A Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-1): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-1) (NCT03422653), a randomized phase 3 study. The primary outcome is Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score at Week 12.

2. Clinical Question

The study tested this question during a 12-week double-blind phase, with a 52-week open-label extension also included in the study. The primary endpoint was a threshold-based measure: a participant counted as meeting it if the specified improvement criterion was reached. Such an endpoint can be easier to interpret as a proportion reaching a defined level of change, but it does not describe the full range of score changes among participants. The posted results report 51.0% for CR845 and 27.6% for placebo, each with a 95% confidence interval. These percentages describe the registered endpoint at Week 12; they do not by themselves explain why any individual participant’s score changed. Details of the eligibility criteria beyond the stated hemodialysis and pruritus population are not reported in the registry record.

3. Trial Design

This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 3 study. The registry record reports enrollment of 378. Participants were assigned to intravenous CR845 at 0.5 mcg/kg or intravenous placebo, administered after each dialysis session. The double-blind phase lasted 12 weeks, and the study also included a 52-week open-label extension. In that extension, the intervention listed was CR845 0.5 mcg/kg. The registry record does not provide further detail about how participants entered or continued in the extension.

The primary outcome was assessed at Week 12. It was the percentage of participants achieving an improvement from baseline of at least 3 points in the weekly mean of daily 24-hour worst-itching intensity NRS scores. The NRS ranges from 0, no itching, to 10, worst itching imaginable. Secondary outcomes included itch-related quality-of-life measures using the 5-D Itch Scale and Skindex-10, as well as a more stringent itch-intensity improvement threshold. Results are posted for the latter threshold; results for the quality-of-life outcomes are not reported in the registry record.

The registry record lists the study as completed and gives a start date of 2018-02-20 and a primary completion date of 2019-04-06. It identifies Cara Therapeutics, Inc. as the sponsor. The primary endpoint description says that estimated percentages, odds ratios, and p-values used a logistic regression model. The registry also reports a sponsor analysis using the Cui, Hung, Wang method for an odds ratio. Details such as the trial’s original sample-size justification, the full statistical analysis plan, the handling of missing primary outcome values, and any interim analyses are not reported in the registry record. The listed enrollment and outcome denominators should therefore be read as registry entries, not as a substitute for fuller participant-flow information.

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: The study includes a Double-blind Phase, an Open-label Extension Phase, and a Follow-up Period. Patients who received at least 30 doses of study drug (either active or placebo) during the 12-week Double-blind Treatment Period and continue to meet other eligibility criteria will be eligible to receive open-label CR845 for an additional 52 weeks.

Period 1: Double-blind Phase

Period 2: Open-label Phase

Analysis population for the primary outcome, as defined in the registry: Data include one patient who had been randomly assigned to the placebo group and who withdrew from the trial before receiving the first dose of placebo.

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 Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥3 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) Score at Week 12, measured over Week 12.

The primary endpoint measures whether participants reached a prespecified degree of improvement in itch intensity by Week 12. It uses the weekly mean of daily ratings of the worst itching experienced over the preceding 24 hours. Participants whose score improved from baseline by at least 3 points were counted as achieving the endpoint; the result is expressed as a percentage of participants. The scale runs from 0, indicating no itching, to 10, indicating the worst itching imaginable.

A threshold endpoint answers a different question from a comparison of average score change. It describes the proportion meeting a defined improvement criterion, while not showing how far beyond that threshold participants improved or how scores changed among those who did not reach it. In general, a threshold can make a result more directly interpretable as the frequency of a specified response. Its meaning depends on the threshold and measurement schedule, so the result should be read as applying to this particular 3-point criterion, weekly averaging approach, and Week 12 assessment.

The registry says estimated percentages, odds ratios, and p-values used a logistic regression model. The posted outcome is therefore a binary response: meeting or not meeting the improvement threshold. The endpoint is not a measure of all symptoms, quality of life, or longer-term change. Those outcomes require their own measurements and analyses.

7. Results Posted in the Registry

• CR845 0.5mcg/kg: 50.8% (96/189) versus 27.5% (52/189) on control; risk difference 23.3 percentage points (95% CI 13.7 to 32.8), risk ratio 1.85 (1.41–2.42); unadjusted two-proportion z-test p = <0.001.

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.

Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥4 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Double-blind CR845 0.5mcg/kg: 39.2% (74/189) versus 18.0% (34/189) on control; risk difference 21.2 percentage points (95% CI 12.3 to 30.0), risk ratio 2.18 (1.53–3.10); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Double-blind CR845 0.5mcg/kg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The posted secondary results show a direction of group contrast consistent with the primary endpoint for the additional itch-intensity threshold: a larger proportion in the CR845 group met that response criterion than in the placebo group. The registry also lists itch-related quality-of-life outcomes based on the 5-D Itch Scale and Skindex-10, but their results are not reported in the registry record. The secondary evidence is therefore incomplete across the full set of listed outcomes.

The secondary itch-intensity result is related to, but not interchangeable with, the primary result. It uses a more demanding improvement threshold, so it asks how many participants reached a different level of change. The primary endpoint remains the principal result for the trial’s stated Week 12 question; secondary findings can add context but do not replace it. Differences in thresholds also mean that response percentages should not be interpreted as if they measured the same outcome.

The registry reports a sponsor odds-ratio analysis and an unadjusted recalculation for the posted secondary itch-intensity outcome. Its reported p-value is unadjusted. When multiple endpoints or comparisons are examined, the chance of observing at least one apparently strong result can increase. In general, multiplicity procedures are used to address that issue, but the registry record does not report a multiplicity adjustment or a plan for controlling it. Accordingly, unadjusted secondary results carry less confirmatory weight than a prespecified primary analysis with a clearly described testing strategy. The registry does not report enough information to determine how the secondary endpoints were prioritized or whether their analyses were prespecified.

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

• Improvement in Itch-related Quality of Life as Assessed by the Change From Baseline in 5-D Itch Scale Score at the End of Week 12
• Improvement in Itch-related Quality of Life as Assessed by the Change From Baseline in Total Skindex-10 Scale Score at the End of Week 12
• Reduction of Itch Intensity as Assessed by the Percentage of Patients Achieving an Improvement From Baseline ≥4 Points With Respect to the Weekly Mean of the Daily 24-hour Worst Itching Intensity NRS Score at Week 12

9. Statistical Interpretation

10. Statistical Methods Explained

The primary response is binary: each participant either met the specified improvement threshold or did not. A percentage summarizes how common that response was in each group. In general, binary outcomes are often analyzed with methods that model the probability of an event while accounting for the group assignment. The registry’s endpoint description states that estimated percentages, odds ratios, and p-values used logistic regression. It does not report the model’s covariates, any stratification factors, or enough detail to reconstruct the full fitted model from the registry record.

What does an odds ratio describe?

Odds are the probability of an event divided by the probability of no event. An odds ratio compares those odds between groups. An odds ratio of 1 corresponds to equal odds under the comparison being made; values above or below 1 indicate different odds, with direction depending on which group is the reference. The sponsor’s reported odds ratio is 2.72 for CR845 relative to placebo. This is a relative measure of odds, not a statement that the response percentage is multiplied by that amount. When an outcome is not rare, an odds ratio and a risk ratio can differ appreciably as measures, so they should not be used interchangeably.

The posted summary counts also allow an unadjusted recalculation of the absolute risk difference. That calculation uses the observed response proportions in the two groups and does not reproduce the logistic-regression model. Its result is a descriptive, unadjusted comparison derived from the posted summaries. The calculated risk difference and the sponsor’s odds ratio answer related but distinct questions, and they use different effect scales. The recalculation is not evidence that the sponsor used the same calculation as its primary analysis.

What is the role of a p-value?

A p-value describes how compatible the observed data are with a specified null hypothesis, under the assumptions of the analysis. In general, a small p-value indicates that data at least as discrepant as those observed would be relatively unusual if that null hypothesis and model assumptions held. It is not the probability that the null hypothesis is true, the probability that the result occurred by chance, or a measure of the size or importance of an effect. The registry reports p < 0.001 for the sponsor’s primary analysis and for the unadjusted recalculation. The p-value does not convey the range of plausible effect sizes; the confidence interval serves a different purpose.

Why do the analysis methods matter?

Different methods can yield estimates on different scales and can rely on different model assumptions. The endpoint description identifies logistic regression for estimated percentages, odds ratios, and p-values. The reported sponsor analysis identifies the Cui, Hung, Wang method and reports an odds ratio. The registry record does not provide full implementation details for either analysis, so the listed method names should not be taken as a complete specification of every modeling decision. The recalculated risk difference is explicitly unadjusted and based on posted summary statistics; it should not be mistaken for a model-adjusted treatment effect.

In general, confidence intervals combine an estimate with information about its sampling uncertainty under the analysis method. They do not account automatically for every possible source of uncertainty, such as missing outcomes, deviations from the analysis plan, or systematic measurement error. A narrow interval can indicate relatively greater precision on the scale being estimated, but precision is not the same as freedom from bias. Interpretation therefore depends both on the numerical interval and on what is known about the trial’s design and analysis.

