Ricolinostat in Patients With Painful Diabetic Peripheral Neuropathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ricolinostat in Patients With Painful Diabetic Peripheral Neuropathy (NCT03176472), a randomized phase 2 study. The primary outcome is Change in Mean Average Pain Intensity (NRS).

2. Clinical Question

3. Trial Design

The registry describes NCT03176472 as a phase 2, randomized, double-blind, placebo-controlled, parallel-group study sponsored by Regenacy Pharmaceuticals LLC. The condition under study was painful diabetic peripheral neuropathy. The record lists quadruple masking, while the brief summary describes the study as double-blind. Both descriptions indicate masking, but the registry record does not explain how the masking terminology is applied.

Participants were assigned to ricolinostat or placebo. Ricolinostat was taken by mouth once daily as a 120 mg dose in a 12 mL liquid formulation; the placebo was a 12 mL liquid formulation with no active ingredient. The parallel-group structure means the reported comparison is between separate treatment groups rather than a crossover in which participants receive both assignments.

The registry lists an enrollment of 282. Its brief summary describes a design for up to 274 evaluable patients. The primary outcome population is defined by availability of measurements at both baseline and the specified visit. The primary endpoint compares baseline-week average pain intensity with the final week at 12 weeks. The secondary outcome listed is change in non-pain neuropathic signs measured with UENS at Week 12.

The study start date is 2020-12-07, primary completion is listed as 2022-10-31, and status is completed. The registry record does not report the original statistical design assumptions, the allocation ratio, or details of the randomization procedure. The posted results include group summaries and endpoint contrasts, but no reported analyses are listed for the secondary outcome.

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.

Double Blind Treatment Period

Reasons for not completing this period:

Open Label Extension

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The number of subjects with non-missing values at both Baseline and specified visit.

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: The Intent To Treat (ITT) Population is defined as all randomized subjects regardless of study drug administration

6. Primary Endpoint

The registry lists the primary outcome as Change in Mean Average Pain Intensity (NRS), measured over Baseline week [Day-7 to Day 1] compared to Final week [12 Weeks].

The primary endpoint is change in mean average pain intensity measured with an 11-point numerical pain rating scale. The scale runs from 0, meaning no pain, to 10, meaning the worst pain. The registry defines the comparison period as the baseline week, Day-7 to Day 1, against the final week at 12 weeks.

A pain-intensity score is a continuous measure: each participant contributes a numerical rating, and the group result is summarized as a mean with a standard deviation. Change from baseline focuses on how ratings differ over time within the study rather than only comparing endpoint scores. The between-group contrast then asks whether the average change differs between the assigned groups.

This type of endpoint is used to describe symptom intensity in a common scale and to quantify the average change across participants with measurements at both time points. The scale’s direction matters for interpretation: a lower score represents less reported pain. The reported group means are changes, not final pain scores. They therefore should not be read as the average pain level at the end of the study.

The registry record does not report a clinically important difference threshold for this measure. A statistical contrast alone does not establish how meaningful a difference would be to participants, and the average does not show how individual experiences varied within each group.

7. Results Posted in the Registry

• Ricolinostat: mean -1.21 versus -1.03 on control; difference -0.18 (95% CI -0.51 to 0.15), standardized effect d = -0.13; z-test p = 0.280.

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 in Non-pain Neuropathic Signs (UENS)

• 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:
  • Ricolinostat: mean -1.51 versus -1.84 on control; difference 0.33 (95% CI 0.24 to 0.42), standardized effect d = 0.84; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Ricolinostat than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry lists one secondary outcome: change in non-pain neuropathic signs measured with UENS. The posted group summaries and unadjusted contrast show a pattern different from the primary pain-intensity comparison, and the reported unadjusted p-value is <0.001. The secondary endpoint concerns signs rather than pain ratings, so it addresses a related but distinct clinical feature.

The secondary result does not overturn or replace the primary result. Each endpoint measures a different aspect of the condition, and a statistically notable result on a secondary measure does not establish a between-group difference on the primary measure. Nor does it establish that the observed contrast on the secondary measure is clinically important. The registry record does not report a clinically important threshold for UENS.

Secondary results commonly carry less confirmatory weight than a prespecified primary endpoint because several outcomes can be examined. If no multiplicity adjustment or testing hierarchy is reported, the chance of finding an apparently notable result across the set of outcomes may be higher than for a single planned test. The registry record does not report a multiplicity plan, and the secondary outcome has no reported analyses listed beyond the posted summaries and unadjusted recalculation.

The overall pattern is therefore that the primary endpoint does not show a clear unadjusted between-group difference, while the secondary endpoint has a statistically notable unadjusted contrast. This pattern is a reason to distinguish outcome-specific evidence rather than combine the endpoints into a single conclusion. It may motivate further study, but it is not by itself proof that the effects are consistent across measures or populations.

