Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition (NCT03926117), a randomized phase 2 study. The primary outcome is Percent Change From Baseline in High-sensitivity C-reactive Protein (Hs-CRP) Levels.

2. Clinical Question

3. Trial Design

The registry record describes a randomized, double-blind, placebo-controlled, parallel-group phase 2b trial with quadruple masking. It records an enrollment of 264 and a completed status. The recorded start date is 2019-06-03, and the primary completion date is 2020-06-26. Novo Nordisk A/S is listed as the sponsor.

The trial compared three monthly subcutaneous ziltivekimab doses—7.5 mg, 15 mg, and 30 mg—with matching placebo over six months. Its stated purpose was to determine a dose for selection for a potential cardiovascular outcome trial. The record therefore frames this as an investigation of inflammation and dose selection, not as a trial designed to establish effects on cardiovascular events.

The primary endpoint was percent change from baseline in hs-CRP at week 13. Baseline was defined as the average of the hs-CRP value before randomization and the value on day 1. The endpoint description says the intended population for analysis included all randomized participants; the reported analyzed number refers to participants with available data. The number randomized to each group and the number analyzed for this endpoint are reported separately in the posted results.

Additional outcomes include inflammatory markers, adverse events, bleeding, blood pressure, and respiratory rate. The posted secondary blood pressure and respiratory-rate results use a week 32 assessment. These outcome timepoints differ from the primary endpoint timepoint, so they address different follow-up measurements. Details of the allocation procedure, masking implementation, stratification, and sample-size justification are not reported in 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: Participants were randomized 1:1:1:1 to one of three Ziltivekimab dose levels (7.5 milligram (mg), 15 mg, or 30 mg) or matching placebo.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT analysis population included all randomized participants. 'Overall Number of Participants Analyzed' = participants with available data.

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: Intent-to-treat (ITT) analysis population included all randomized participants.

6. Primary Endpoint

The registry lists the primary outcome as Percent Change From Baseline in High-sensitivity C-reactive Protein (Hs-CRP) Levels, measured over Baseline (average of the hs-CRP value prior to randomization and day 1), week 13.

High-sensitivity C-reactive protein, or hs-CRP, is a blood marker used to quantify systemic inflammation. The primary endpoint is percent change from baseline in hs-CRP at week 13. Baseline is defined as the average of the measurement before randomization and the measurement on day 1. Expressing change as a percentage describes the relative movement from that baseline, rather than the absolute hs-CRP concentration at week 13.

The registry record summarizes this endpoint using the median and interquartile range. The median describes the midpoint of the observed values: half are at or below it and half are at or above it. The interquartile range describes the central half of the distribution, from the lower to the upper quartile. It is a measure of spread, not a confidence interval for the median.

Hs-CRP is relevant to the trial’s question because the study focused on inflammation and aimed to select a dose for possible later testing. A change in this marker can address whether the treatment groups had different biomarker responses at the specified timepoint. It cannot by itself establish whether cardiovascular events, kidney outcomes, symptoms, or survival differ. Those outcomes are not the primary endpoint described in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

How to read the primary summaries. The primary endpoint is reported as a median percent change and an interquartile range for each group. The median is useful when a distribution is asymmetric or includes values far from the center, because it is less affected by extreme observations than the arithmetic mean. The interquartile range records the spread of the middle half of observations. General explanation: a wide interquartile range indicates more variation among observed values in that central portion, while a narrow one indicates less. It does not quantify uncertainty in the estimated median.

What the comparison estimates. The sponsor used the Hodges-Lehmann method and reported a median difference for each dose versus placebo. General explanation: this method estimates a location shift between two distributions by considering differences between observations in the groups. It is not necessarily equal to subtracting one group median from another. The comparison confidence interval represents uncertainty in the estimated between-group contrast under the method’s assumptions. If the interval excludes zero, it is consistent with a nonzero location difference at the stated confidence level. The sponsor reported 95% confidence intervals for the three comparisons.

The p-value addresses how compatible the observed comparison is with a null hypothesis of no difference, under the statistical test and assumptions used. It does not give the probability that the null hypothesis is true, nor does it measure clinical importance. The record reports a p-value below < 0.001 for each primary comparison. These are sponsor-reported analyses, not the simple unadjusted re-calculations presented for selected secondary outcomes.

