This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Safety and Tolerability During Open-label Treatment With LCZ696 in Patients With CHF and Reduced Ejection Fraction (NCT02226120), a na phase 3 study. The primary outcome is Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability of LCZ696.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02226120 |
| Phase | Phase 3 |
| Condition | Chronic Heart Failure With Reduced Ejection Fraction |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 1980 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Novartis Pharmaceuticals |
| Results posted | Yes |
2. Clinical Question
Population
Eligible participants from PARADIGM-HF with chronic heart failure and reduced ejection fraction who entered this open-label study. The safety population was defined as enrolled participants who received at least one dose of open-label study medication.
Intervention
Open-label LCZ696. The listed target dose was 200 mg bid. The registry record describes the study as collecting safety and tolerability data during treatment.
Comparator
There was no comparison group. The study is recorded as single-group, with allocation listed as NA and masking listed as none. Its figures therefore describe participants treated in this study; they do not estimate a difference against a control group.
Primary question
What treatment-emergent adverse events, serious adverse events, and deaths were reported during LCZ696 treatment and the stated follow-up period? The primary assessment was descriptive and included safety events of interest and other safety measures specified in the registry record.
The clinical question is about the observed safety experience, not whether LCZ696 was more or less effective or safer than another treatment. The registry record identifies the study as phase 3 and reports enrollment of 1980. The primary outcome timeframe extends from the first dose of study treatment to 30 days after the last dose, up to 30 months. That timeframe defines the period for collecting the listed safety outcomes; it does not by itself establish how long every participant was followed.
The study enrolled eligible participants from the parent PARADIGM-HF trial. The record says that the parent trial had been terminated early after a prespecified interim analysis in March 2014, but this extension study’s stated purpose was to collect safety and tolerability information. Its single-group structure means the reported event counts provide a description of the treated cohort, not a controlled estimate of treatment effect or comparative risk.
3. Trial Design
This was a completed phase 3, multicenter, open-label study of LCZ696 in participants with chronic heart failure and reduced ejection fraction who were eligible from PARADIGM-HF. The registry record lists a single-group model, no masking, and allocation as NA. It reports enrollment of 1980 and one listed intervention, LCZ696. No control group is identified.
The study’s stated purpose was to collect safety and tolerability data during open-label treatment. The treatment description gives a target dose of 200 mg bid. “Open-label” generally means that treatment assignment is not concealed from participants and study personnel; in a single-group study such as this one, it also means that the safety observations were gathered without a blinded comparison arm. That general description does not establish whether particular measurements or event assessments used additional procedures, which are not reported in the registry record.
The safety population is defined in the registry record as all enrolled participants who received at least one dose of open-label study medication. The primary outcome timeframe runs from the first dose to 30 days after the last dose, up to 30 months. The registry record gives start and primary-completion dates and marks the study completed, but the timeframe does not mean that every participant necessarily had the same duration of observation.
The primary safety assessment included angioedema, adverse events suspected to be related to LCZ696, adverse events leading to study-drug discontinuation, and serious adverse events, including death. The description also names sitting systolic and diastolic blood pressure, heart rate, and serious adverse events suspected by investigators to be related to LCZ696. It states that only descriptive analysis was done. Further details on the schedule and operational definitions for these assessments are not reported in the registry record.
Because there is no control group, the design can describe events during treatment but cannot separate treatment-associated events from events that might occur in the absence of treatment or under another treatment. The registry record does not report a randomized comparison for this study.
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 total number in the participant flow and baseline characteristics sections reflects the number of participants treated (1980).
Overall Study
| Stage | LCZ696 |
|---|---|
| STARTED | 1980 |
| COMPLETED | 1660 |
| NOT COMPLETED | 320 |
Reasons for not completing this period:
| Reason | LCZ696 |
|---|---|
| Adverse Event | 60 |
| Death | 172 |
| Study terminated by sponsor | 1 |
| Technical problems | 4 |
| Lost to Follow-up | 13 |
| Physician Decision | 21 |
| Withdrawal by parent/guardian | 36 |
| Non-compliance with study drug | 10 |
| Protocol deviation | 1 |
| missing treatment disposition pages | 2 |
Analysis population for the primary outcome, as defined in the registry: Safety Set (SAF), which consisted of all enrolled participants who received at least one dose of open-label study medication, was considered. Only descriptive analysis done.
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.
| Characteristic | Unit | LCZ696 |
|---|---|---|
| Participants analysed | 1980 | |
| Age, Continuous | years | 67.2 (SD 10.56) |
| Sex: Female, Male: Female | Participants | 453 |
| Sex: Female, Male: Male | Participants | 1527 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 39 |
| Race (NIH/OMB): Asian | Participants | 305 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 80 |
| Race (NIH/OMB): White | Participants | 1450 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 106 |
6. Primary Endpoint
The registry lists the primary outcome as Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability of LCZ696, measured over From first dose of study treatment to 30 days after last dose of study treatment, up to 30 months..
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary outcome is titled as the percentage of participants with treatment-emergent adverse events, serious adverse events, and deaths, as a measure of LCZ696 safety and tolerability. The registry record describes the outcome parameter as a count of participants and gives the unit as participants. The posted safety figures include counts for serious adverse events, other adverse events, and deaths.
