Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure (NCT03016325), a randomized phase 2 study. The primary outcome is Percentage of Participants With Clinically Relevant Hypotension up to 6 Hours After the End of Study Drug Infusion.

2. Clinical Question

3. Trial Design

This was a Phase 2b, randomized, double-blind, parallel-group, placebo-controlled, dose-ranging study of continuous 48-hour intravenous infusions of BMS-986231 in hospitalized patients with heart failure and impaired systolic function. The listed allocation was randomized, the masking was quadruple, and the model was parallel. The registry record identifies Bristol-Myers Squibb as the sponsor.

Enrollment was 329. The trial is marked completed, with a start date of 2017-01-13 and a primary completion date of 2019-06-23. The listed conditions include heart failure. The registry record's description identifies HNO donor and placebo interventions. It lists Part I and Part II groups, with Part II including placebo and BMS-986231 at 6 µg/kg/Min and 12 µg/kg/Min. Separate Japan cohort groups are also listed for Part II. The arm descriptions do not provide further details for Part I or Part II Cohort 1.

The primary endpoint is a percentage of participants with clinically relevant hypotension, measured from infusion start through 6 hours after the infusion ended. Secondary outcomes include changes in NT-proBNP at specified post-baseline times and Day 32, participant-reported resting dyspnea through Hour 72, hypotension measures, discontinuations or dose changes associated with blood pressure, serious adverse events assessed up to Day 32, and adverse events assessed up to 120 Hours.

The registry record does not report the randomization procedure, the precise allocation proportions, the details of the masking procedures, or the rationale for the dose choices. It also does not report a sample-size justification or the statistical analysis plan.

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: Main study cohorts: 100 participants in Part I and 222 in Part II were assigned to treatment (322 randomized in total), of which 97 and 214, respectively, were treated (311 total treated). Reasons not treated (Part I): 3 other reasons. Reasons not treated (Part II): 2 no longer met study criteria; 1 adverse event (AE); 5 other reasons. Japanese-specific cohort: 18 participants were randomized and treated in Part II (Japan cohort)

Only the first 6 of 8 groups are shown.

Treatment Period

Reasons for not completing this period:

32-Day Follow-Up Period

Reasons for not completing this period:

182-Day Follow-Up Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All treated participants

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.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Clinically Relevant Hypotension up to 6 Hours After the End of Study Drug Infusion, measured over From start of infusion up to 6 hours post end of infusion.

The primary endpoint is the percentage of treated participants with clinically relevant hypotension during the interval from the start of infusion through 6 hours after the end of study drug infusion. The definition includes either SBP < 90 mm Hg, confirmed by a repeated value < 90 mm Hg, or symptoms of hypotension. The registry record describes this as a percentage of participants and gives a 95% confidence interval as the dispersion measure, but does not report the observed percentages or confidence intervals.

A binary endpoint classifies each participant as meeting or not meeting the event definition within the specified interval. Such endpoints can describe how often a prespecified event occurred in each group. A threshold based on repeated blood pressure readings can distinguish a confirmed low value from a single reading; including symptoms also captures a clinical feature not represented by the pressure threshold alone. These are general reasons for using a defined event endpoint, not claims about the trial's rationale.

The window matters for interpretation: this endpoint concerns hypotension from infusion start through the stated post-infusion period, not every blood pressure outcome during the full follow-up. It should not be conflated with the separately listed secondary outcomes concerning symptomatic hypotension up to 6 hours after infusion, SBP < 90 mm Hg, or discontinuations related to blood pressure. The registry record does not report the operational details for assessing symptoms, the handling of repeated or missing measurements, or the endpoint results by treatment group.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies the primary outcome as a percentage of participants and gives a 95% confidence interval as the measure of dispersion. It does not report the estimates, confidence intervals, analysis method, or a treatment-effect comparison. The explanations below describe general statistical concepts and do not imply that a particular method was used in this trial.

What does a percentage describe?

For a binary outcome, each participant is classified according to whether the event definition was met. The group percentage represents the event frequency in that group. In this trial, the event definition is clinically relevant hypotension, based on a confirmed SBP threshold or symptoms within a stated time window. A percentage is descriptive: it indicates the frequency in the group being summarized, but by itself does not quantify the uncertainty or establish a difference between groups.

Comparisons can be expressed in different ways, such as a difference between group percentages or a ratio of those percentages. These are distinct measures and answer different questions. The registry record does not report a primary treatment-effect estimate or specify which measure was used. No comparison should be inferred from the endpoint definition alone.

What does a confidence interval add?

In general, a confidence interval gives a range of values compatible with an estimate under the statistical model and procedure used. A narrower interval indicates greater statistical precision than a wider interval, while the interval's location reflects the estimated values. A 95% confidence interval is not a guarantee that a particular interval contains the true value; the confidence level describes the long-run behavior of the procedure under its assumptions. Since the registry record supplies no primary endpoint interval, its precision cannot be evaluated.