How to interpret the confidence interval. A confidence interval is a range generated by a procedure that, under repeated use and its assumptions, would cover the target parameter at the stated rate. For an individual trial, it communicates the precision of the estimate, rather than assigning a probability to every possible value after observing the data. The primary comparison intervals are specific to the Hodges-Lehmann estimates. They should not be confused with the interquartile ranges shown for the groups.

Secondary continuous outcomes. The posted secondary summaries for systolic blood pressure, diastolic blood pressure, and respiratory rate use means and standard deviations. A mean represents the arithmetic average; the standard deviation describes spread around that average. The accompanying re-calculations are unadjusted comparisons based on posted summary statistics. They are not the sponsor’s reported analyses, and the registry record contains no sponsor-reported comparison analysis for these endpoints in the data summarized for this page. Their p-values and confidence intervals should therefore be understood as exploratory, unadjusted summaries rather than confirmatory tests.

General explanation: the standard error describes the sampling variability of an estimate. A confidence interval is formed by combining an estimate with its standard error under a chosen method. The secondary re-calculations use normal-approximation methods. These methods can be useful for a transparent summary of group means, but they may not reproduce a trial’s formal analysis, especially if the formal analysis used adjustment, a different population, or a different model. Details of a sponsor analysis for these outcomes are not reported in the registry record.

Why over-dispersion matters. General explanation: when outcome variability is greater than a model assumes, standard errors can be too small, confidence intervals too narrow, and tests too likely to declare a difference. A model that accounts for extra variability may better reflect the data. This concern is particularly relevant to count outcomes, where the variance can exceed the mean. The primary endpoint is reported as a median and interquartile range, not as a count model, so an over-dispersion adjustment is not described for that analysis. The registry record does not report the underlying participant-level distributions or a detailed model specification.

Planning illustrations. The posted sample-size illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They scale the effect to detect to the stated fraction of the observed effect. These are planning illustrations based on an observed estimate, not the trial’s own design justification and not observed power. The record does not report the sample-size assumptions used when designing this trial. General explanation: using a smaller target effect in a planning calculation generally requires a larger sample to obtain the same nominal power, all else equal. Such illustrations are sensitive to the observed effect and variability and should not be read as a guarantee that a future study will achieve its intended precision.

The trial’s listed enrollment is 264, while the analysis counts vary by endpoint and group. A group’s analyzed count can differ from its number randomized when outcome data are unavailable. The endpoint description specifically says the analysis population included all randomized participants, but defines the number analyzed as participants with available data. This distinction matters: intention-to-treat describes the population assigned by randomization, whereas an available-data count describes which participants contributed observed measurements to a particular endpoint summary.

10. Analyses Reported by the Sponsor

The primary comparisons are sponsor-reported analyses using the Hodges-Lehmann method. They should be distinguished from simple re-calculations based on arm-level summary statistics. The sponsor’s estimates are median differences in final values, with 95% confidence intervals and p-values, while the arm summaries report median percent change from baseline and interquartile ranges. Those quantities are related to the same endpoint but are not interchangeable calculations.

The sponsor’s reported comparisons show a negative estimated difference for each ziltivekimab dose versus placebo, with confidence intervals below zero and p-values below < 0.001. The arm-level medians also show larger reductions in the active-dose groups than in the placebo group. Taken together, these descriptions are directionally consistent, but the sponsor’s formal comparison is the appropriate result to cite for the trial’s primary analysis. The registry record does not identify a discrepancy between the reported analysis and the other available results.

Any unadjusted re-calculation from summary statistics is, by design, a simplified analysis. It may not reflect participant-level data, a prespecified model, or adjustments used in the sponsor’s analysis. It should not replace the sponsor’s method or be presented as if it were the trial’s formal inferential result. For the primary outcome, the reported sponsor analysis is available directly; no extra calculation is needed to interpret its stated estimate and uncertainty.

11. Multiplicity, Missing Data and Analysis Populations

The registry record identifies hs-CRP percent change at week 13 as the primary outcome and lists a broad set of secondary outcomes. It reports three sponsor comparisons of active doses with placebo for the primary endpoint. A multiplicity adjustment, testing hierarchy, or rule governing interpretation across those comparisons is not reported in the registry record. It is also not reported whether any interim analyses were conducted or whether any results were used to change the analysis plan.

