Safety of New Formulation of Glatiramer Acetate: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of New Formulation of Glatiramer Acetate (NCT00947752), a randomized phase 3 study. The primary outcome is Subject-reported Pain Associated Immediately After Each Injection.

2. Clinical Question

This is a question about a patient-reported experience rather than a directly observed clinical event. The score captures the participant’s own rating of pain after an injection. The registry description also identifies injection-site reactions and side effects as study interests, but the posted primary endpoint is specifically pain associated immediately after each injection.

The result should be read as a comparison of average scores in this trial, not as a statement about every participant’s experience. A difference between group means can coexist with variation among individuals, and the reported standard deviations indicate that scores varied within each formulation group. The registry record does not report how individual responses changed across the crossover periods or how the sequence of formulations was handled in the analysis.

3. Trial Design

The registry identifies this as a phase 3, randomized, open-label, multicenter crossover study. Its title describes an evaluation of the tolerability and safety of two formulations of glatiramer acetate for subcutaneous injection. The study status is completed. The registry lists enrollment as 147 and gives a start date of 2009-07 and a primary completion date of 2009-09.

The comparison was between F1, glatiramer acetate 20mg/1.0ml, and F2, glatiramer acetate 20mg/0.5ml. Randomization means assignment was described as randomized, but the registry record does not report the allocation sequence, concealment procedures, or the method used to generate assignments. Masking is listed as none, so participants and study personnel were not described as blinded.

A crossover design compares interventions across periods rather than limiting the comparison to separate parallel groups. In general, such a design can make observations from the same participant relevant to more than one intervention, but the registry record does not give the treatment sequence, period structure, washout arrangements, or the analysis method for accounting for within-participant correlation. Those details matter to understanding how the reported mean difference was estimated. They cannot be reconstructed from the design label alone.

The primary outcome was subject-reported pain associated immediately after each injection, measured during 5 weeks of injections. The registry also posts a secondary outcome for degree of pain within 5 mins after injection. It lists 2 outcome measures, but does not report any analyses under the trial-level analysis count, and the secondary record lists no reported analyses. The posted outcome summaries therefore give descriptive statistics and a comparison estimate, but they do not disclose a complete statistical analysis plan.

The registry record does not report the trial’s original sample-size justification, intended precision, planned primary analysis, prespecified handling of missing observations, or the crossover-specific statistical model. The planning illustrations are calculations based on the observed effect, not evidence of the assumptions that guided the trial’s design.

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.

Before assignment: To ensure the standardization, all study sites were instructed to train subjects to complete the daily diary, with special attention to the Visual Analog Scale (VAS) used to measure pain.

7-Day Run-in Treatment Period

1st 14-day Treatment Period

Crossover to 2nd 14-day Treatment Period

Analysis population for the primary outcome, as defined in the registry: Of the 147 subjects to be analyzed, 3 were excluded for discontinuations due to withdraw of consent.

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 Subject-reported Pain Associated Immediately After Each Injection, measured over 5 weeks of injections.

The primary endpoint is subject-reported pain associated immediately after each injection. Participants rated their experience on a visual analog scale (VAS), marking a continuous line between endpoints. The registry describes 0 mm as “no pain” and 100 mm as “worst possible pain.” A higher score therefore represents a report closer to the worst-pain endpoint, while a lower score represents a report closer to no pain.

Pain is subjective and cannot be measured directly in the way a laboratory value can. A VAS is used to translate a participant’s perception into a quantitative score so that scores can be summarized and compared. The endpoint’s relevance is that injection pain is an experience reported by the person receiving the injection, and the study’s purpose explicitly includes comparing pain associated with injections.

The primary measure is a mean, with standard deviation describing the spread of scores within each formulation group. The posted mean for F1 was 11.89, with standard deviation 14.32; for F2, the mean was 8.64, with standard deviation 10.82. These summaries describe the observed distributions at the group level and do not show the full range of responses or how each participant’s score changed across the crossover periods.

The outcome is distinct from injection-site reactions and from broader side effects. Although those topics are described in the study purpose, the primary endpoint reported in the registry is the immediate post-injection pain score. The record does not report additional detail about the exact timing of every primary rating beyond the outcome title and the stated 5 weeks of injections.

