A Study to Assess the Efficacy, Safety, and Tolerability of KPL-716 in Reducing Pruritus in Chronic Pruritic Diseases: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess the Efficacy, Safety, and Tolerability of KPL-716 in Reducing Pruritus in Chronic Pruritic Diseases (NCT03858634), a randomized phase 2 study. The primary outcome is Change From Baseline in Weekly Average WI-NRS at Week 8.

2. Clinical Question

3. Trial Design

This was a randomized, double-blind, placebo-controlled, parallel-group Phase 2 pilot study of KPL-716 in chronic pruritic diseases. The registry describes quadruple masking. The specific roles covered by that masking designation are not reported in the registry record, so the masking label alone does not establish which study personnel or participants were blinded.

The registry reports enrollment of 58 participants and a completed study. The recorded start date was 2019-05-29, and primary completion was 2020-04-01. Participants were assigned to KPL-716 or placebo, with both treatments given weekly for 8 weeks. The study examined five disease cohorts: CIU, CIP, LP, LSC, and PPs. The posted arm sizes varied substantially by cohort. In particular, the LP cohort had no placebo participants, and several other cohort arms included only a small number of participants.

The primary endpoint was change from baseline in weekly average WI-NRS at Week 8. The record defines the analysis population as the modified intent-to-treat set, including randomized participants who received at least one dose and had at least one post-baseline efficacy assessment during the double-blind treatment period. Missing endpoint data in that population were imputed using last observation carried forward (LOCF).

The registry record does not report the sample-size justification, detailed randomization procedures, allocation concealment, or the specific operational details of masking. It also does not report interim analyses or a full statistical analysis plan. The design and posted results should therefore be interpreted as a pilot study record rather than as a complete account of every prespecified trial procedure.

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: This study assigned participants to active treatment or placebo in 5 individual disease-specific cohorts: chronic idiopathic urticaria (CIU), chronic idiopathic pruritus (CIP), lichen planus (LP), lichen simplex chronicus (LSC) and plaque psoriasis (PPs). The participant flow data are presented by combined cohorts for public reporting purposes because the low numbers of participants in the individual disease-specific cohorts may cause re-identification concerns if presented separately.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified intent to treat (mITT) set: all randomized participants who received at least 1 dose of KPL-716 or placebo and had at least 1 post-baseline efficacy assessment in the double-blind treatment period. Missing data were imputed using the last observation carried forward (LOCF) method.

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 baseline characteristics data are presented by combined cohorts for public reporting purposes because the low numbers of participants in the individual disease-specific cohorts may cause re-identification concerns if presented separately.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Weekly Average WI-NRS at Week 8, measured over Baseline, Week 8.

The primary endpoint was change from baseline in weekly average WI-NRS at Week 8. Participants assigned a daily numerical score for the intensity of their worst pruritus in the past 24 hours, using a scale from 0 to 10, where 0 meant no pruritus and 10 meant the worst imaginable pruritus. Daily scores were averaged to form a weekly score. A negative change from baseline indicates improvement in the measured score.

This endpoint is used to represent participants’ reported itch severity over time. Using a weekly average, rather than relying on one daily rating, summarizes the daily scores across the week. The Week 8 change expresses the difference between the baseline score and the score at the end of the stated treatment period. The reported endpoint is a continuous measure, so the arm summaries are means and the analysis reports least-squares mean comparisons.

General statistical context: a continuous symptom score can retain information about the degree of change across its scale, rather than reducing outcomes to categories such as improved or not improved. Its interpretation still depends on the scale, the study population, the timing of assessment, and the way missing observations are handled. The registry record does not report a threshold for a clinically important WI-NRS change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is continuous: each participant’s daily worst-pruritus ratings contribute to a weekly average, and the endpoint is the change from baseline to Week 8. The arm summaries are least-squares means, and the reported dispersion for the arm summaries is standard error. A standard error describes the estimated precision of a mean, rather than the spread of individual participant scores. It should not be interpreted as a range containing most participants’ values.

The sponsor reports ANCOVA comparisons for CIU, CIP, LSC, and PPs. ANCOVA is a general statistical method for comparing groups while accounting for one or more covariates in the model. The registry record does not identify the covariates, model specification, or other implementation details, so those aspects cannot be evaluated from the posted description. The comparisons are reported as least-squares mean differences, which are model-based contrasts rather than simple differences between the displayed arm means.

General statistical context: adjustment can account for specified baseline or design variables and may affect both the estimated contrast and its precision. An adjusted model’s estimate need not equal a direct subtraction of the arm means. The registry’s sponsor-reported ANCOVA results should therefore be distinguished from any simple unadjusted recalculation based on posted summary statistics. Numerical values for an unadjusted recalculation are not reported in the registry record.