Multiplicity matters because each additional hypothesis test creates another opportunity for a result to appear statistically notable by chance. General explanation: a prespecified adjustment can control the chance of false-positive findings across a family of tests, while a hierarchy can specify which tests are interpreted confirmatorily and in what order. Without a reported strategy, the primary comparisons can be described as reported, but the record does not support assuming how multiplicity was handled. The same caution applies especially to the many secondary outcomes, for which no adjustment is described.

The primary outcome description states that the intention-to-treat analysis population included all randomized participants. It also defines the number analyzed as participants with available data. This means that the population definition and the observed-data count are not identical concepts. The record does not report the amount or pattern of missing hs-CRP data, reasons for missing measurements, imputation procedures, sensitivity analyses, or whether missingness differed by group. These omissions limit assessment of how missing data might affect the estimates.

For secondary outcomes, group-specific analyzed numbers are posted, but detailed missing-data methods are not reported in the registry record. It is therefore not possible to determine from the recorded information whether all randomized participants contributed to every endpoint or how incomplete observations were handled. The available-data summaries describe the observations included in the posted results; they do not establish that missingness was unrelated to outcome or treatment assignment.

The registry record also does not report a detailed statistical analysis plan, protocol-specific rules for the primary analysis, or sample-size justification. Those details would help clarify prespecification and the intended interpretation of the testing strategy. Their absence should be treated as uncertainty about reporting, not as evidence that a particular procedure was or was not used.

12. 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: acute kidney injury (3.1%), corona virus infection (3.1%), septic shock (3.1%), abdominal pain (1.5%), ankle fracture (1.5%).

The safety summaries report the number at risk and the number affected by serious adverse events and other adverse events for each group, alongside deaths. These are descriptive counts. The serious adverse event counts were 10 in placebo, 13 with ziltivekimab 7.5 mg, 9 with 15 mg, and 8 with 30 mg. The posted death counts were 1, 0, 0, and 0, respectively. These summaries should be read as events recorded in this trial rather than as estimates of comparative risk adjusted for follow-up or participant characteristics.

The registry also lists serious adverse-event terms with percentages, including acute kidney injury, corona virus infection, and septic shock at 3.1% each, and abdominal pain, ankle fracture, and arteriovenous graft site infection at 1.5% each. The record does not provide a detailed comparative statistical analysis for these terms in the information. A term’s presence in the list does not establish that it was caused by treatment.

Counts alone do not indicate whether group differences are statistically reliable or clinically important. Interpretation also depends on event definitions, timing, exposure, follow-up, and the number of participants with safety data. The record does not report enough detail to resolve all of those considerations. These descriptive summaries are useful for understanding what was recorded, but should not be treated as a definitive comparative safety assessment.

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

The primary result describes a difference in hs-CRP percent change at week 13 between the ziltivekimab dose groups and placebo in this randomized trial. The medians and the sponsor’s Hodges-Lehmann comparisons consistently indicate lower endpoint values in the active-dose groups relative to placebo. The confidence intervals communicate uncertainty in the sponsor’s estimated contrasts, while the interquartile ranges describe variation among participants within each group.

What this result establishes is limited to the endpoint and population studied. It is evidence about an inflammatory biomarker over the reported follow-up, not a direct estimate of cardiovascular events, kidney disease progression, symptoms, or survival. The trial summary states that dose selection for a potential cardiovascular outcome trial was the purpose. The registry record does not report a primary clinical-outcome result that would answer whether cardiovascular risk or other patient-important outcomes changed.

The study’s randomized, masked, placebo-controlled design is relevant to interpreting the between-group comparison, but design labels alone do not answer every question about bias or precision. The registry record does not provide detailed information on allocation procedures, missing-data methods, or multiplicity handling. The listed enrollment and endpoint-specific analyzed counts also show why the analysis population for a measurement should be considered alongside its estimate.

The secondary findings should be interpreted separately. Their measurements use different outcomes and timepoints, and the available re-calculations are unadjusted. They do not establish a comprehensive benefit-risk profile or resolve the primary biomarker result. Likewise, a small p-value is not a measure of the size or clinical importance of an effect. The reported effect estimates and confidence intervals are needed to describe magnitude and precision.

