Renin and Renal Biomarker Response to Angiotensin II: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Renin and Renal Biomarker Response to Angiotensin II (NCT04558359), a non-randomized phase 4 study. The primary outcome is Change in Plasma Renin Levels.

2. Clinical Question

The study’s stated focus was the response of renin to angiotensin II in septic shock. Its brief description discusses the rationale for examining this biomarker, including interest in renin as a possible indicator of the renin-angiotensin system. That rationale does not itself demonstrate that renin changed in this study or that any change had clinical consequences. Other listed outcomes included cystatin C, NGAL, catecholamine discontinuation, ICU length of stay, in-hospital mortality, renal replacement therapy-free days, and prespecified safety outcomes. Results for these outcomes are not reported in the registry record.

3. Trial Design

NCT04558359, titled Renin and Renal Biomarker Response to Angiotensin II, is listed as a completed Phase 4 study. It was open-label, non-randomized, and conducted in sequential periods. The registry lists a planned enrollment of 30 and identifies septic shock and acute kidney injury as conditions. The study start date is 2020-10-19, and the primary completion date is 2023-07-24.

The cohorts were standard of care and angiotensin II. The registry describes the standard-of-care cohort as receiving standard-of-care treatment and the angiotensin II cohort as receiving angiotensin II. Because allocation was non-randomized, these cohorts should not be treated as exchangeable groups created by random assignment. Sequential recruitment can leave treatment and comparison groups differing in patient characteristics, clinical context, or other factors. The registry record does not report enough detail to assess whether or how such differences were measured or addressed.

The study was unmasked, meaning the record lists no masking. The primary outcome was change in plasma renin levels through shock resolution, up to 14 days. Measurements were planned at baseline, 24 hours, and shock resolution; a 3-hour measurement was specified for the angiotensin II cohort only. The outcome description notes that participant death could preclude later measurements, so the number analyzed could vary by time point.

The registry lists eight outcome measures, including the primary renin outcome and secondary renal, treatment-duration, length-of-stay, mortality, and safety outcomes. It records zero analyses. The protocol’s sample-size justification, detailed statistical analysis plan, interim analyses, and methods for adjusting for baseline differences are not reported in the registry record. The stated completion status indicates that the study is completed, but it does not supply outcome findings.

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: 2 enrolled participants in the angiotensin II arm had changes in status that deemed them ineligible for the study and they subsequently did not receive open label angiotensin II.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Number analyzed in one or more rows may be different from overall number due to participant death which would preclude subsequent measurements. 3-hour sample was only done in the angiotensin II arm.

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 Change in Plasma Renin Levels, measured over Until shock resolution, up to 14 days (at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days).

The primary endpoint is change in plasma renin levels, expressed in pg/mL. Renin is a biomarker involved in the body’s regulation of blood pressure and fluid balance. Measuring it over time can describe whether levels vary during treatment and as shock resolves. The study’s stated rationale is to examine renin response in the setting of septic shock and angiotensin II treatment.

The registry specifies medians and inter-quartile ranges as the summary approach. A median describes the middle of the ordered observations, while the inter-quartile range describes the spread of the central portion of those observations. These summaries can be useful when data are skewed or contain unusually high or low values, although the registry record does not state why this summary was selected or describe the distribution of the measurements.

Measurements were planned at baseline, 3 hours, 24 hours, and shock resolution, up to 14 days. The 3-hour measurement was only specified for the angiotensin II cohort. This difference matters when interpreting time profiles: the registry does not describe a matching 3-hour measurement in the standard-of-care cohort. The outcome description also warns that deaths could prevent later observations, so the participants contributing measurements may differ by time point.

The registry record does not report renin values, changes from baseline, comparisons between cohorts, confidence intervals, or tests of statistical significance. Consequently, the endpoint definition explains what was intended to be measured, but the posted record does not show the outcome magnitude or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help distinguish a measured pattern from a reliable estimate of a treatment contrast. For this study, the registry identifies an outcome, a summary measure, a measurement schedule, and a non-randomized sequential design. It does not report the numerical outcome results or a detailed analysis plan. The following concepts explain how such information is generally interpreted without attributing unreported methods to this study.

What does the median and inter-quartile range describe?

In general, the median is the central value after observations are ordered. The inter-quartile range describes the spread of the central half of observations. These summaries do not assume that values are symmetrically distributed in the way a mean and standard deviation can imply. They can be informative for biomarker measurements when a small number of observations are especially high or low. The registry specifies this summary for plasma renin but does not report the actual medians or inter-quartile ranges, nor does it state whether a particular distributional concern motivated the choice.

What would a change over time mean?

Repeated measurements can describe how a biomarker varies from baseline through later assessment times. A within-cohort change describes the pattern among participants with the relevant measurements; it is not automatically the same as a treatment effect. A treatment contrast requires comparing outcomes between cohorts in a way that accounts for the study design and the question being asked. The registry gives no renin values or calculated changes, so no time trend or contrast can be characterized from its reported results.