Intervals around individual group percentages and intervals around a between-group contrast serve different purposes. Overlap or non-overlap of separate group intervals is not a substitute for a direct interval for the contrast. The registry record does not state which confidence intervals would be used for the main comparison, nor does it report any result to interpret.

Why does the endpoint window matter?

A binary event rate depends on both the event definition and the period in which events count. Here, the primary period extends from infusion start to 6 hours after infusion end. An event outside that interval would not meet the stated timing criterion for this endpoint, although it could be recorded under another outcome or adverse-event measure. The record separately lists secondary hypotension and blood pressure outcomes. Those endpoints should be kept distinct because their definitions or assessment periods may differ.

Using repeated confirmation for the SBP threshold is a rule for classifying the event, while including symptoms adds an alternative event criterion. The registry record does not report how the components were combined in analysis beyond the endpoint description, how a participant meeting both criteria was handled, or how repeated measurements and missing readings were treated.

What does randomization contribute?

In general, random assignment is intended to make treatment groups comparable at the time of allocation, on average, so that differences in outcomes can be interpreted as evidence about the assigned interventions when follow-up and analysis are appropriate. The record identifies this study as randomized, double-blind, parallel-group, and placebo-controlled. It does not report the sequence-generation method, allocation concealment, allocation ratio, stratification factors, or the details of who was masked. These details are not reported in the registry record.

The primary endpoint population is described as all treated participants. That is not enough to identify every analysis population used in the trial or to determine whether the analysis followed assignment, treatment received, or another rule. The registry record does not report a participant flow for the primary endpoint or a statistical plan specifying the primary analysis population.

How should multiple groups and outcomes be considered?

The record lists treatment groups in Part I and Part II, two Part II dose levels, placebo groups, and Japan cohort groups. It also lists 32 outcome measures and 36 analyses. With multiple outcomes, groups, or time points, testing many hypotheses can increase the chance of at least one apparently notable result by chance. General methods to address multiplicity include selecting a primary comparison in advance, adjusting significance thresholds, or using a hierarchical testing strategy. The registry record does not report which, if any, approach was used. The number of listed outcomes and analyses does not by itself reveal how the trial's inferential claims were controlled.

Likewise, a planned sample-size calculation and observed results answer different questions. The record describes a planning illustration based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects set as stated fractions of the observed effect. Such illustrations are planning scenarios, not observed power, and they do not replace the trial's original sample-size justification. That justification is not reported in the registry record. No participant-per-arm values or endpoint effect estimate are reported in the registry record for this explanation, so no planning estimate can be interpreted.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 32 outcome measures and 36 analyses. The trial includes groups in Part I and Part II, two Part II BMS-986231 dose levels, placebo groups, and Japan cohort groups. The primary outcome itself has several categories or time points and is not reduced to one comparison in the registry record. These features make the choice of comparison and the handling of multiple analyses important to interpretation.

In general, examining many outcomes, time points, doses, or subgroups can increase the chance that at least one result appears notable by chance. A prespecified testing hierarchy, adjustment procedure, or clear distinction between confirmatory and exploratory analyses can help readers understand how evidence is evaluated. The registry record does not report a multiplicity strategy, the hierarchy of endpoints, or which comparisons were designated for primary inference.

Missing data can also affect a binary endpoint when some participants lack an assessment during the defined window. The registry record describes the primary endpoint population as all treated participants but does not report how many had evaluable measurements, the amount or reasons for missingness, or how missing endpoint status was handled. It does not report imputation, sensitivity analyses, or rules for participants who discontinued or had incomplete blood pressure or symptom assessments.

The record does not report the full analysis populations or explain how participants were assigned to analyses. Thus, the all-treated description attached to the endpoint should not be assumed to answer every question about analysis inclusion. These details are 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypotension (16.7%), myocardial ischaemia (16.7%), cardiac failure (12.2%), acute kidney injury (6.2%), cardiogenic shock (4.2%).

The serious adverse-event summary gives, for each listed group, the number at risk and the number affected. The listed groups include Placebo - Part I, BMS-986231 - Part I, placebo and BMS-986231 dose groups in Part II, and corresponding Japan cohort groups. The record also gives counts for other adverse events and deaths. These are descriptive counts, not estimates of a comparative treatment effect.

The record lists HYPOTENSION and MYOCARDIAL ISCHAEMIA at 16.7% each among the top serious adverse-event terms, CARDIAC FAILURE at 12.2%, ACUTE KIDNEY INJURY at 6.2%, and CARDIOGENIC SHOCK and ACUTE MYOCARDIAL INFARCTION at 4.2% each. These terms and percentages are registry summaries. They do not indicate by themselves whether an event was caused by study treatment, and they should not be conflated with the primary endpoint's defined assessment window.

