Evaluation of Efficacy and Safety of VX-548 for Painful Diabetic Peripheral Neuropathy (DPN): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Efficacy and Safety of VX-548 for Painful Diabetic Peripheral Neuropathy (DPN) (NCT05660538), a randomized phase 2 study. The primary outcome is Change From Baseline in the Weekly Average of Daily Pain Intensity on a Numeric Pain Rating Scale (NPRS).

2. Clinical Question

The study’s purpose was to evaluate the efficacy and safety of VX-548 doses for painful DPN. The central statistical question is descriptive: how much did the average pain-intensity score change within each group, and how precisely were those group-level changes estimated? A within-group change does not by itself estimate the effect of one treatment relative to another. That requires a direct comparison that accounts for the trial’s analysis plan and uncertainty in both groups.

The primary measure is a patient-reported rating of pain intensity over the preceding 24 hours. Secondary outcomes add other views, including thresholds for pain reduction, sleep interference, global impression of change, and safety. The record contains posted estimates for the primary endpoint and selected secondary outcomes, but no reported analysis results for direct comparisons of the primary endpoint. The conclusions therefore need to distinguish the observed group summaries from comparative evidence.

3. Trial Design

This was a phase 2, randomized, quadruple-masked, parallel-design, active-controlled, dose-ranging study. The registry identifies Vertex Pharmaceuticals Incorporated as the sponsor and records an enrollment of 194. The study began on 2022-12-20, had a primary completion date of 2023-10-12, and is listed as completed. These registry entries describe the design and conduct status; they do not establish how the trial’s statistical analysis was specified.

The four treatment groups represented in the primary outcome results are pregabalin and three suzetrigine doses. Pregabalin was administered at 100 mg 3 times per day for 12 weeks. The suzetrigine groups received 23 mg, 46 mg, or 69 mg once daily for 12 weeks. The registry also lists matched placebos for suzetrigine and pregabalin among the interventions. The posted primary outcome results do not include placebo groups, so the primary results concern the active treatment groups shown in the record.

Randomization is intended to support fair comparisons by assigning participants to treatment groups through a chance-based process. Masking is intended to limit the influence of knowledge about assigned treatment on care, participant reporting, and assessment. The registry labels masking as quadruple but does not report which roles were masked or the procedures used to maintain masking. It also does not report the allocation ratio or details of randomization implementation. Those features should not be inferred from the study’s labels.

The primary endpoint is a continuous measure of change in pain intensity from baseline to Week 12. Its reported parameter is a least-squares mean, with a 95% confidence interval for each group. The outcome population is the mFAS, defined as randomized participants who received at least 1 dose of study drug and were not from Site 115. The record does not report the primary endpoint’s model specification, covariates, handling of repeated measurements, or missing-data method. Consequently, the displayed group estimates can be described, but the statistical details behind their adjustment cannot be reconstructed from the registry record.

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: A total of 194 participants were randomized in this study, out of which 192 participants received the study drug. Of these 192 participants, 19 participants from one of the sites were excluded due to lack of compliance with the study drug. Therefore, 173 participants are reported below for Baseline section and Efficacy outcomes and 192 participants are reported for Safety outcome and Adverse event section.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified Full Analysis Set (mFAS) included all randomized participants who have received at least 1 dose of study drug and are not from Site 115. Here "Overall Number of Participants Analyzed" signifies those participants who were evaluated for this outcome measure.

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.

Population: Baseline data was analyzed based on the Modified Full Analysis Set (mFAS), defined as all randomized participants who have received at least 1 dose of study drug and are not from Site 115.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in the Weekly Average of Daily Pain Intensity on a Numeric Pain Rating Scale (NPRS), measured over Baseline, At Week 12.

The primary endpoint is change from baseline in the weekly average of daily pain intensity on the NPRS, assessed at baseline and Week 12. Participants rated average pain intensity in the last 24 hours on an 11-point scale ranging from 0 to 10, where 0 means no pain and 10 means worst imaginable pain. The endpoint combines repeated daily ratings into a weekly average and then expresses the Week 12 result relative to baseline.

A change score is used to describe how the measured outcome differs from its starting level over the study period. Negative values in this trial indicate a lower pain-intensity score at the endpoint than at baseline; the scale itself does not tell whether a change was caused by treatment. A comparison between randomized groups is needed to estimate how outcomes differ under the assigned treatments. The registry’s primary endpoint results present each group’s least-squares mean change and 95% confidence interval, but do not report a direct inferential comparison between suzetrigine and pregabalin for this outcome.