The reported confidence intervals are 80% intervals. In general, a confidence interval represents a range of values compatible with the data and the model under repeated use of the same procedure. It conveys uncertainty around the estimated contrast, not the probability that a particular interval contains the true value. The intervals for CIU and CIP include zero; those for LSC and PPs do not. The reported p-values are 0.398, 0.665, 0.071, and 0.019, respectively. A p-value is a measure of how incompatible the observed data are with a specified null model under the analysis assumptions; it is not a measure of treatment effect size or clinical importance.

General statistical context: over-dispersion means that observed variability is greater than a model expects. When present, it can make standard errors too small and uncertainty appear less than it is if the analysis does not accommodate it. The registry describes standard errors for the arm summaries but does not report an assessment of over-dispersion. The primary outcome is a continuous score, and no over-dispersion result is reported.

The stated analysis population is the modified intent-to-treat set. It includes randomized participants who received at least one dose of assigned treatment and had at least one post-baseline efficacy assessment during the double-blind period. This definition is narrower than an analysis of every randomized participant, because it excludes participants who did not meet those conditions. The registry reports that missing data were imputed using last observation carried forward (LOCF). Under LOCF, a participant’s last observed value is carried forward for a later missing assessment. General statistical context: this approach relies on an assumption about how the participant’s unobserved outcome would relate to the last observed value. The registry record does not report sensitivity analyses comparing LOCF with other missing-data approaches.

The registry lists 21 outcome measures and 404 analyses, and 19 secondary outcomes are posted. The listed secondary outcomes include changes and percentage changes in WI-NRS, pruritus VAS, and 5-D Pruritus scores over time; a threshold-based WI-NRS outcome; and a CIU-only itch severity score. The record does not report a multiplicity adjustment plan. General statistical context: when many outcomes, time points, or subgroup comparisons are examined, the chance of at least one apparently unusual result can increase. Without a reported plan for handling multiplicity, the cohort p-values should be interpreted as individual reported comparisons, not as proof that the full set of analyses controls a prespecified overall error rate.

The registry also includes an instruction that some continuous two-arm comparisons are skipped when values are missing or not estimable. For the primary endpoint, the LP placebo arm has zero participants and no reported outcome estimate, so a two-arm LP contrast cannot be interpreted. The record does not report an across-disease pooled comparison or a common estimate combining all five cohorts.

The study is described as a randomized, double-blind, quadruple-masked, parallel-group pilot. General statistical context: randomization is intended to reduce systematic differences in allocation, while masking can limit certain sources of biased assessment or conduct. The registry does not report procedural details sufficient to assess how these protections were implemented. It also does not report interim analyses, a sample-size justification, or the full prespecified analysis plan. Those omissions limit assessment of how the posted analyses relate to all planned analyses.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("KPL-716: CIU Cohort", "Placebo: CIU Cohort", "KPL-716: CIP Cohort", "Placebo: CIP Cohort", "KPL-716: LP Cohort", "KPL-716: LSC Cohort")
n   <- c(4, 2, 14, 9, 3, 4)
m   <- c(-4.3, -1.1, -4.3, -3.7, -3.1, -6.9)
sp  <- c(1.84, 2.66, 0.77, 0.96, 0.82, 0.81)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  KPL-716: CIU Cohort  4  -4.300  3.680  -10.156  1.556
CARM  Placebo: CIU Cohort  2  -1.100  3.762  -34.899  32.699
CARM  KPL-716: CIP Cohort  14  -4.300  2.881  -5.963  -2.637
CARM  Placebo: CIP Cohort  9  -3.700  2.880  -5.914  -1.486
CARM  KPL-716: LP Cohort  3  -3.100  1.420  -6.628  0.428
CARM  KPL-716: LSC Cohort  4  -6.900  1.620  -9.478  -4.322

11. Analyses Reported by the Sponsor

The registry reports the sponsor’s ANCOVA results as least-squares mean differences with 80% confidence intervals and p-values for four cohort comparisons. These are model-based results, not simple arithmetic contrasts between the arm summaries. An unadjusted recalculation from the posted summary statistics is not reported in the registry record, so a numerical comparison between such a recalculation and the sponsor’s analysis cannot be made from the registry information.

No discrepancy is flagged in the registry record. The sponsor-reported estimates therefore remain the reported analysis for the four available two-arm comparisons. This does not make the estimates definitive: the cohort arm sizes are small, the intervals differ in width, and the record does not report the ANCOVA covariates or a multiplicity plan. For LP, no placebo participants were enrolled, so there is no sponsor-reported two-arm primary endpoint comparison to set against a recalculation.

