two weeks after rTMS and measures concerning the Timed up and go Test, Medical Research Council Scale, and Modified Ashworth Scale. Outcome assessments were described as taking place before and after therapy and again two weeks later.

A crossover design can allow each participant to contribute experience under more than one condition, which may help account for stable differences between participants. In general, however, interpretation depends on the treatment sequence, period effects, possible carryover, and appropriate within-participant analysis. Those details and the trial's original statistical plan are not reported in the registry record. The posted comparison is presented as an active-versus-sham mean difference, so the available summaries do not establish how the original crossover structure was incorporated in the analysis.

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 Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Directly After rTMS, measured over Before rTMS, directly (on the same day) after rTMS.

The primary endpoint measures the change in walking time over 10 meters from before rTMS to directly after treatment on the same day. Participants walked barefoot at maximal speed while remaining safe. Time is recorded in seconds, and the registry describes the outcome as a mean with standard deviation.

A timed walking task is a direct performance measure: it records how long a participant takes to cover a fixed distance under the specified test conditions. Because the endpoint is a change from baseline, the value describes movement between the two assessments rather than the absolute walking time at either assessment. A negative change indicates that the recorded time decreased; a positive change indicates that it increased. The treatment comparison then contrasts the mean changes in the active and sham conditions.

In general, a short walking test can provide a focused measure of gait performance and can be repeated at defined assessment times. Its interpretation is specific to the test conditions and timing. It does not alone describe other aspects of mobility, strength, spasticity, daily activities, or longer-term change. The registry includes other measures and a two-week walking assessment, but the primary question is confined to the immediate change in 10-meter walking time.

The endpoint is clinically connected to the gait disturbance named in the study rationale, while remaining a limited measure of that broader concern. The registry record does not report a threshold for a change considered important to participants or a protocol-defined clinically meaningful difference.

7. Results Posted in the Registry

• Active rTMS: mean -5.41 versus 1.70 on control; difference -7.11 (95% CI -16.80 to 2.58), standardized effect d = -0.54; z-test p = 0.150.

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.

Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Two Weeks After rTMS

• 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:
  • Active rTMS: mean -5.84 versus 0.93 on control; difference -6.77 (95% CI -16.57 to 3.03), standardized effect d = -0.51; z-test p = 0.176.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Active rTMS and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists four secondary outcomes: the Timed up and go Test, the Medical Research Council Scale, the Modified Ashworth Scale, and 10-meter walking time measured two weeks after rTMS. The posted numeric summaries include the two-week walking-time comparison. Numeric results for the other listed secondary outcomes are not reported in the registry record.

The follow-up walking-time estimate has the same broad directional pattern as the immediate primary estimate: the point estimate favors a greater reduction in walking time in the active condition, while its interval includes zero. This offers descriptive consistency across the two timing assessments, but does not establish that a treatment difference persisted or that it was statistically distinguishable from no difference. The registry record does not report a repeated-measures analysis combining the immediate and follow-up measurements.

Secondary outcomes can add context because they examine different aspects of function or assess change at a different time. They should not automatically be treated as independent confirmations of the primary result. In general, examining multiple endpoints increases the chance that at least one result appears notable by chance, especially when no adjustment or hierarchy has been specified. The registry record does not report a multiplicity plan, an outcome hierarchy, or adjusted secondary analyses. It also does not list reported analyses for the named secondary outcomes beyond the numeric walking-time summary.

Accordingly, the secondary information is best read as limited supporting context rather than as a separate body of confirmatory evidence. The consistency in direction between the posted walking-time summaries is worth noting, while the uncertainty in both and the absence of numeric results for the other named outcomes limit the strength of any broader conclusion.

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

• Change in Timed up and go Test
• Change in Medical Research Council Scale (MRC)
• Modified Ashworth Scale
• Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Two Weeks After rTMS

9. Statistical Interpretation

10. Statistical Methods Explained

The posted primary result is a comparison of mean changes in a continuous outcome. The outcome is walking time in seconds, and each condition's summary gives a mean and standard deviation. The comparison is expressed as the active-condition mean change minus the sham-condition mean change. In these summaries, the active mean change is -5.41 seconds and the sham mean change is 1.7 seconds, producing the posted mean difference of -7.11 seconds.

What does a mean change describe?

In general, a mean is an average that represents the center of a set of measurements. A change score is calculated for each observation by comparing a later measurement with baseline, then summarizing those changes. The sign matters: for walking time, a negative change means less time was recorded at the later measurement than at baseline, while a positive change means more time was recorded. Comparing average changes between conditions asks whether the average movement differs between active and sham treatment.