General statistical explanation: A continuous score retains more information about the amount of change than a binary threshold does. It can distinguish different magnitudes of change rather than classifying participants only as having or not having crossed a chosen cutoff. The weekly averaging also summarizes daily ratings, though the registry does not report further details about how daily observations were handled when ratings were missing.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical explanation: The primary outcome is continuous, so its reported estimate is a least-squares mean change rather than a proportion of participants. A least-squares mean is a model-based group mean. Depending on the analysis model, it may account for specified features such as baseline values or other covariates. The registry identifies the estimate as a least-squares mean but does not report the model, covariates, or adjustment details. It is therefore not possible to say which factors, if any, were included in its calculation.

A 95% confidence interval expresses the uncertainty associated with an estimate under the assumptions of the method used to calculate it. In repeated use of the same procedure under its assumptions, intervals would cover the target value at the stated rate. For these results, each interval concerns a group’s mean change. It does not directly answer whether a suzetrigine group differs from pregabalin. A difference estimate and its own interval would be needed for that comparison. Comparing whether separate group intervals overlap is not a replacement for calculating the interval around a treatment contrast.

General statistical explanation: The sign and scale of a change estimate must be interpreted using the outcome’s definition. Here, lower NPRS values represent less reported pain intensity on the rating scale, so negative change values describe a lower score relative to baseline. The numeric direction alone does not establish the cause of change. Changes may reflect multiple influences over time, and a randomized comparison is needed to assess differences associated with assignment to treatment.

For binary secondary outcomes, each participant is classified according to whether a stated reduction threshold was met. The posted values are percentages of participants. The recalculated comparisons express the difference between a suzetrigine group’s observed proportion and the pregabalin group’s observed proportion as a risk difference, with a confidence interval and an unadjusted p-value. These are simple unadjusted recalculations from the posted summary statistics, not reported sponsor analyses. They do not incorporate any adjustment or modeling that may have been used in an analysis not present in the registry record.

A risk difference is expressed on the probability scale. Its confidence interval represents uncertainty in the difference, not uncertainty in either percentage alone. If the interval includes zero, the data are compatible with no difference under that calculation, as well as with differences in either direction within the interval. A p-value measures how unusual data at least as discrepant as those observed would be under a specified null hypothesis and test assumptions. It is not the probability that the null hypothesis is true, nor a measure of clinical importance. Because these comparisons are unadjusted and secondary, a small p-value does not by itself establish a reliable treatment effect.

The record reports no sponsor analyses for the posted secondary comparisons. The calculated pairwise estimates should therefore be kept separate from trial-reported inferential conclusions. When sponsor analyses are available, their prespecified methods and results take precedence over simple recalculations. The discrepancy indicator is false for the posted calculations, but that does not transform them into prespecified analyses or resolve the absence of a reported statistical plan.

The planning illustrations are based on observed effects and are not observed power. They describe hypothetical sample sizes under the stated planning assumptions: a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect set to the stated fraction of the observed effect. The figures are participants per arm for 80% or 90% power. They illustrate how a planning target changes when the effect to detect is smaller or larger under those assumptions; they do not show the trial’s actual design rationale, the chance that this completed trial detected an effect, or a sponsor’s sample-size justification. The registry record does not report that justification.

General statistical explanation: Planning from an observed effect is particularly uncertain because the observed estimate itself varies from sample to sample. A planning illustration based on that estimate can overstate or understate the effect likely to recur. A smaller target effect generally requires a larger sample under otherwise fixed assumptions, but this general relationship does not validate any particular planned or observed treatment effect. The illustrations should be read as conditional calculations rather than a statement about the trial’s adequacy.

The record reports an mFAS for the primary outcome: randomized participants who received at least 1 dose of study drug and were not from Site 115. It clarifies that the reported number analyzed refers to participants evaluated for the outcome. This definition is not identical to a claim that every randomized participant contributed an endpoint measurement. The registry does not report why Site 115 was excluded, how missing data were treated, whether sensitivity analyses were performed, or whether other analysis populations were used.

Different secondary endpoints use different outcome definitions and can have different numbers analyzed. A threshold outcome discards information about the precise amount of change by grouping participants according to whether they reached a cutoff. The continuous primary score and threshold outcomes therefore answer related but not interchangeable questions. Their estimates can show different patterns without necessarily being inconsistent.

General statistical explanation: Over-dispersion matters when binary or count data vary more than a statistical model assumes; standard errors can then be too small if that extra variation is ignored. The registry’s recalculated secondary comparisons use simple summary-statistic methods, and no over-dispersion adjustment is reported. This is not evidence that over-dispersion occurred in this trial. Rather, it illustrates why the method and its assumptions matter, particularly when event counts are limited or proportions are near the edge of their possible range.