General statistical context: an unadjusted recalculation based on summary statistics would not necessarily reproduce an adjusted ANCOVA estimate, because the estimand and adjustment may differ. Any such recalculation should be identified as an unadjusted analysis, not substituted for the sponsor’s model-based result. The registry record does not report enough model detail to reproduce the sponsor’s analysis independently.

12. Multiplicity, Missing Data and Analysis Populations

The registry identifies a substantial set of outcome and analysis entries: 21 outcome measures, 404 analyses, and 19 posted secondary outcomes. Secondary measures include repeated assessments of WI-NRS, pruritus VAS, and 5-D Pruritus scores, both as changes and percentage changes; a percentage of participants reaching a specified WI-NRS reduction; and a CIU-only itch severity score. These outcomes vary in measure, timing, and population.

The multiplicity strategy is not reported in the registry record. It is therefore unclear whether the analyses were organized around a prespecified hierarchy, whether p-values were adjusted, or how emphasis was assigned across outcomes and time points. General statistical context: examining multiple outcomes and comparisons can increase the likelihood of observing at least one small p-value by chance. A nominal p-value should consequently be read in light of the full set of analyses, rather than treated in isolation as a complete account of evidence.

The primary analysis population was the modified intent-to-treat set: randomized participants who received at least one dose and had at least one post-baseline efficacy assessment in the double-blind period. The registry states that missing data were imputed by LOCF. The number of participants excluded from that population, the amount and pattern of missingness, and sensitivity analyses using alternative assumptions are not reported in the registry record.

General statistical context: LOCF fills a missing later measurement with the participant’s last observed value. That can simplify analysis, but the carried-forward value may not represent the unobserved outcome at the later assessment. The validity of conclusions can depend on why values are missing and how outcomes would have changed. Without missingness details or sensitivity analyses, robustness to the imputation choice cannot be assessed from the registry record.

The record does not report interim analyses, a sample-size justification, or a full statistical analysis plan. It also does not report a multiplicity adjustment plan. These gaps limit reconstruction of which comparisons were primary to the analysis strategy and how the full set of outcomes was intended to be interpreted.

13. 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: angioedema (2.6%).

The posted safety counts are reported across the KPL-716 and placebo groups, not separately by disease cohort. Serious adverse events affected 1 of 39 participants in the KPL-716 group and 0 of 19 in the placebo group. Other adverse events affected 15 of 39 and 11 of 19 participants, respectively. No deaths were reported in either group. The registry lists angioedema at 2.6% among the top serious adverse event terms.

These counts describe events recorded during the study; they do not by themselves establish that an event was caused by assigned treatment. The registry record does not provide event timing, detailed participant-level information, or a causal assessment for the listed term. The recorded counts are also based on relatively small groups, so they provide limited precision about event frequency.

General statistical context: safety counts are descriptive unless a specific comparative analysis and its uncertainty are reported. A count of zero observed events does not establish that the underlying risk is zero. The registry record does not report a statistical comparison of adverse event rates, and the serious-event figures should not be interpreted as evidence that one group has a greater or smaller underlying risk.

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

The results describe changes in a participant-reported pruritus score over the study period and sponsor-reported comparisons within several disease cohorts. The arm means were negative in all reported KPL-716 cohorts, and in three of the four placebo cohorts; the LSC placebo mean was 0.7. The reported ANCOVA contrasts were negative in all four available two-arm comparisons. These directions describe the posted score changes and estimated contrasts; they do not alone establish clinical importance or a general effect across chronic pruritic diseases.

The uncertainty differs across cohorts. The CIU and CIP 80% confidence intervals include zero, while the LSC and PPs intervals do not. The reported p-values likewise vary across comparisons. Because the study is a pilot and the arm sizes are small, the estimates are not precise enough to support broad conclusions about all five disease groups. No two-arm LP comparison is available, because the LP placebo arm had no participants.

The results do not establish that the treatment works or does not work. They do not answer whether the observed changes meet a threshold that participants would consider important, because such a threshold is not reported in the registry record. Nor do they establish that the findings apply to people outside the study’s defined population, to other treatment durations, or to outcomes not reported in the registry.

General statistical context: statistical evidence, effect magnitude, precision, and clinical meaning are related but distinct. A p-value does not quantify the size of a change, and a confidence interval does not determine whether a change is important to participants. Interpretation also depends on the analysis population, imputation of missing data, the number of comparisons, and the study design. The registry record does not report enough information to assess all of these aspects fully.