The standard deviation describes how spread out individual change values are around the mean. It is not the same as the uncertainty in the estimated mean or mean difference. In general, the standard deviation reflects variation among observations, while a confidence interval for a mean difference reflects uncertainty about the estimated contrast. The posted standard deviations are 16.42 for active rTMS and 8.52 for sham rTMS at the immediate assessment. These summaries indicate that individual changes varied, and the variation contributes to the width of the interval around the comparison.

How should the mean difference be read?

The posted mean difference is -7.11 seconds for active relative to sham. A negative estimate means the observed average change was more negative in the active condition. That direction is a description of the point estimate, not a stand-alone determination of benefit or clinical importance. The registry record does not report a threshold for an important difference, and a point estimate does not show how much uncertainty surrounds it.

In general, the crossover structure matters because the same participant may contribute measurements under multiple treatment conditions. An analysis that accounts for pairing can use the within-participant comparison and may differ from a comparison treating observations as independent. Period and carryover effects can also matter in crossover trials. The registry record does not report the original crossover analysis, treatment sequence, period-specific estimates, or a washout description. The posted summary comparison should therefore be interpreted as presented, without assuming which features of the crossover design were accounted for.

What does the confidence interval add?

In general, a confidence interval gives a range of values compatible with the observed data under a specified statistical procedure and its assumptions. It shows the precision of the estimate more directly than the point estimate alone. For the primary mean difference, the posted interval is -16.8 to 2.58. Because this range includes zero, the data are compatible with no difference as well as with differences in either direction. The interval is also broad, so the estimate does not pin down the size of the contrast precisely. The registry record does not state the interval's confidence level or provide the procedure used to construct it.

What does the p-value say?

The posted unadjusted p-value for the primary comparison is 0.15. In general, a p-value measures how unusual results at least as incompatible with a null hypothesis as the observed results would be, if that null hypothesis and the model assumptions were true. It is not a measure of effect size, a probability that the observed result occurred by chance, or a direct measure of clinical importance. An unadjusted p-value does not account for the possibility that many outcomes or comparisons were examined. The registry record does not report the original inferential procedure or any multiplicity adjustment.

The comparison summary is described as an unadjusted re-calculation from posted summary statistics. Such a calculation is a simple contrast of the posted summaries and may not reproduce an original analysis that used participant-level data, crossover pairing, covariate adjustment, or a different model. No discrepancy between the posted comparison and the sponsor's analysis is identified in the registry record, and no reported primary analysis details are listed. This limits what can be concluded about the exact analysis used by the trial team.

Why does variability matter?

In general, over-dispersion means observed variation is greater than a model expects. When that occurs, standard errors based on the simpler model can be too small, making intervals too narrow and p-values too optimistic. The posted outcome is continuous and its reported standard deviations show dispersion, but the registry record does not report a formal assessment of over-dispersion or a model-based adjustment. More generally, the amount and structure of variation must be considered alongside the average difference; a mean alone does not describe the full distribution of participant changes.

The registry record identifies a pilot study, but does not report a formal sample-size justification, a prespecified primary analysis, interim analyses, missing-data methods, or analysis populations. Those elements cannot be inferred from the posted estimates. The planning illustrations are separate from the original trial design and use assumptions stated with those illustrations; they do not demonstrate the power of the completed study.

11. Confidence Intervals and Precision

The primary estimate is a mean difference of -7.11 seconds, with a confidence interval from -16.8 to 2.58. The interval is the key companion to the point estimate: it shows a range of values compatible with the observed data under the interval's statistical procedure. It includes zero, so the results are compatible with no average difference between active and sham conditions. It also includes values on either side of zero, leaving uncertainty about the direction and size of the difference.

The width of the interval indicates limited precision. In general, intervals are narrower when the data contain more information and less variability, and wider when the estimate is less precise. The posted summaries report 14 observations in each condition and substantial standard deviations for change. The registry record does not report the interval's confidence level or how the calculation accounts for the crossover design, so the interval should be interpreted as the one posted rather than as a reconstruction of the original trial analysis.

The two-week walking-time contrast is also uncertain, with its posted interval extending from -16.57 to 3.026. It likewise includes zero. The immediate and follow-up point estimates have a similar direction, but the intervals do not tightly identify the size of any difference. A similar direction across these summaries is not a substitute for a prespecified repeated-measures analysis.

In general, a confidence interval is not a guarantee that the true value lies within its endpoints, nor does it indicate the probability that a particular treatment effect is true. It describes uncertainty under a method and its assumptions. The registry record does not provide a clinically meaningful threshold against which to judge the interval. Thus, the posted estimates leave uncertainty both about statistical separation from zero and about whether any difference would matter in practice.