7. Results Posted in the Registry

• F2 Glatiramer Acetate 20mg/0.5ml: mean 8.64 versus 11.89 on control; difference -3.25 (95% CI -6.18 to -0.32), standardized effect d = -0.26; z-test p = 0.030.

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.

Degree of Pain Within 5 Mins After Injection

• 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:
  • F2 Glatiramer Acetate 20mg/0.5ml: mean 11.85 versus 17.19 on control; difference -5.34 (95% CI -9.15 to -1.53), standardized effect d = -0.32; z-test p = 0.006.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for F2 Glatiramer Acetate 20mg/0.5ml than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry posts a secondary endpoint for degree of pain within 5 mins after injection. It follows the same broad direction as the primary endpoint: the posted F2 mean is lower than the F1 mean, and the unadjusted comparison is negative. The secondary record includes a confidence interval and an unadjusted p-value, but no reported analysis entry explaining how that result was generated.

This directional agreement is relevant as a pattern across the posted pain outcomes. It suggests that the secondary pain measure does not point in the opposite direction from the primary result. However, the outcomes are related measures of injection pain, so agreement between them should not be treated as independent confirmation. Their relationship and the precise timing of the ratings could make the results correlated.

The secondary finding carries less weight than the primary endpoint for interpreting the trial’s main question. The registry identifies pain immediately after each injection as primary, while the within-5-minutes measure is secondary. Secondary results are often more exploratory, and the registry record does not report a multiplicity adjustment or a prespecified hierarchy for interpreting secondary outcomes. An unadjusted p-value does not account for the possibility of examining multiple outcomes.

The record lists 2 outcome measures, while one secondary outcome is posted. It does not include reported analyses for the secondary endpoint. This limits assessment of the analysis population, model, and missing data, just as it does for the primary comparison. The secondary pattern can be described as consistent in direction, but it should not replace the primary result or be treated as decisive evidence on its own.

More broadly, the posted secondary result concerns pain, not every aspect of tolerability or safety named in the study purpose. It cannot be used to fill gaps in unreported injection-site reaction analyses or other side-effect outcomes. The registry record does not report a comprehensive secondary-outcome analysis plan.

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

• Degree of Pain Within 5 Mins After Injection

9. Statistical Interpretation

10. Statistical Methods Explained

Continuous outcome summaries describe measurements that can take values along a scale. For this endpoint, the registry reports the mean and standard deviation for each formulation. The mean is the arithmetic average of the recorded scores. The standard deviation describes how dispersed the scores are around that average: greater spread means observations tend to lie farther from the mean. These two summaries are informative, but they do not show the shape of the score distribution or the pattern of individual participant responses.

The comparison is expressed as a mean difference, with F2 compared against F1. A negative estimate indicates that the F2 mean is lower than the F1 mean on this scale. The estimate is -3.25. The sign depends on the stated comparison direction; reversing the order of the formulations would reverse the sign without changing the underlying contrast. Interpreting the direction also requires knowing the scale: in this case, higher VAS scores correspond to more pain, so a lower score indicates lower average reported pain.

General: a confidence interval is a range of estimates compatible with the observed data and the statistical procedure used to calculate it. It conveys uncertainty around a point estimate; it is not a range containing every participant’s score, and it is not a guarantee that the true value lies within the displayed limits. The primary interval runs from -6.183 to just below zero. The registry does not report the interval’s confidence level or the method used to calculate it, so those details should not be inferred.

The posted p-value is unadjusted. General: a p-value measures how strongly the data conflict with a null hypothesis under the assumptions of a statistical test. It does not indicate the probability that a treatment effect is real, quantify the size of an effect, or provide a measure of clinical importance. The primary unadjusted p-value is 0.03. The registry record does not describe the test statistic, degrees of freedom, covariance assumptions, or any model terms used to produce that value.

General: a standard error describes the sampling uncertainty of an estimate, whereas a standard deviation describes variation among observations. The posted record includes standard errors for the arm means as well as standard deviations. A standard error is not a measure of how much individual scores vary; it reflects the precision of an estimated mean under the assumptions of its calculation. Because the crossover-specific analysis is not reported, the interpretation of the listed standard errors should remain tied to the summaries as posted.