Why does non-randomized allocation matter?

In general, random assignment helps balance measured and unmeasured factors between groups, on average. In a non-randomized study, treatment groups may differ before treatment begins. Sequential periods can also coincide with changes in clinical practice, patient mix, or other circumstances. These are general design concerns, not documented events in this trial. The registry does not report a baseline comparison, an adjusted model, or another method for handling possible confounding. Any observed cohort difference would therefore need cautious interpretation, and the posted record contains no such result to evaluate.

How should precision be assessed?

A confidence interval is a range of values compatible with the data and the assumptions of the analysis; its width conveys precision. A narrow interval indicates a more precise estimate than a wide interval, while neither alone determines clinical importance. A p-value addresses compatibility with a specified null hypothesis under model assumptions; it does not give the size or practical meaning of an effect. The registry record does not report confidence intervals or p-values for the primary endpoint. Precision and statistical evidence for the renin comparison cannot be assessed from the record.

Why might over-dispersion matter?

In general, over-dispersion occurs when variability in the data is greater than a statistical model expects. If a model assumes less variability than is present, standard errors and uncertainty estimates may be too small. This concept is relevant to some count outcomes, but the registry does not identify an analysis model for the listed outcomes or report evidence of over-dispersion. It should not be assumed that this issue was assessed or that a particular model was used.

What can planning illustrations say?

In general, sample-size planning illustrates how many participants might be needed under stated assumptions about an effect, allocation, significance level, and analysis. Such calculations are design scenarios, not observed evidence and not a measure of the probability that a completed study found a real effect. The registry’s stated planning assumptions refer to a two-sided significance level of 0.05, equal allocation, a normal approximation, and a target effect defined as a fraction of the observed effect. The resulting planning values are not reported in the registry record, and the registry does not present this as the trial’s own design justification. No sample-size illustration can replace the missing endpoint estimates.

The record states that there were zero analyses. It does not report the statistical model, covariate adjustment, handling of repeated measurements, uncertainty estimation, or any interim analysis. These details should not be inferred from the endpoint summary format or from general statistical practice.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists eight outcome measures, including plasma renin and secondary measures of renal biomarkers, catecholamine discontinuation, ICU length of stay, in-hospital mortality, renal replacement therapy-free days, and safety outcomes. When a study examines multiple outcomes or repeated time points, the chance of at least one apparently notable result can increase if many tests are conducted. Statistical plans may address this through prespecified primary outcomes, testing hierarchies, or adjustments. The registry identifies a primary outcome but does not report a multiplicity strategy. Whether any adjustment was planned or used is not reported in the registry record.

The primary endpoint includes repeated measurement times, with a 3-hour sample only in the angiotensin II cohort. Multiple time points can raise questions about which contrast or time point is primary and how within-participant correlation is handled. The registry describes the outcome timing but does not report a model, a rule for combining measurements, or a planned contrast across time.

Missingness is directly relevant: the outcome description says that death could preclude subsequent measurements and that the number analyzed may differ across rows. This means later measurements may not represent the same set of participants as earlier measurements. In general, missing-data methods rely on assumptions about why measurements are unavailable. The record does not report an imputation method, a sensitivity analysis, or assumptions about missingness. It also does not state how other unavailable measurements were handled.

The registry does not define analysis populations such as intention-to-treat or per-protocol populations, and it does not report time-specific numbers analyzed for the primary endpoint. The safety entries list their own at-risk counts, but those counts do not establish the analysis population for the renin outcome. The detailed analysis plan, including multiplicity and missing-data procedures, is not reported in the registry record.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry lists serious adverse events and other adverse events by cohort. For serious adverse events, it reports 0 affected among 10 at risk in the standard-of-care cohort and 0 affected among 18 at risk in the angiotensin II cohort. For other adverse events, it reports 0 affected among 10 at risk and 0 affected among 18 at risk, respectively. These are counts recorded in the registry, not estimates of comparative risk.

The same safety record lists 9 deaths in each cohort. It does not provide the timing, causes, relationship to treatment, or an analysis comparing mortality. The safety figures should therefore be read as reported counts rather than as proof that either treatment caused, prevented, or had no effect on an event.

Zero recorded events do not establish that an event is impossible or that the risk is absent. The counts are limited to the participants and follow-up represented in the registry entries. The record does not report enough detail about event definitions, surveillance, exposure duration, or follow-up completeness to assess how these factors shaped the counts. In particular, the at-risk counts in the safety entries should not be assumed to equal the number analyzed at every primary renin measurement time.

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

The registry record establishes that a completed, open-label, non-randomized sequential study was designed to examine plasma renin response to angiotensin II versus standard care in septic shock. It specifies the primary outcome, its units and summaries, and the intended measurement schedule. It also lists secondary renal, treatment-duration, mortality, and safety outcomes.