The registry record does not report an interim analysis, an analysis plan, multiplicity control, or the full methods for handling outcome data. In their absence, interpretation should remain anchored to the stated outcome definitions, group estimates, and uncertainty, while avoiding claims about unreported procedures.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report how multiplicity was handled. The study includes a primary pain-intensity endpoint and secondary measures that include sleep interference, multiple pain-reduction thresholds, patient global impression, and safety. Comparisons across several outcomes, doses, and thresholds create multiple opportunities for an apparently unusual result. Without a prespecified testing hierarchy or an adjustment method, unadjusted secondary p-values do not control the overall false-positive risk across all those questions. The record also does not identify which secondary outcomes, if any, were intended as confirmatory.

The posted primary results give group estimates and confidence intervals but do not report a direct inferential comparison between suzetrigine and pregabalin. The registry lists no reported analyses for the comparisons recalculated from the secondary summary data. Those recalculations are unadjusted, and they should not be mistaken for the sponsor’s analysis plan or results. The registry record does not report whether interim analyses were conducted.

The primary analysis population is the mFAS, defined as randomized participants who received at least 1 dose of study drug and were not from Site 115. The record says that the number analyzed for an outcome means the participants evaluated for that outcome. The primary outcome counts and the secondary outcome counts differ by endpoint and group. The registry does not explain these differences, state why Site 115 was excluded, or detail the handling of unavailable outcome measurements.

Missing-data methods can affect estimates when participants with unavailable outcomes differ from those with observed outcomes. General statistical explanation: Complete-case summaries rely on the observed measurements, while other approaches may use modeling or assumptions about unobserved values. Each method answers under different assumptions, and sensitivity analyses can explore how conclusions change under alternatives. The registry record does not report which method was used for the primary endpoint, whether imputation was applied, or whether sensitivity analyses were conducted. These omissions limit assessment of how robust the estimates are to missing data.

The record also does not report a statistical analysis plan, primary-endpoint model details, or sample-size justification. Those elements cannot be reconstructed from the posted results. Their absence is an evidence gap, not proof that the procedures were not conducted.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: atrial fibrillation (1.9%), cellulitis (1.8%), hypoglycaemia (1.8%), arteriosclerosis (1.8%).

The registry reports serious adverse event counts among participants at risk in each group. For pregabalin, 1 participant was reported with a serious adverse event among 54 at risk; the low-dose suzetrigine group reported 0 among 28; the mid-dose group reported 2 among 55; and the high-dose group reported 1 among 55. The registry also reports other adverse event counts: 12 among 54 for pregabalin, 4 among 28 for low-dose suzetrigine, 5 among 55 for mid-dose suzetrigine, and 7 among 55 for high-dose suzetrigine. These are participant counts, not estimates of comparative risk adjusted for differences in group size or follow-up.

Deaths were reported as 0 for pregabalin, 0 for low-dose suzetrigine, 1 for mid-dose suzetrigine, and 0 for high-dose suzetrigine. These counts do not establish whether an event was caused by a study treatment. The registry lists atrial fibrillation at 1.9%, cellulitis at 1.8%, hypoglycaemia at 1.8%, and arteriosclerosis at 1.8% among its top serious-event terms; the record does not assign these listed terms to a specific treatment group in the information.

Small counts are inherently imprecise, and an absence of reported events in a group is not proof that the underlying risk is zero. The registry record does not provide enough detail to assess event timing, duration, relatedness, or exposure-adjusted comparisons. These safety summaries describe what was reported; they are not a basis for medical advice or a definitive ranking of treatments.

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

The posted primary results show negative mean changes in weekly average daily NPRS pain intensity from baseline to Week 12 in all four reported groups. The estimates describe the analyzed participants and have 95% confidence intervals that quantify uncertainty in each group’s mean change. The registry record does not report a direct inferential comparison of the primary outcome between suzetrigine and pregabalin, so the within-group estimates cannot establish whether one treatment produced a greater change than another.

The results also do not establish that the treatments caused the observed changes. Randomization is a design feature that can support causal comparisons, but interpretation depends on a relevant between-group analysis, appropriate methods, and assumptions about outcome data. The reported group summaries alone do not supply that complete comparative inference. The record’s missing details on model specification, missing-data handling, multiplicity, and sample-size justification further limit what can be concluded from the registry entry.

Secondary outcomes offer descriptive information about threshold responses, sleep interference, global impression, and safety. They do not all measure the same construct, and the pain-threshold patterns are not uniform across dose levels and cutoffs. The secondary comparisons are unadjusted recalculations rather than reported sponsor analyses, and the registry does not report a multiplicity strategy. They should not override the limitations of the primary outcome results or be treated as conclusive evidence on their own.