Why can over-dispersion matter?

For some outcomes, the variability in observed data is greater than a simple statistical model expects. This is called over-dispersion. In general, a model that does not allow for extra variability can understate uncertainty and produce intervals that are too narrow or tests that appear more decisive than warranted. This concern is especially relevant to count or clustered data, where observations may vary more than a basic model assumes. The primary endpoint in this trial is binary, and the registry identifies logistic regression; it does not report over-dispersion diagnostics or describe an over-dispersion adjustment. There is therefore no registry basis for asserting that over-dispersion was present or that any particular correction was used.

The trial’s original statistical plan is not reported in the registry record. That includes details such as prespecified covariates, missing-data handling, analysis populations, multiplicity procedures, and any interim analyses. Those omissions limit how fully an outside reader can assess whether the posted analyses match the original plan. They do not erase the posted estimates, but they mean that the reported results should be interpreted alongside the limits of the available methodological description.

11. Confidence Intervals and Precision

The CR845 group’s primary endpoint percentage is 51.0%, with a 95% confidence interval from 42.9% to 58.9%. The placebo group’s percentage is 27.6%, with a 95% confidence interval from 20.2% to 36.6%. Each interval describes uncertainty around its group’s response percentage under the analysis used. The intervals are not guarantees that the true value lies inside them, nor do they describe variation in individual participants’ responses.

For the unadjusted risk difference, the estimate is 0.233 and the 95% confidence interval ranges from 0.137 to 0.328. This interval is on the risk-difference scale and describes uncertainty about the absolute group contrast calculated from the posted summaries. The sponsor’s odds-ratio estimate is 2.72, with a 95% confidence interval from 1.72 to 4.30. Because the risk difference and odds ratio are different measures, their numerical values and interval limits should not be compared as though they were on one scale.

In general, a confidence interval is a range generated by a statistical procedure that, over repeated use under its assumptions, would cover the target parameter at its stated confidence level at the corresponding frequency. It conveys both an estimate and its precision. The primary comparison intervals indicate uncertainty remains about the size of the group contrast, even though the interval for the risk difference is entirely above zero and the sponsor’s interval for the odds ratio is entirely above 1. Confidence intervals reflect sampling uncertainty under the analysis; they do not automatically incorporate uncertainty from missing information, model choice, or possible bias.

The registry does not provide enough detail to assess all sources of uncertainty in the primary analysis. In particular, missing-data methods and the full analysis population are not reported in the registry record. The intervals should therefore be read as statistical precision conditional on the reported analysis, not as a complete accounting of every limitation affecting the result.

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 for 80% power and the number of participants per arm for 90% power. They are not total event counts. The sample-size assumptions listed for these illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is set to the stated fraction of the observed effect. The trial’s own original design assumptions and sample-size justification are not reported in the registry record.

In general, power is the probability that a planned statistical test will reject its null hypothesis under a specified effect and other assumptions. The 80% column means the illustration targets an 80% chance of detecting the assumed effect under those planning conditions; the 90% column uses a higher target chance. These are design calculations, not descriptions of what happened in this trial. The displayed scenarios use the observed effect as a reference and consider smaller fractions of it. As the assumed effect becomes smaller, more participants are needed to distinguish it from random variation at the same power target and significance level.

The figures are planning illustrations computed from the observed effect rather than the trial’s original design calculation. They do not establish that the study had a particular probability of success after the data were collected. This is not observed power. The estimates depend on the assumptions stated for the illustration, and a future study’s actual requirements could differ if its expected effect, allocation, outcome frequency, analysis, or other design features differ. The curve should be read as a visual representation of the planning relationship between assumed effect size and participants per arm, not as a prediction of a future study’s result.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.275; treatment proportion p₁ = 0.508; average p̄ = 0.392.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6903 = 1.3529.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6704 = 0.5642.
4. n = (1.3529 + 0.5642)² / (0.2328)² = 67.8, rounded up to 68 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
p0 <- 0.275132275132275                          # control proportion
p1 <- 0.507936507936508                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(3422653)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 68 (80% power), 91 (90% power)
 75% of observed effect: n per arm = 118 (80% power), 158 (90% power)
 50% of observed effect: n per arm = 257 (80% power), 343 (90% power)
power.prop.test: 67.8 
Simulated power at n = 68 per arm: 0.803 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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. Analyses Reported by the Sponsor

The sponsor’s reported primary analysis uses the Cui, Hung, Wang method and gives an odds ratio of 2.72, with a 95% confidence interval from 1.72 to 4.30 and p < 0.001. The unadjusted recalculation from the posted summary statistics also gives an odds ratio of 2.72, but its 95% confidence interval is 1.773 to 4.173. The recalculation is a simple unadjusted calculation and is not a replacement for the sponsor’s analysis.