General: crossover data can have within-participant dependence because observations from the same person may be more alike than observations from different people. An analysis that accounts for this dependence may differ from a method that treats all observations as independent. Period effects, treatment sequence, and carryover may also be relevant design considerations in crossover research. The registry record does not report how these issues were addressed, so no particular adjustment or model can be attributed to the investigators.

Over-dispersion is a general concern when a statistical model assumes less variability than is present in the data. If variation is understated, standard errors can be too small and uncertainty can appear narrower than warranted. For this continuous VAS outcome, the posted standard deviations show substantial variation in the scores, but the record does not report a dispersion diagnostic or a model assessment. Over-dispersion should not be asserted as a finding in this trial; it is a general reason to examine whether model assumptions match the data.

Randomization supports a comparison based on assigned interventions when allocation and analysis are properly handled, but a registry designation of randomized does not supply every detail needed to assess that process. The record does not describe allocation concealment, the randomization procedure, or whether the posted outcome analysis followed assignment or used another population definition. It also does not report a protocol-defined analysis population beyond the endpoint description that says 3 discontinuations due to withdrawal of consent were excluded from the 147 subjects to be analyzed.

The registry lists 144 observations for each formulation in the posted primary result. The identical entries do not, on their own, establish how many participants contributed paired observations, whether missing ratings were imputed, or whether all available measurements were used. The record does not report a missing-data method or a sensitivity analysis. No assumptions about missingness can therefore be checked from the posted summaries.

The listed p-value and confidence interval are useful descriptions of the reported contrast, but they cannot substitute for a statistical analysis plan. The registry record does not report the prespecified model, multiplicity strategy, analysis population, or whether the primary analysis accounted for the crossover structure. A detailed protocol or analysis report would be needed to evaluate those choices; they are not reported in the registry record.

11. Confidence Intervals and Precision

The primary estimate is a mean difference of -3.25 points, with a confidence interval from -6.183 to just below zero. The interval communicates uncertainty in the estimated average contrast. It is not an interval for individual participant scores, and it does not describe the full range of pain ratings in either formulation group.

The interval is entirely on the negative side of zero, but its endpoint nearest zero is close to that boundary. This means that the posted range includes estimates pointing toward a relatively small negative difference as well as estimates farther from zero. The result is therefore more informative about the direction of the average contrast than about a precisely established magnitude. The registry record does not state the confidence level or interval-calculation method.

The group standard deviations, 14.32 for F1 and 10.82 for F2, describe variability in reported scores. They are not confidence intervals and should not be read as the precision of the mean difference. The mean difference’s precision depends on the analysis and the way the data were collected, including the crossover structure. Since that method is not reported, the uncertainty estimate cannot be independently assessed from the registry record alone.

Precision is also distinct from importance. A narrow interval would indicate more precision, but would not by itself establish that a difference matters to participants. Conversely, an interval’s location relative to zero does not establish whether its values correspond to meaningful changes in pain. The registry record does not report a threshold for a clinically important difference on the VAS.

The posted p-value, 0.03, offers a related but different summary of the data under a null model. It does not convey the range of plausible effect sizes as directly as the interval, and it does not resolve the limitations of the unreported analysis details. The estimate, interval, variation in scores, and outcome scale should be considered together.

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 planning figures are participants per arm, not total event counts. The sample-size assumptions state that these illustrations use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to a stated fraction of the observed effect. The original trial’s sample-size assumptions and justification are not reported in the registry record.

The 80% power column describes the planned number of participants per arm for a design with an 80% chance of detecting the specified effect under the listed assumptions, if that effect and the model assumptions were correct. The 90% power column describes the corresponding planning target for a 90% chance under those assumptions. These are design calculations, not measures of what happened in the completed trial.

The rows use planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For the primary outcome, those rows give 240, 426, and 959 participants per arm for 80% power, and 321, 571, and 1,283 participants per arm for 90% power. Smaller effects require more participants to detect under the same assumptions, which is why the participant targets rise as the assumed fraction of the observed effect falls.

The curve is a visual representation of how the planning target changes with the assumed effect size. It should be read as an illustration conditional on the stated assumptions, not as a record of the trial’s actual design process. The observed enrollment and posted outcome counts do not validate the planning assumptions. These calculations are not observed power.

Because the effect sizes used in the illustration are based on the observed result, the figures are sensitive to uncertainty in that result. They are not evidence that the original investigators planned around those values, and they do not indicate how many participants would be needed for a different outcome or analysis model.