The study is most appropriately understood as a small, disease-specific pilot investigation with cohort-level endpoint estimates. Its posted results can inform understanding of the range and uncertainty of those estimates, but they should not be collapsed into a single conclusion across conditions or treated as a definitive test.

15. Why This Trial Matters Statistically

This trial is statistically notable because it reports a continuous patient-reported pruritus measure across several distinct disease cohorts within one pilot study. The same general symptom scale is used across conditions, but the cohort-specific results remain separate. That distinction matters: a common endpoint does not mean the underlying disease groups are interchangeable, and the cohort estimates should not automatically be combined.

The registry also makes visible how much estimates can depend on the information available within each subgroup. Cohort arm sizes range from no placebo participants in LP to larger, though still modest, arms in CIP and PPs. Comparisons based on few participants tend to carry greater uncertainty, and the posted confidence intervals illustrate differing precision across cohorts. The absence of an LP comparator is a design and data limitation for interpreting that cohort’s treatment contrast.

The report further illustrates the difference between arm summaries and an adjusted model comparison. The sponsor’s ANCOVA estimates are least-squares mean differences, and the registry does not report enough model detail to reproduce them. This is a useful reminder that a model-based result and an unadjusted contrast can answer related but not identical statistical questions.

Finally, the study highlights the importance of interpreting a set of results in context. The record lists many outcomes and analyses, but does not report a multiplicity plan, sample-size justification, or full statistical analysis plan. Missing-data handling is described as LOCF, but sensitivity analyses are not reported. Those omissions do not erase the posted estimates; they do constrain how confidently the full analysis can be reconstructed and how broadly its findings can be interpreted.

16. 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 principal limitation is the small, cohort-specific allocation. The posted arm sizes are 4 and 2 for CIU, 14 and 9 for CIP, 3 and 0 for LP, 4 and 1 for LSC, and 14 and 7 for PPs. These sizes limit precision, particularly where one or both arms have very few participants. The LP cohort has no placebo participants, preventing a comparative primary endpoint estimate.

The registry reports 80% confidence intervals for the ANCOVA contrasts, rather than a more commonly used 95% interval. The record does not explain why that interval level was selected. The study is identified as a pilot, but its sample-size justification is not reported in the registry record. Consequently, the intended precision or decision purpose of the planned enrollment cannot be assessed from the registry information.

The ANCOVA covariates and full model specification are not reported in the registry record. The record also does not provide numerical results for an unadjusted recalculation, so the adjusted sponsor results cannot be compared numerically with one. A full statistical analysis plan, interim analysis information, and a multiplicity adjustment plan are also not reported.

For missing data, the registry states that LOCF was used, but it does not report the extent or pattern of missingness, reasons for missing observations, or sensitivity analyses under alternative assumptions. The modified intent-to-treat definition excludes randomized participants who did not receive at least one dose or did not have at least one post-baseline efficacy assessment; the number excluded is not reported in the registry record.

Finally, the results are presented by disease cohort, and the record does not report an overall pooled effect across conditions. The endpoint is a participant-reported score, and a clinically important change threshold is not reported. These limitations constrain conclusions about precision, clinical relevance, and generalizability beyond the populations and comparisons represented in the posted results.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: A Study to Assess the Efficacy, Safety, and Tolerability of KPL-716 in Reducing Pruritus in Chronic Pruritic Diseases — NCT03858634.
• Registry record last updated 2025-03-18; status last verified 2025-03.
• Results first posted 2021-12-28.
• 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.

20. Record Summary

This completed randomized, double-blind, quadruple-masked, parallel-group Phase 2 pilot study compared weekly KPL-716 with weekly placebo over 8 weeks in participants with chronic pruritic diseases. Enrollment was 58. The primary endpoint was change from baseline in weekly average WI-NRS at Week 8, analyzed in a modified intent-to-treat population with missing data imputed by LOCF.

The registry reports cohort-level arm summaries and sponsor ANCOVA comparisons for CIU, CIP, LSC, and PPs. No placebo participants were enrolled in LP, so a two-arm LP comparison is unavailable. The sponsor-reported estimates vary by cohort, and their uncertainty is represented by 80% confidence intervals. The record lists 21 outcome measures, 404 analyses, and 19 posted secondary outcomes, but does not report a multiplicity plan, sample-size justification, or full statistical analysis plan.

The findings should be read as pilot estimates from small disease-specific groups, not as a single conclusion across all conditions. The registry record does not report a clinically important WI-NRS change threshold or sensitivity analyses for the LOCF approach.