Group sizes differ, and the Japan cohort groups have small listed numbers at risk. Counts should therefore be read alongside their group denominators, not in isolation. The registry record does not provide comparative statistical analyses for these figures, event-level timing, severity detail beyond the serious-event category, or an attribution assessment. Death counts are reported by group, but the record does not provide enough detail to interpret causes or treatment relationships.

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

The registry record establishes that a randomized, double-blind, placebo-controlled, dose-ranging Phase 2b study was conducted in hospitalized patients with heart failure and impaired systolic function. It identifies a primary endpoint focused on clinically relevant hypotension during infusion and the stated post-infusion period, as well as several secondary outcomes and adverse-event summaries. Those details clarify what the trial set out to assess and the broad structure of its comparison.

The record does not report primary endpoint results. It therefore does not show the event percentage in any treatment group, the size or direction of a between-group difference, or the precision of an estimate. It cannot support a statement that the intervention increased, decreased, or had no effect on the primary endpoint. Absence of a reported result is not evidence that no event occurred or that groups were equivalent.

The adverse-event summaries describe participants affected within listed groups, with denominators and several serious-event terms. These counts are not a complete comparative safety analysis and do not establish causation. A registry listing of deaths or serious events should not be interpreted as attributing them to the intervention without the relevant clinical assessment and analysis.

More broadly, an endpoint result would need to be interpreted in light of the analysis population, missing data, selected treatment contrast, uncertainty, and any multiplicity handling. Those details are not reported in the registry record. The record also does not provide the complete trial report, the detailed statistical analysis plan, or a sample-size justification. Any conclusion about the study's comparative efficacy or safety beyond its stated design and posted summaries would go beyond what the registry record reports.

13. Why This Trial Matters Statistically

This trial illustrates why a registry entry's design and endpoint definitions are not the same as a complete statistical result. The record identifies randomization, masking, parallel groups, placebo control, a dose-ranging structure, and a clinically defined binary primary endpoint. Those details help frame the intended comparison, but without group estimates and uncertainty measures they cannot answer how the endpoint differed across groups.

The study's several parts, dose groups, and Japan cohort groups also make the definition of the principal contrast important. The record lists 32 outcome measures and 36 analyses, yet does not report a multiplicity strategy or a single primary comparison. This is a reminder that the number and organization of analyses affect how readers should assess statistical evidence, particularly when several groups, outcomes, or time points are considered.

The primary outcome combines a repeated SBP threshold with symptoms and uses a specific interval around a 48-hour infusion. That makes operational definitions and assessment completeness relevant: a clear endpoint rule supports consistent classification, while missing readings or symptoms can affect whether participants are classed as having the event. Those handling details are not reported in the registry record.

Finally, adverse-event counts are useful descriptive information, but they do not replace comparative estimates or an account of uncertainty and event attribution. The record's safety figures should be read in the context of their denominators and group structure. Statistically, the main lesson is to separate what the design intended to measure from what the posted results actually establish; in this case, the primary endpoint results are not reported in the registry record.

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 principal limitation for interpreting this registry record is that it does not report the primary endpoint results. Group percentages, confidence intervals, and treatment contrasts are absent, so the endpoint's observed frequency and precision cannot be assessed. The primary outcome is also not reduced to one comparison in the registry record.

The record does not report a statistical analysis plan, the sample-size justification, a multiplicity approach, or details of missing-data handling. Although the endpoint population is described as all treated participants, the record does not specify the number with evaluable endpoint data or the analysis population used for each result. It also does not report the randomization procedure, allocation ratio, or detailed masking procedures.

Arm descriptions for Part I and Part II Cohort 1 are blank, limiting interpretation of those groups beyond their listed names. The record lists distinct Part II dose and Japan cohort groups, but does not give the full rationale or planned contrasts for those groups. The adverse-event summary provides group counts and selected serious-event terms, but does not report comparative inference, event attribution, or detailed timing and context for each event.

These limitations concern what the registry record reports; they do not establish that the information was absent from the full study materials. However, without those details in the registry record, the trial's comparative endpoint findings and their statistical reliability cannot be reconstructed from the reported material.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure — NCT03016325.
• Registry record last updated 2021-01-06; status last verified 2020-12.
• Results first posted 2020-08-19.
• 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

NCT03016325 is a completed, randomized, double-blind, parallel-group, placebo-controlled, dose-ranging Phase 2b study sponsored by Bristol-Myers Squibb. It enrolled 329 hospitalized patients with heart failure and impaired systolic function and evaluated continuous 48-hour intravenous infusions of BMS-986231, an HNO donor, against placebo. The listed start date is 2017-01-13, and the primary completion date is 2019-06-23.

The primary endpoint was the percentage of treated participants with clinically relevant hypotension from infusion start through 6 hours after the infusion ended, defined by confirmed SBP < 90 mm Hg or symptoms of hypotension. The registry record does not report the primary endpoint results, the analysis plan, or the sample-size justification. It does provide group-level adverse-event counts and selected serious-event terms.