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 illustrations translate the observed mean difference into hypothetical planning requirements. They show participants per arm for 80% power and participants per arm for 90% power, under the listed planning assumptions. These are participant counts per arm, not total event counts; the event-count convention applies to time-to-event outcomes, which are not the outcome in this trial.

The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect. The rows therefore illustrate planning for the full observed effect, 75% of the observed effect, and 50% of the observed effect. For each assumed effect, the 80% power column gives the participants per arm needed under those assumptions for an 80% chance of detecting that effect if it is real; the 90% column gives the corresponding count for a 90% chance.

Smaller effects require more participants to detect under the same assumptions. The illustration is based on a two-arm calculation and does not establish how a future crossover study should be designed. The original trial's sample-size assumptions and justification are not reported in the registry record. These figures are planning illustrations, not observed power, and they do not describe the probability that the completed pilot produced a true result.

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 = -7.110; pooled standard deviation σ = 13.081.
2. n = 2 × (1.96 + 0.842)² × 13.081² / -7.110² = 53.1, rounded up to 54 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 <- -7.11                      # observed difference in means
sigma <- 13.0806498309526                     # 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(3627416)
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 = 54 (80% power), 72 (90% power)
 75% of observed effect: n per arm = 95 (80% power), 127 (90% power)
 50% of observed effect: n per arm = 213 (80% power), 285 (90% power)
power.t.test: 54.1 
Simulated power at n = 54 per arm: 0.799 (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. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary walking-time endpoint and several secondary outcomes, but does not report a multiplicity strategy. Multiplicity arises when multiple outcomes, time points, or comparisons are tested: even when no true differences exist, repeated testing can make at least one apparently notable result more likely. In general, investigators may address this through a prespecified hierarchy, adjusted significance thresholds, or other methods. The registry record does not say whether any such approach was planned or used.

The posted p-value is identified as unadjusted. It should therefore not be read as accounting for tests across the secondary outcomes or time points. The registry record does not report an analysis plan that specifies which tests were confirmatory, how outcomes were prioritized, or whether any secondary tests were adjusted. That missing information limits the role of secondary findings in strengthening or qualifying the primary result.

The registry record also does not report the missing-data method, the number or reasons for missing outcome observations, or the analysis populations used. Enrollment was 15, while the posted arm summaries contain 14 observations per condition. The record does not explain this difference, so no reason for it can be assigned. Without a stated missing-data approach and participant-level flow, it is difficult to assess whether the outcome summaries represent all randomized participants or how incomplete measurements were handled.

For a crossover study, analysis populations and missingness can be especially relevant because participants may have observations under one treatment condition but not another. The registry record does not report whether the primary analysis required complete paired observations, how incomplete periods were addressed, or whether analyses followed an intention-to-treat principle. The treatment sequence, period effects, carryover assessment, and any corresponding analysis methods are also not reported in the registry record.

These omissions do not establish that the trial lacked an analysis plan or that data were missing; they mean the registry record does not describe those matters. The posted results can be interpreted as recorded summaries, but the available information is insufficient to evaluate the full analysis pathway or the influence of missingness and multiplicity on inference.

15. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: seizure (6.7%).

The adverse-event summary lists 15 participants at risk in each condition. One serious adverse event was reported for active rTMS and none for sham rTMS. The top serious-event terms include seizure, listed as 6.7%. Other adverse events were reported for 4 participants in the active condition and none in the sham condition. No deaths were reported in either condition.

These counts describe the registry's safety summaries; they do not establish that an event was caused by treatment. In a crossover study, safety interpretation may depend on the timing of events in relation to each treatment period and on how participants are counted across conditions. Those details are not reported in the registry record. The outcome summaries list 14 observations per condition, whereas the adverse-event summaries list 15 participants at risk per condition; the registry record does not explain this distinction.

In general, small safety datasets provide limited ability to characterize uncommon events or compare event rates precisely. The posted figures should therefore be read as event counts in this study, not as a complete estimate of risk. The registry record does not provide further event narratives or a detailed attribution assessment.

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

The posted data describe a small randomized, double-masked crossover pilot comparing active rTMS with sham stimulation for short-term changes in walking time. At the immediate assessment, the active condition had a more negative mean change than sham, and the estimated active-versus-sham mean difference was negative. The confidence interval includes zero and extends across values favoring either condition. The point estimate therefore describes the observed direction, while the interval shows that its magnitude and direction remain uncertain.