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 = -3.250; pooled standard deviation σ = 12.696.
2. n = 2 × (1.96 + 0.842)² × 12.696² / -3.250² = 239.6, rounded up to 240 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 <- -3.25                      # observed difference in means
sigma <- 12.6961854507565                     # 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(947752)
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 = 240 (80% power), 321 (90% power)
 75% of observed effect: n per arm = 426 (80% power), 571 (90% power)
 50% of observed effect: n per arm = 959 (80% power), 1,283 (90% power)
power.t.test: 240.5 
Simulated power at n = 240 per arm: 0.795 (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

Multiplicity arises when more than one outcome, comparison, subgroup, or analysis is examined. In general, evaluating multiple results can increase the chance that at least one appears unusual by chance. Statistical plans may address this through prespecified outcome hierarchies, adjustment procedures, or other strategies. The registry record does not report a multiplicity strategy for this trial.

The record identifies a primary pain outcome and a secondary pain outcome, and lists 2 outcome measures. The posted primary and secondary comparison p-values are described as unadjusted. No correction or decision rule for interpreting multiple outcomes is reported. Accordingly, the secondary result should be interpreted cautiously, and the primary p-value should be understood as unadjusted rather than as evidence that multiplicity was handled.

The registry gives no reported analyses under the trial-level analysis count, and the secondary record lists no reported analyses. It does not state whether a prespecified analysis plan included additional outcomes, subgroup analyses, interim looks, or other comparisons. Such procedures are not reported in the registry record and should not be inferred.

Missing-data reporting is limited. The primary outcome description states that 3 subjects were excluded for discontinuations due to withdrawal of consent from the 147 subjects to be analyzed. The arm summaries list 144 for each formulation. The registry does not explain how missing observations at particular injection times were handled, whether participants contributed partial records, or whether any imputation or sensitivity analyses were conducted.

The registry also does not define a full analysis population, such as an intention-to-treat or per-protocol population. The endpoint description gives a brief exclusion statement, but it does not specify all eligibility rules for the analysis or how deviations from treatment sequence were handled. That omission is especially relevant to a crossover study, where periods and within-participant observations can contribute to the analysis.

Finally, the registry record does not report the original statistical analysis plan, the primary model, the treatment of crossover effects, or the rationale for the sample size. These omissions limit independent assessment of prespecification, robustness, and the relationship between the posted summaries and the planned analysis.

15. Safety Results

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

Other (non-serious) adverse events

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

The registry lists serious adverse events and other adverse events separately for each formulation. For both F1 and F2, the posted figures show 0 serious adverse events among 147 at risk and 0 other adverse events among 147 at risk. These are the adverse-event figures recorded for the groups; they are not the pain-score results.

These counts should be read as events reported in the registry, not as proof that no adverse experiences occurred outside the recorded categories or reporting period. The registry record does not provide event terms for serious adverse events, and no serious-event terms are listed. Death counts are not reported in the registry record.

The event figures are separate from the primary endpoint and do not resolve the interpretation of the pain comparison. They also do not establish that the formulations have identical safety profiles. The record does not give event definitions, monitoring detail, exposure-adjusted rates, or a safety analysis method. The counts are therefore a limited description of what was posted, rather than a complete characterization of safety.

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

The primary result describes a lower average immediate post-injection pain score for F2 than for F1 in the posted summaries. The estimated mean difference is -3.25 points, and the confidence interval runs from -6.183 to just below zero. The unadjusted p-value is 0.03. Together, these figures describe the direction and statistical uncertainty of the posted comparison, subject to the analysis details that the registry does not report.

The result does not establish how any particular participant would rate pain, whether individual participants consistently preferred one formulation, or whether every injection produced the same experience. The standard deviations show variation in scores, and group means cannot show the distribution of individual changes. Nor does a difference in average score alone establish the importance of that difference to participants. The registry does not report a threshold for meaningful change on this scale.

The result also does not answer every question about the formulations. The primary endpoint concerns reported pain immediately after injection. It is not, by itself, a comprehensive measure of injection-site reactions, all side effects, long-term outcomes, or comparative safety. The posted adverse-event counts provide a separate and limited record of events.