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

• Change in Non-pain Neuropathic Signs (UENS)

9. Statistical Interpretation

10. Statistical Methods Explained

What does a mean change represent?

A mean is the arithmetic average of the participant-level changes included in an endpoint analysis. For this trial, a change in pain intensity refers to the difference between the average rating during the baseline week and the average rating during the final week at 12 weeks. A negative mean change represents a decrease on the scale. Since lower pain ratings correspond to less pain, the direction is interpretable, but a mean alone does not describe every participant’s experience.

The standard deviation describes how dispersed individual changes are around the mean. It is not the uncertainty in the mean and it is not a confidence interval. The primary endpoint standard deviation was 1.4 in each group. That spread is relevant because a modest difference between group averages can coexist with considerable overlap in participants’ individual changes.

How is the between-group contrast read?

The mean difference compares the ricolinostat group’s mean change with the placebo group’s mean change. For the primary outcome, the contrast is -0.18 units. A negative contrast means the average change was more negative in the ricolinostat group, which corresponds to a numerically larger decrease in pain intensity. The sign describes direction; it does not, by itself, show that the difference is reliable or important.

The reported p-value for this unadjusted primary contrast is 0.28. A p-value measures how unusual data at least as incompatible with a specified no-difference model would be under that model and the analysis assumptions. It is not the probability that the no-difference model is true, and it is not a measure of the size or importance of the effect. The p-value does not establish equivalence between groups.

What is a confidence interval?

A confidence interval expresses uncertainty around an estimated contrast. Wider intervals indicate less precision; narrower intervals indicate greater precision under the analysis assumptions. For the primary outcome, the reported interval crosses zero, so the estimate is compatible with a negative difference, no difference, and a positive difference. The interval should be considered alongside the point estimate and the spread in the group data, rather than treated as a separate verdict.

The contrast and its interval in this analysis are unadjusted recalculations from posted group summaries. They are not described as a sponsor-reported inferential analysis in the registry record. A recalculation can be useful for understanding the posted group data, but it does not replace an analysis that accounts for the trial’s prespecified methods, if any. Those original methods are not reported in the registry record.

Why do analysis populations matter?

The registry defines the primary endpoint population as participants with non-missing values at both baseline and the specified visit. This is a complete-measurement definition for the endpoint, not a statement that all randomized participants were included. The primary group summaries list 140 participants for ricolinostat and 142 for placebo. The registry record does not explain how missing measurements were handled beyond the stated population definition, nor does it report whether other analysis populations were used.

When outcome data are unavailable, restricting an analysis to participants with measurements can affect interpretation if the likelihood of having data is related to assignment or outcome. The registry record does not report enough detail to assess whether missingness differed by group or whether sensitivity analyses examined it.

Why can multiple outcomes complicate interpretation?

Testing multiple outcomes can increase the chance that at least one result appears statistically notable by chance, particularly when results are interpreted without a prespecified hierarchy or adjustment. The registry lists a secondary outcome and posts an unadjusted p-value for it, but the registry record does not report a multiplicity strategy or a hierarchy linking secondary and primary endpoints. The secondary result should therefore be interpreted as supportive or exploratory rather than as a stand-alone confirmatory finding.

The registry record also does not report details of the original statistical analysis plan, including model specification, covariate adjustment, or handling of repeated measurements. General statistical practice can explain why these choices matter, but their use in this trial is not reported in the registry record.

11. Confidence Intervals and Precision

The primary mean difference is -0.18 units, while the confidence interval extends from a negative value to a positive value. Because the interval includes zero, the data do not pin down the direction of the between-group difference with confidence. The estimate points toward a larger average decrease in pain in the ricolinostat group, but plausible values also include no difference and a contrast in the other direction.

Precision depends on both the amount of information and the variability in the outcome. The primary endpoint standard deviation was 1.4 units in each group, while the group mean changes were relatively close. The interval’s span reflects uncertainty around the contrast rather than variation among individuals alone. A confidence interval should not be interpreted as containing a fixed proportion of individual participant outcomes.

The registry record does not report a clinically important difference threshold for average pain intensity. It is therefore not possible to determine from the posted results alone whether a particular value within the interval would represent a meaningful change to participants. Statistical uncertainty and clinical importance are related questions, but they are not interchangeable.

The reported interval is an unadjusted recalculation based on posted summary statistics. It does not account for any trial-specific analysis features that are not available in the registry record. The displayed p-value, 0.28, likewise indicates that the unadjusted primary contrast is not statistically persuasive under conventional interpretation; it does not establish that the true contrast is exactly zero.