The two-week walking-time summary has a similar directional pattern, also with an interval that includes zero. This is not enough to establish persistence of a treatment difference. The registry lists other secondary outcomes, but numeric results for those outcomes are not reported in the registry record. The available results consequently do not establish a consistent effect across all measured domains.

In general, a nonsignificant p-value does not prove that there is no effect, just as a point estimate in one direction does not prove that an effect exists. Here, the unadjusted p-value is 0.15, and the estimate is imprecise. The data are compatible with a range of possible differences. The record does not report a clinically meaningful threshold, so statistical estimates cannot be translated into a judgment about practical importance from the registry information alone.

The findings also do not answer questions about longer-term outcomes, everyday mobility, or effects outside the enrolled population. Assessments were described before and after treatment and two weeks later; later follow-up is not reported in the registry record. Details of the crossover analysis, treatment sequence, missing-data handling, and original statistical plan are also not reported. These limits matter when interpreting a comparison whose summaries do not describe how within-participant dependence was handled.

The results should therefore be understood as preliminary estimates from the posted pilot data. They identify a direction of observed change and quantify uncertainty, but they do not establish a definitive treatment effect, its clinical importance, or its durability.

17. Why This Trial Matters Statistically

This trial is statistically notable because it combines a pilot sample with a randomized, double-masked crossover design. Each feature affects interpretation. A pilot can produce useful estimates and reveal the variability of an outcome, but a small dataset generally yields less precise estimates. A crossover can make within-participant comparisons informative, but the analysis must account for repeated observations and the structure of treatment periods.

The posted immediate walking-time estimate is negative for active relative to sham, but its confidence interval spans zero and has considerable width. That pairing of a directional point estimate with an uncertain interval illustrates why results should not be reduced to a single p-value or the sign of an estimate. Precision, outcome variability, and the design-specific analysis all matter.

The registry also gives a basis for discussing future planning without treating the pilot as definitive. The sample-size illustrations show how required participants per arm increase when planning for smaller fractions of the observed effect. Such calculations depend on the stated assumptions and are not evidence that the completed study had adequate power. The trial's original sample-size justification is not reported in the registry record.

Finally, the record highlights the importance of transparent reporting. Details about the crossover analysis, missing data, multiplicity, and analysis populations are not reported, making it difficult to assess how the posted summaries relate to the design and the full set of outcomes. For clinical researchers, the central statistical lesson is to distinguish an observed estimate from the uncertainty around it, and to distinguish planning calculations from evidence generated by the completed study.

18. 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 limitations specific to this trial affect how the posted results can be interpreted. The study was a pilot with planned enrollment of 15, and the primary outcome summaries contain 14 observations in each condition. The registry record does not explain the relationship between enrollment and the outcome counts or give participant flow details. The relatively small outcome summaries and the reported spread in walking-time changes leave the primary comparison imprecise.

The crossover design creates questions that cannot be resolved from the registry record. Treatment sequence, period-specific results, washout details, carryover assessment, and the method used to account for paired observations are not reported. A simple active-versus-sham mean difference may not capture all features of a crossover analysis; the posted information does not establish how those features were handled in the original analysis.

The registry record does not report the trial's original sample-size justification, prespecified statistical plan, interim analyses, or analysis populations. It also does not report methods for missing data, a clinically meaningful threshold for walking-time change, or a multiplicity plan. The unadjusted comparison and lack of posted numeric results for several listed secondary outcomes limit the ability to evaluate the full outcome pattern.

The primary endpoint is a short-term, timed walking task under specified conditions. It does not on its own represent all dimensions of gait, daily function, strength, spasticity, or long-term change. The registry describes a follow-up at two weeks, but later follow-up is not reported. Safety summaries give event counts but not detailed timing or attribution. These limitations constrain interpretation of both efficacy-related summaries and safety information without establishing that unreported procedures were not conducted.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy — NCT03627416.
• Registry record last updated 2021-09-27; status last verified 2021-08.
• Results first posted 2021-09-27.
• 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.

22. Record Summary

The registry record describes a completed randomized, double-masked crossover pilot of active versus sham rTMS for hereditary spastic paraplegia and adrenomyeloneuropathy. Planned enrollment was 15. The primary endpoint was change in 10-meter walking time from baseline to directly after treatment. The posted immediate comparison favors a greater reduction in walking time with active rTMS, but its confidence interval includes zero and the estimate is imprecise.

A two-week walking-time summary has a similar direction and also includes zero within its confidence interval. The registry lists additional secondary outcomes, but numeric results for those measures are not reported in the registry record. The crossover analysis details, original sample-size justification, missing-data methods, multiplicity plan, and analysis populations are not reported. The results are best treated as preliminary estimates rather than a definitive account of treatment effect or clinical importance.