The registry indicates no discrepancy between the posted sponsor result and the recalculation. Even so, the sponsor’s own analysis takes precedence as the trial’s reported analysis. Its method and interval are the appropriate reference for describing the sponsor’s analysis; the recalculated interval is useful as a transparent check based on the posted counts. The different interval limits can arise because the calculations do not use identical methods, despite reporting the same rounded odds-ratio estimate. The registry record does not provide enough detail to reproduce the sponsor’s model in full or to determine all reasons for the interval differences.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint and several secondary outcomes. It reports a primary Week 12 itch-intensity comparison and a secondary itch-intensity threshold result. It also names two itch-related quality-of-life outcomes, but their results are not reported in the registry record. The reported secondary p-value is unadjusted. No multiplicity procedure, hierarchy for testing endpoints, or family-wise error strategy is reported in the registry record. Without those details, the secondary findings should be treated as supportive and exploratory rather than as independent confirmation of the primary result.

Multiplicity matters because evaluating several outcomes can increase the chance that at least one result appears statistically persuasive even when none reflects a real group difference. In general, a prespecified approach can limit that risk by defining which comparisons are confirmatory and how their error rates are controlled. The registry record does not say whether such an approach was used in the trial’s full analysis plan, so it is not possible to assess the confirmatory status of each secondary analysis from the posted record alone.

The primary endpoint note says the data include one participant assigned to placebo who withdrew before receiving the first placebo dose. The registry does not describe how missing Week 12 scores were handled, whether participants with missing measurements were imputed, or what analysis population was used for each outcome. It also does not report the extent or pattern of missing primary outcome data beyond that note. These details matter because the result may depend on how missing outcomes are treated and on which randomized participants contribute to the analysis.

The registry’s primary endpoint summaries list 189 participants in each group, while the double-blind placebo safety summary lists 188 at risk. These are distinct reported denominators for different summaries; they should not be combined or assumed to represent the same analysis population. The record does not provide a full participant flow or a complete explanation of these denominator choices. Interim analyses and any associated statistical adjustments are not reported in the registry record.

16. 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: pneumonia (7.3%), fluid overload (5.1%), hyperkalaemia (3.8%), cardiac failure congestive (3.5%), respiratory failure (3.5%).

The registry reports serious adverse events for the double-blind CR845 group as 49 participants affected among 189 at risk, and for the double-blind placebo group as 41 affected among 188 at risk. It reports 2 deaths in each double-blind group. For the open-label CR845 group, the registry reports 167 participants affected by serious adverse events among 313 at risk and 22 deaths. The open-label figures describe a different study phase and should not be treated as a randomized comparison with the double-blind placebo group.

The registry also lists serious-event terms and their reported percentages, including pneumonia at 7.3%, fluid overload at 5.1%, hyperkalaemia at 3.8%, cardiac failure congestive at 3.5%, respiratory failure at 3.5%, and sepsis at 3.2%. These entries identify reported event categories; they do not establish that an event was caused by the study intervention. The registry record does not provide enough detail to assess timing, exposure duration, event-level overlap, or adjusted comparative safety estimates. The figures should be read as descriptive safety information, not as proof of causation or a complete assessment of risk.

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

The posted primary results show a higher observed percentage meeting the Week 12 itch-improvement threshold in the CR845 group than in the placebo group. The sponsor’s reported odds ratio and the unadjusted recalculation both indicate a group contrast in the same direction, and their reported p-values are below 0.001. The confidence intervals express uncertainty about the group-specific percentages and the comparison; they do not make the estimated effect exact.

This finding applies to the specific threshold endpoint, assessment schedule, population, and double-blind phase described in the registry. It does not establish the amount of improvement for every participant, the average change in itch score, or whether the same pattern holds for quality of life. The listed 5-D Itch Scale and Skindex-10 outcomes do not have results reported in the registry record. Nor should the Week 12 randomized comparison be extended to conclusions about the 52-week open-label extension, whose outcomes are not included in the primary result summary.