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 illustrations express the number of participants per arm, not total events. They 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. These are illustrative calculations based on the observed effect, not the trial’s original design assumptions, which are not reported in the registry record.

For 100% of the observed primary effect, the illustration gives 950 participants per arm for 80% power and 1,272 participants per arm for 90% power. For planning for 75% of the observed effect, the corresponding figures are 1,689 and 2,261 participants per arm. For planning for 50% of the observed effect, they are 3,799 and 5,086 participants per arm.

The 80% power column describes a planning scenario in which a study of the stated size would have an 80% chance of detecting the specified effect under the stated assumptions. The 90% column uses a higher chance of detection and therefore gives larger planning figures for the same assumed effect. Smaller effects require more participants because they are harder to distinguish from random variation.

These values are not observed power. They should not be read as a retrospective measure of whether the completed trial was adequately powered, nor as evidence that the original trial was designed around the observed effect. They are illustrations that depend on assumptions about the effect size and analysis, and the registry record does not report the trial’s original sample-size justification.

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 = -0.180; pooled standard deviation σ = 1.400.
2. n = 2 × (1.96 + 0.842)² × 1.400² / -0.180² = 949.6, rounded up to 950 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 <- -0.18                      # observed difference in means
sigma <- 1.4                     # 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(3176472)
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 = 950 (80% power), 1,272 (90% power)
 75% of observed effect: n per arm = 1,689 (80% power), 2,261 (90% power)
 50% of observed effect: n per arm = 3,799 (80% power), 5,086 (90% power)
power.t.test: 950.6 
Simulated power at n = 950 per arm: 0.798 (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 pain-intensity endpoint and a secondary UENS endpoint. It does not report whether the secondary outcome was part of a prespecified testing hierarchy, whether any multiplicity adjustment was planned, or how the family of tests was defined. Without that information, an unadjusted secondary p-value should be read cautiously because considering multiple outcomes can increase the chance of at least one apparently notable result.

The posted primary contrast has an unadjusted p-value of 0.28, and the secondary contrast has an unadjusted p-value of <0.001. These values do not indicate whether any adjustment was made in the trial’s own analysis. The registry record does not report a sponsor analysis for the secondary result, and its reported analyses list is empty. The recalculated contrast is based on posted summaries and should not be confused with an undocumented prespecified analysis.

For the primary endpoint, the registry defines the population as participants with non-missing values at both baseline and the specified visit. The group summaries include 140 participants assigned to ricolinostat and 142 assigned to placebo. The record does not report the number missing at each time point, the reasons for missingness, or a method for imputing missing outcomes. It also does not report sensitivity analyses to assess how missing data could affect the estimated contrast.

Those omissions matter because an analysis limited to participants with measurements can be biased if data availability is related to assigned group or outcome. The record also does not report whether the primary analysis followed an intention-to-treat principle, whether participants were analyzed according to assignment, or whether other analysis populations were used. These details are not reported in the registry record, so the posted summaries cannot resolve those methodological questions.

The registry record does not report the original statistical analysis plan, model specification, covariate adjustment, interim analyses, or sample-size justification. These are distinct issues: missing-data methods address unavailable outcomes, multiplicity methods address repeated testing, and an analysis plan documents how comparisons were intended to be conducted. The available summaries do not establish what choices were made for these parts of the trial.

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: invasive ductal breast carcinoma (0.7%), atrial tachycardia (0.7%), stroke (0.7%), diverticulitis (0.7%), skin abrasion (0.7%).

The registry lists serious adverse events affecting 6 participants at risk in the ricolinostat group and 2 participants at risk in the placebo group. In the registry’s serious-event summaries, the at-risk counts are 142 for ricolinostat and 140 for placebo. The listed death count is 0 in each of those groups. These are counts, not a basis for calculating an adjusted comparison, and they do not show when events occurred or whether they were judged related to treatment.

The registry also reports an open-label extension group, with 4 serious adverse events among 252 at risk and 0 deaths. That group is a separate registry category and should not be combined with the randomized-group figures. The record lists several serious-event terms at 0.7% each, including invasive ductal breast carcinoma, atrial tachycardia, stroke, diverticulitis, skin abrasion, and nasal bone fracture.

These summaries describe reported safety events; they do not establish causation or provide a full account of event severity, timing, or exposure duration. The registry record does not report whether serious events were considered related to study treatment.

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

The posted primary results describe average change in pain intensity over the study period. Both groups had negative mean changes, and the ricolinostat group’s mean change was numerically more negative. The estimated between-group difference was -0.18 units, with an unadjusted p-value of 0.28 and a confidence interval that crosses zero. The data therefore do not provide a precise estimate that separates the groups on the primary measure.