The study’s enrollment, phase, masking label, and completion status describe its registry record but do not establish the precision or validity of every estimate. Outcome-specific analyzed counts are smaller than the enrollment figure, and the reasons and missing-data procedures are not reported. Safety counts are also descriptive and cannot establish causation or precisely characterize uncommon events.

In short, the registry supports a description of mean pain-score change and other posted outcomes in the listed groups. It does not support a definitive comparative claim about suzetrigine versus pregabalin from the primary endpoint results alone. Statistical interpretation should keep the distinction clear between an observed change, an estimated treatment contrast, and a conclusion about treatment effects.

13. Why This Trial Matters Statistically

This trial is statistically informative because it reports a continuous primary pain measure alongside several threshold-based secondary outcomes. That combination highlights a common interpretive issue in clinical research: average change and the proportion reaching a chosen response threshold summarize different features of the outcome. Their patterns can differ without either measure being erroneous, and readers need to keep the endpoint definitions in view.

The active-control structure and three suzetrigine doses also make the distinction between descriptive dose patterns and a formal dose-response analysis important. The posted primary means do not show a steadily increasing change across dose levels, but the registry does not report a dose-response test. Describing the observed pattern is possible; attributing statistical evidence to it is not.

The record further illustrates why precision and comparison must be separated. Group-level confidence intervals show uncertainty around mean changes, but they do not substitute for an interval and test of the difference between groups. A randomized design is valuable for comparative questions, yet the relevant primary contrast is not reported in the registry results. Readers should not infer it by subtracting group estimates or comparing separate intervals.

Finally, the secondary recalculations and planning illustrations have narrower roles. Unadjusted comparisons can help describe the posted summaries, but they do not replace prespecified analyses or account for multiple testing. Planning figures based on observed effects illustrate conditional sample-size requirements under stated assumptions; they are not observed power or evidence that the original design was adequate. These distinctions help prevent descriptive statistics from being read as stronger evidence than they contain.

14. 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 are specific to the information recorded for this trial. The primary outcome is reported as separate least-squares mean changes by treatment group, without a reported treatment contrast, its confidence interval, or its p-value. As a result, the registry entry does not provide the main comparative estimate needed to assess the primary question statistically. The model behind the least-squares means is also not described, so the adjustment and assumptions cannot be evaluated.

The primary analysis population excludes participants from Site 115, in addition to requiring randomization and receipt of at least 1 dose. The record does not explain the site exclusion or state whether it was planned. Outcome-specific analyzed counts vary, and the reasons for those differences are not reported. Missing-data methods and sensitivity analyses are also not reported, which limits assessment of whether the results depend on assumptions about participants without evaluated outcomes.

The registry lists matched placebos as interventions, but placebo groups are not present among the reported primary outcome arms. The available summaries therefore do not provide a placebo comparison for this endpoint. The registry also does not specify the roles covered by quadruple masking, the randomization procedure, the allocation ratio, or the details of the active-control comparison.

For secondary outcomes, no sponsor analyses are reported for the comparisons recalculated from summary statistics. The recalculated comparisons are unadjusted, and the record does not report multiplicity control or identify confirmatory secondary outcomes. The safety summaries are counts, with limited information about event timing, relatedness, or exposure. These constraints mean that descriptive patterns should not be interpreted as definitive comparative evidence.

The record does not report a sample-size justification, statistical analysis plan, or interim-analysis information. Planning illustrations based on observed effects cannot fill those gaps. These limitations concern what can be assessed from the registry record; they do not establish that unreported procedures were not performed.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluation of Efficacy and Safety of VX-548 for Painful Diabetic Peripheral Neuropathy (DPN) — NCT05660538.
• Registry record last updated 2025-07-01; status last verified 2025-06.
• Results first posted 2025-07-01.
• 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.

18. Record Summary

NCT05660538 is a completed phase 2 randomized, quadruple-masked, parallel, active-controlled, dose-ranging study of VX-548 for painful DPN. The registry records enrollment of 194 and identifies Vertex Pharmaceuticals Incorporated as the sponsor. The primary outcome is change from baseline in weekly average daily NPRS pain intensity at Week 12, reported as least-squares mean changes with 95% confidence intervals for pregabalin and three suzetrigine dose groups.

All reported primary group estimates are negative, but the registry does not report a direct comparative analysis for that endpoint. Secondary outcomes include pain-reduction thresholds, sleep interference, patient global impression, and safety. The registry record does not report the statistical plan, multiplicity approach, missing-data methods, or sample-size justification. The posted results support descriptive interpretation, with important limits on comparative conclusions.