Important analysis details are absent. The registry does not explain how the crossover structure was handled, how missing observations were treated, or whether the statistical procedure was prespecified. Those omissions make it difficult to assess whether the posted uncertainty fully reflects the design and available data.

In general, statistical evidence and clinical importance are related but distinct. A p-value and confidence interval characterize the data under a statistical framework; they do not decide whether a difference matters in practice. The posted information supports a careful description of the observed score contrast, not a treatment recommendation or a broad conclusion about efficacy or safety.

17. Why This Trial Matters Statistically

This trial is statistically instructive because it combines a patient-reported continuous outcome with a randomized crossover design. The VAS turns a subjective pain experience into a quantitative score that can be summarized by means and standard deviations. That makes the result interpretable as an average difference, while also requiring care not to mistake a group average for an individual experience.

The crossover label highlights the importance of matching the analysis to the design. Measurements from the same participant may be correlated, and period or sequence effects can matter. The registry record does not report how those features were addressed. Thus, the design is visible in the registration, but the methods needed to evaluate its statistical implementation are not.

The primary estimate and confidence interval also illustrate why effect size and precision should be considered together. A negative mean difference conveys direction, while the interval indicates uncertainty around that estimate. The group standard deviations show that scores varied considerably. Looking only at the unadjusted p-value would omit both the size of the contrast and the spread in reported pain.

The planning illustration offers another statistical lesson: sample-size targets depend on the effect selected for planning. Smaller assumed effects lead to larger participant requirements under the stated assumptions. Because the original sample-size rationale is not reported, the illustration should not be mistaken for a reconstruction of the investigators’ design decisions.

Finally, this record demonstrates the value of distinguishing posted results from unreported methods. Outcome summaries can describe what was recorded, but missing analysis details constrain assessment of multiplicity, missing data, and crossover handling. Recognizing those boundaries is part of interpreting trial statistics accurately.

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.

The registry record provides limited detail about the trial’s statistical conduct. It identifies a randomized open-label crossover design but does not report the allocation procedure, treatment sequence, period structure, washout arrangements, or whether the primary comparison accounted for within-participant correlation. This leaves uncertainty about how the posted contrast relates to the crossover design.

The outcome information is also incomplete for evaluating individual-level data. The record provides means, standard deviations, and group entries of 144, but does not describe paired observations, changes within participants, score distributions, or missing ratings across injection times. It reports that 3 subjects were excluded after withdrawing consent, but gives no further missing-data method or sensitivity analysis.

The registry does not report a primary analysis model, a multiplicity plan, or a detailed statistical analysis plan. It does not state the confidence level or method for the displayed interval, or the test used to obtain the unadjusted p-value. Without these details, independent verification of the inferential results is limited.

The primary outcome is a self-reported pain rating. This is appropriate to describing a subjective experience, but the registry does not report a threshold for a meaningful difference on the VAS. The group summaries also cannot show whether the observed average difference reflects a broadly shared experience or a pattern concentrated among some participants.

Safety information is sparse. The registry posts zero serious and zero other adverse events in the listed groups, but does not report event terms, deaths, monitoring detail, or a fuller safety analysis. These limitations mean that the record supports a bounded reading of the posted endpoint summaries, rather than a comprehensive assessment of tolerability or safety.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety of New Formulation of Glatiramer Acetate — NCT00947752.
• Registry record last updated 2017-03-14; status last verified 2017-02.
• Results first posted 2011-06-09.
• 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

NCT00947752 is a completed phase 3 randomized, open-label, multicenter crossover study comparing glatiramer acetate 20mg/1.0ml with glatiramer acetate 20mg/0.5ml in relapsing remitting multiple sclerosis. The registry lists enrollment as 147, a start date of 2009-07, and a primary completion date of 2009-09.

The primary endpoint was subject-reported pain immediately after each injection during 5 weeks of injections, measured with a VAS. The posted means were 11.89 for F1 and 8.64 for F2. The estimated mean difference for F2 relative to F1 was -3.25, with a confidence interval from -6.183 to just below zero and an unadjusted p-value of 0.03.

The record also posts a secondary pain outcome and adverse-event figures. It does not report the crossover-specific analysis method, the original sample-size justification, a multiplicity strategy, or detailed missing-data handling. These omissions constrain interpretation of the posted estimates.