A statistically strong comparison does not by itself determine clinical importance, explain individual experiences, or answer every question about study conduct. In general, clinical interpretation also depends on the relevance of the threshold, the measurement’s properties, missing data, analysis choices, and how outcomes were selected and tested. Some of those details are not reported in the registry record. The adverse-event entries provide descriptive counts and reported event terms but do not establish that the intervention caused those events, or settle the comparative safety profile.

The result should therefore be read as evidence about one registered, short-term, binary itch-intensity outcome in a randomized comparison, alongside the stated precision and limits of the registry record. It is not a guarantee of an individual response and is not a complete account of all benefits, harms, longer-term outcomes, or other treatment options.

18. Why This Trial Matters Statistically

This trial illustrates why the effect scale matters when interpreting a binary clinical endpoint. A percentage meeting a threshold, an absolute risk difference, and an odds ratio describe related aspects of the same comparison, but they are not interchangeable. The group percentages communicate how common the defined response was in each arm; the risk difference expresses an absolute contrast; and the odds ratio expresses a relative contrast in odds. Reading the measures together helps prevent a relative estimate from being mistaken for a direct multiplication of the response percentage.

The study also shows the value of separating the primary endpoint from secondary outcomes. The primary threshold gives the main registered answer at Week 12, while a different secondary threshold asks a related but distinct question. Listed quality-of-life outcomes add potentially relevant dimensions, but their results are not reported in the registry record. Without a reported multiplicity plan, secondary analyses have less confirmatory force than the primary analysis.

Precision and analysis transparency matter alongside the point estimates. Confidence intervals show the uncertainty attached to estimates, while missing-data procedures, analysis-population definitions, and model details affect how those estimates should be understood. Those details are only partly available in the registry record. The sponsor analysis and the unadjusted recalculation provide complementary views, but the sponsor’s analysis remains the reported trial analysis.

Finally, the registry includes both a double-blind randomized phase and an open-label extension, as well as descriptive safety counts. Keeping randomized comparative evidence separate from open-label follow-up and descriptive safety summaries is important: those data structures answer different questions and do not support the same kind of inference.

19. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record does not report the full statistical analysis plan, the original sample-size justification, or the covariates and other details of the primary logistic-regression model. It also does not report how missing Week 12 outcome data were handled, the exact analysis population, or the extent and pattern of missing outcome measurements. The endpoint note identifies one placebo-assigned participant who withdrew before receiving the first dose, but that note is not a substitute for a complete participant-flow account.

Results for the listed 5-D Itch Scale and Skindex-10 quality-of-life outcomes are not reported in the registry record. The registry reports an unadjusted p-value for the secondary itch-intensity analysis but does not report a multiplicity procedure or testing hierarchy. Those omissions limit assessment of how strongly the secondary findings support confirmatory conclusions. The posted primary result is also specific to a threshold response at Week 12; it does not provide the distribution of score changes or outcomes at other times.

The open-label extension is described in the study design, and a safety group is listed for open-label CR845, but extension efficacy outcomes are not included in the primary result information. Open-label safety summaries cannot be treated as randomized comparisons with the double-blind placebo group. The serious-event counts and terms are descriptive; the registry record does not provide enough information to attribute individual events to treatment or assess all comparative safety questions.

Finally, the planning illustrations are based on the observed effect and stated simplifying assumptions, not the trial’s original design calculation. They should not be used as evidence about the study’s achieved power or as a definitive prescription for another study. These limitations describe gaps in the registry record and the scope of the posted results, rather than demonstrating that any particular analysis or study procedure was inappropriate.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-1) — NCT03422653.
• Registry record last updated 2022-04-26; status last verified 2022-03.
• Results first posted 2022-04-26.
• 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.

23. Record Summary

NCT03422653 is a completed, multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 3 study sponsored by Cara Therapeutics, Inc. It enrolled 378 people with moderate-to-severe pruritus receiving hemodialysis. The double-blind phase compared intravenous CR845 at 0.5 mcg/kg with intravenous placebo after dialysis sessions and lasted 12 weeks; the study also included a 52-week open-label extension.

The primary Week 12 endpoint was the percentage achieving at least a 3-point improvement in the weekly mean daily worst-itching NRS score. The registry reports 51.0% for CR845 and 27.6% for placebo, with a sponsor odds ratio of 2.72 and p < 0.001. The reported confidence intervals indicate uncertainty around both group percentages and the comparison. Secondary itch-intensity results follow the same direction, while the listed quality-of-life results are not reported in the registry record.

Interpretation is limited by unreported details on missing data, analysis populations, multiplicity, and the full statistical plan. Safety entries are descriptive and do not establish causation.