It does not report the numerical primary outcome results. Without renin values or a between-cohort estimate, it is not possible to describe whether levels rose or fell, whether the cohorts differed, or how precise any estimated difference was. No confidence intervals or p-values for the primary outcome are reported in the registry record. The listed outcome definitions and the completed status are not evidence of a particular result.

Even if a cohort contrast were available, the non-randomized sequential design would require caution. The contrast could reflect differences between cohorts other than treatment, and the registry does not describe an adjustment approach. The additional 3-hour measurement in only the angiotensin II cohort also means that the early measurement schedule is not parallel across cohorts. Death could prevent later measurements, and the record says that the number analyzed may vary by outcome time.

The safety record reports zero affected participants in the listed serious and other adverse-event categories, alongside 9 deaths in each cohort. These entries do not identify causes or treatment attribution and do not constitute a comparative safety analysis. They should not be interpreted as demonstrating absence of risk or as establishing a treatment effect on mortality.

The study’s rationale describes interest in renin as a biomarker, but a biomarker response would not by itself establish a patient-important benefit. The registry record does not report findings for the primary renin endpoint or the listed secondary outcomes. Accordingly, the statistical meaning is limited to the study question and design that were registered; the direction, magnitude, precision, and clinical implications of its outcomes remain unreported.

13. Why This Trial Matters Statistically

This study raises a useful statistical question: how to describe a biomarker measured repeatedly during a rapidly changing clinical condition when treatment groups are not randomized. The primary outcome is plasma renin, and the registry identifies both a measurement schedule and a summary based on medians and inter-quartile ranges. Those details define the intended evidence, even though the numerical results are not reported in the registry record.

The design makes the distinction between description and causal comparison especially important. Sequential non-randomized cohorts can be useful for pilot investigation, but a difference between them cannot automatically be attributed to treatment. Patient characteristics, timing, and other contextual factors may also differ. The record does not report a strategy for assessing or adjusting for such factors, so the limitations of group comparability remain central to interpretation.

The study also highlights how the availability of repeated outcomes can change over time. The record notes that death may prevent later measurements, and the early schedule differs because the 3-hour sample was planned only for the angiotensin II cohort. These features affect which observations are available for each time point and the comparisons that can be made. A transparent account of participants measured at each time and the handling of unavailable values would be important for assessing the results, but those details are not reported in the registry record.

Finally, listing multiple outcomes creates questions about which findings were primary and how multiple comparisons were handled. The registry names a primary endpoint but does not report a multiplicity strategy or analysis plan. These issues matter because statistical interpretation depends not only on the measured values but also on prespecified analysis choices. With the results and detailed methods absent, the record is informative about the study question but does not permit assessment of the strength of evidence for a renin response.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for statistical interpretation is that the registry record does not report the primary renin results. It provides no observed values, changes from baseline, between-cohort contrasts, confidence intervals, or p-values. The direction, magnitude, and precision of the primary outcome are therefore unknown from the record.

The non-randomized sequential design limits causal interpretation. The registry does not report baseline characteristics, the extent of cohort comparability, or a statistical method for adjusting for differences. Open-label treatment is also recorded, but the effect of unmasked treatment on measurement and care is not described. These limitations do not show that bias occurred; they mean that its extent cannot be evaluated from the registry record.

Measurement opportunities were not identical across cohorts because the 3-hour renin sample was specified only for the angiotensin II cohort. The outcome description further states that deaths could prevent later samples, so the number analyzed may change over time. Actual numbers measured at each time, reasons for missingness beyond death, and methods for handling missing data are not reported.

The record lists multiple secondary outcomes but does not report their results, a multiplicity approach, or a detailed statistical analysis plan. It also records zero analyses. The protocol’s sample-size justification, interim analyses, and methods for repeated measurements are not reported in the registry record. The planned enrollment of 30 alone does not show whether the study was adequately sized for a particular effect. These omissions prevent a full assessment of statistical precision, robustness, and the risk of selective emphasis among outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Renin and Renal Biomarker Response to Angiotensin II — NCT04558359.
• Registry record last updated 2024-09-04; status last verified 2024-08.
• Results first posted 2024-09-04.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT04558359 is a completed Phase 4, open-label, non-randomized sequential study titled Renin and Renal Biomarker Response to Angiotensin II. It lists septic shock and acute kidney injury, with a planned enrollment of 30, and compares a standard-of-care cohort with an angiotensin II cohort.

The primary outcome is change in plasma renin levels, measured in pg/mL and summarized using medians and inter-quartile ranges. Measurements were planned at baseline, 24 hours, and shock resolution, up to 14 days; a 3-hour measurement was specified only for the angiotensin II cohort. The outcome description notes that deaths could prevent later measurements.

The registry lists eight outcomes and zero analyses. It reports no primary endpoint results, confidence intervals, or p-values. The safety entries list no affected participants for the reported serious and other adverse-event categories, and 9 deaths in each cohort. The detailed statistical analysis plan, multiplicity procedures, and missing-data methods are not reported in the registry record.