This does not show that the groups were exactly the same. A result that is not statistically persuasive can reflect a small underlying difference, substantial uncertainty, or both. The interval indicates that the estimate is compatible with values on either side of zero. It also does not establish that a clinically important effect is absent, because the registry record does not report a threshold for clinical importance.

The secondary UENS result is a separate outcome and should not be used to claim a demonstrated benefit on pain intensity. Its unadjusted statistical result carries less weight when the record does not report how multiple outcomes were handled. Results on one measure cannot be assumed to transfer to another.

Group averages also do not describe the range of individual experiences. The standard deviations show that participant-level changes varied around the means, but the registry record does not provide distributions or responder summaries in the information reported for these outcomes. The mean contrast cannot establish how many participants improved, worsened, or had no change.

Finally, the registry results do not alone establish generalizability beyond the people studied, treatment effects over longer periods, or a causal explanation for the observed changes. Randomization supports a comparison of assigned groups, but interpretation also depends on analysis methods, missing data, and trial conduct details that are not reported in the registry record. These results are statistical evidence about the posted endpoints, not medical advice.

17. Why This Trial Matters Statistically

This trial illustrates why an estimated effect and its uncertainty should be read together. The primary point estimate favors a larger average decrease in pain intensity for ricolinostat, but the magnitude of the difference is modest relative to the variability in participant changes, and the confidence interval crosses zero. Looking only at the direction of the means would overstate what the results establish; looking only at the p-value would omit the size and uncertainty of the contrast.

It also demonstrates the distinction between a primary and a secondary outcome. The secondary UENS comparison has a more statistically notable unadjusted result, but it measures non-pain neuropathic signs rather than average pain intensity. Without a reported multiplicity strategy, it should not be treated as equivalent in evidential standing to a prespecified primary comparison.

The posted summaries can support transparent recalculation and interpretation, yet they do not replace the trial’s full statistical plan. The record does not report the sponsor’s inferential analyses, missing-data methods, or original sample-size assumptions. Those gaps limit how fully readers can evaluate whether the analysis followed a plan established before results were observed.

The sample-size illustrations add another useful statistical lesson: planning requirements rise when the target effect is smaller or the desired probability of detection is higher. Because these illustrations use the observed effect, they are not evidence about the original trial’s design or its observed power. Keeping planning calculations separate from trial results helps avoid retrospective claims that the study was or was not adequately powered based only on the observed estimate.

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 gives group means and standard deviations but does not report participant-level outcome distributions. The posted summaries therefore cannot show whether the mean reflects a broadly similar pattern across participants or is influenced by a more varied set of changes. The primary outcome population requires non-missing measurements at both time points, while details about missingness, reasons for missing data, and sensitivity analyses are not reported.

The primary comparison is an unadjusted recalculation from posted summaries. The registry record does not report the sponsor’s inferential analysis or its model specification, covariates, or handling of repeated measurements. No discrepancy is flagged, but the recalculation remains limited to the information available in the posted group summaries.

The registry lists a secondary outcome, but the record does not report a multiplicity plan or analysis hierarchy. That makes the unadjusted secondary finding harder to interpret as confirmatory evidence. The record also does not report a clinically important difference threshold for either the primary endpoint or UENS, limiting assessment of clinical meaning.

The study description uses both double-blind language in the brief summary and quadruple masking in the registry design fields; the record does not explain the terminology. The exact original sample-size justification and statistical plan are not reported. Safety summaries provide counts but do not report event timing, treatment relatedness, or an adjusted comparison. These limitations restrict interpretation of the posted results without negating the descriptive value of the reported group data.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Ricolinostat in Patients With Painful Diabetic Peripheral Neuropathy — NCT03176472.
• Registry record last updated 2023-09-21; status last verified 2023-09.
• Results first posted 2023-09-21.
• 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

NCT03176472 is a completed randomized phase 2 parallel-group study of ricolinostat versus placebo in painful diabetic peripheral neuropathy. The primary endpoint was change in mean average pain intensity from the baseline week to the final week at 12 weeks, measured on an 11-point numerical pain rating scale.

The primary group mean changes were -1.21 for ricolinostat and -1.03 for placebo, with an unadjusted mean difference of -0.18 and p = 0.28. The confidence interval crosses zero, indicating uncertainty about the direction and size of the between-group contrast. The secondary UENS result has an unadjusted p-value of <0.001, but the registry record does not report a multiplicity plan or sponsor analysis for that outcome.

The registry includes serious adverse-event counts for the randomized groups and an open-label extension. It does not report key analysis details such as missing-data methods, the original sample-size justification, or the statistical analysis plan.