Overall, the posted data support a clear difference in the primary biomarker summaries between ziltivekimab and placebo in this trial. They do not by themselves determine the relevance of that biomarker change to later clinical outcomes or justify extrapolation beyond the studied setting. Any such conclusions require evidence from outcomes and populations that the registry record does not report as part of this primary analysis.

14. Why This Trial Matters Statistically

This trial illustrates a common role for phase 2b studies: examining biological response across multiple doses to inform whether and how to proceed to a later outcomes study. The registry record explicitly describes dose selection for a potential cardiovascular outcome trial as the purpose. The primary endpoint is an inflammatory biomarker, which can be measured at a specified follow-up and compared across randomized groups without being mistaken for a cardiovascular event itself.

Statistically, the record is useful because it pairs group-level medians and interquartile ranges with sponsor-reported between-group estimates and confidence intervals. These summaries answer different questions. The group summaries describe the observed distributions; the Hodges-Lehmann estimates quantify the location contrast between groups. Keeping those quantities distinct avoids treating a comparison estimate as a simple difference between reported medians.

The trial also shows why analysis populations, endpoint-specific counts, and missing-data reporting matter. The primary analysis population is described as all randomized participants, but the analyzed number is defined by available data. A reader needs both pieces of information to understand the scope of the estimate. The record’s limited detail on missingness and multiplicity makes it important not to overstate what can be inferred from the posted results.

Finally, secondary outcomes can add context without carrying the same evidential weight as a designated primary outcome. Unadjusted analyses across many outcomes can be exploratory, while planning calculations based on observed effects are illustrations rather than evidence of a trial’s achieved power. Clear separation of confirmatory results, descriptive safety summaries, and planning assumptions helps make statistical interpretation more accurate and useful for clinical research.

15. 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 posted primary result is a biomarker endpoint assessed at week 13. The registry record does not provide a clinically important threshold for hs-CRP change or establish how a change in this marker relates to later cardiovascular outcomes. The trial’s stated purpose was dose selection for a potential cardiovascular outcome trial, so the primary result should not be read as a clinical-outcome finding.

The record presents arm-level medians and interquartile ranges and sponsor-reported Hodges-Lehmann comparisons, but does not report detailed participant-level data or a full statistical analysis plan. The primary analysis population is described as all randomized participants, while the number analyzed is defined as participants with available data. Missing-data amounts, reasons, handling methods, and sensitivity analyses are not reported in the registry record. The effect of missing observations therefore cannot be assessed from these summaries alone.

Multiplicity procedures for the three dose comparisons and the listed secondary outcomes are not reported. This makes nominal secondary results harder to interpret as confirmatory evidence. Sponsor-reported analyses are not available for the posted secondary continuous-outcome comparisons described in the re-calculations, which are unadjusted and based on summary statistics.

The safety information is also limited to group counts and selected serious adverse-event terms. Detailed event timing, exposure-adjusted analyses, comparative uncertainty, and attribution are not reported in the registry record. Descriptive counts cannot by themselves establish differences in safety between groups.

Finally, the registry record does not report the sample-size justification or the detailed procedures for allocation and masking. The planning illustrations based on observed effects should not be mistaken for the original design assumptions or observed power. These reporting limits do not invalidate the posted results, but they constrain how fully their precision, robustness, and broader applicability can be evaluated.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition — NCT03926117.
• Registry record last updated 2025-12-31; status last verified 2025-12.
• Results first posted 2023-08-09.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes a completed randomized, double-blind, placebo-controlled phase 2b trial of monthly subcutaneous ziltivekimab at 7.5 mg, 15 mg, and 30 mg versus matching placebo. The recorded enrollment was 264. The study focused on patients with advanced chronic kidney disease and systemic inflammation, with dose selection for a potential cardiovascular outcome trial as its stated purpose.

The primary endpoint was percent change from baseline in hs-CRP at week 13. The posted medians showed larger reductions in each ziltivekimab group than in placebo, and the sponsor reported a Hodges-Lehmann comparison for each dose versus placebo. Secondary results included safety summaries and physiological outcomes; unadjusted re-calculations for selected secondary continuous outcomes should be treated as exploratory.

The registry record does not report detailed missing-data methods, multiplicity procedures, or the trial’s sample-size justification. The primary finding concerns a biomarker and does not itself establish effects on cardiovascular or other clinical outcomes.