In general, a treatment-emergent adverse event is an event recorded after treatment begins, whether or not the event is judged to have been caused by treatment. A serious adverse event is an event classified as serious under the study’s safety criteria. These general descriptions do not replace the study’s detailed definitions; those operational definitions are not reported in the registry record. The registry record separately identifies events suspected by investigators to be related to LCZ696, so event occurrence and suspected treatment relationship should not be treated as interchangeable.
Safety outcomes are used to characterize the types and frequency of unwanted events during treatment and follow-up. Counts can show how many participants were recorded with an event under the registry’s reporting categories. They do not, by themselves, establish that treatment caused an event or provide a comparison with another treatment. The listed timeframe starts at the first dose and continues to 30 days after the last dose, up to 30 months.
Although the outcome title uses the word “percentage,” the registry’s posted figures are counts. No percentage estimate, uncertainty interval, or inferential comparison for the primary outcome is reported in the registry record. The event categories may overlap, and the record does not specify whether the counts are mutually exclusive. Therefore, they should be read as separate reported safety counts rather than added together.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted safety results describe events recorded among participants treated with open-label LCZ696. The registry lists 1980 participants at risk for serious adverse events and 555 with a serious adverse event. It also lists 1980 at risk for other adverse events and 352 with an other adverse event, along with 186 deaths. These are descriptive counts from a single-group study. They do not estimate a difference from an untreated group or another treatment.
The serious-event terms shown in the registry include Cardiac failure at 7.3%, Pneumonia at 2.4%, Cardiac failure chronic at 1.6%, Ventricular tachycardia at 1.6%, Cardiac failure acute at 1.1%, and Cardiac failure congestive at 1.0%. The registry record does not provide further detail alongside these term percentages about the calculation method or the degree to which event terms may overlap. The terms should therefore be read as reported categories, not as mutually exclusive groups or as a complete account of all events.
The study description says that analysis was descriptive only. No inferential analysis is listed in the registry record. As a result, the reported counts do not come with a registry-reported confidence interval or statistical test for the primary outcome. Without those, the precision of the event estimates cannot be assessed from the registry record using inferential statistics. The counts still convey what was recorded, but they should not be mistaken for precise estimates of event probability in other populations or treatment settings.
The record’s safety population is defined as enrolled participants who received at least one dose. The at-risk counts displayed for the event categories are 1980, matching the enrollment count, but the registry record does not provide participant-level details that would clarify all analysis-population and follow-up issues. It also does not report how missing or incomplete safety observations were handled. The stated timeframe allows observation to 30 days after the last dose, up to 30 months; it does not establish equal follow-up for all participants.
Interpretation is further constrained by the absence of a control group and the open-label design. An event occurring during treatment may be related to the underlying condition, other factors, treatment, or more than one of these; the event count alone cannot distinguish among those possibilities. The registry describes some assessments as involving events suspected by investigators to be related to LCZ696, but the posted counts do not provide a separate treatment-attribution analysis for every event category.
The results are consequently best understood as a descriptive safety record from this treated cohort. They support a summary of reported events under the study’s observation period and definitions, but not a controlled estimate of comparative safety, a causal conclusion, or a claim about what would have happened to the same participants under a different treatment.
9. Statistical Methods Explained
The registry describes a single-group study and states that only descriptive analysis was done. The posted safety figures are counts of participants in event categories, rather than estimates from a randomized treatment comparison. No inferential analyses are listed in the registry record. The following statistical explanations are general context for reading such results, not additional analyses reported for this study.
What does a descriptive count tell the reader?
A count records the number of participants assigned to a reporting category. It is useful for describing the recorded safety experience in the study population. A count does not, on its own, show how uncertain the underlying event frequency may be, and it does not establish why an event occurred. To interpret a count as a proportion, the numerator and the appropriate denominator must be clearly defined and refer to compatible populations and observation periods. The registry lists event counts and at-risk counts, but does not give a primary-outcome confidence interval or an inferential test.
Counts also depend on how events are defined, collected, coded, and grouped. For example, one participant may experience more than one event, and one event may be represented in more than one category if the coding rules allow it. Whether that occurred in these data is not reported in the registry record. For that reason, the separate category counts should not be summed to create a total number of participants with any event.
Why does the lack of a comparator matter?
A treatment comparison asks how outcomes differ between groups that receive different interventions or treatment conditions. In a randomized comparison, random allocation is intended to make the groups comparable in expectation, so between-group differences can be interpreted under the design’s assumptions. This study has no listed control group and no randomized comparison. Its event counts therefore describe what was recorded during LCZ696 treatment, rather than what changed because of LCZ696 relative to a comparator.
Even if the observed counts are clinically important, a single-group study cannot directly distinguish treatment effects from the underlying disease, participant characteristics, other care, or chance. This is a limitation of the design, not a defect that can be corrected by interpreting the counts as though a comparison existed.
What would a confidence interval add?
In general, a confidence interval gives a range of values compatible with the data under a specified statistical model and procedure. It communicates sampling uncertainty around an estimate; it is not a guarantee that the true value lies in that particular interval. A narrower interval generally indicates greater precision under the same method and assumptions. No confidence interval for the primary safety outcome is reported in the registry record, so its inferential precision cannot be read from the posted results.
A confidence interval would not remove the study’s design limitations. It could quantify uncertainty around a descriptive rate or a treatment contrast, but a single-group interval would still not create a counterfactual comparison or establish causation. The registry record does not report a treatment contrast for this study.
How should event categories and attribution be understood?
The primary description includes treatment-emergent adverse events, serious adverse events, deaths, events suspected to be related to LCZ696, and events leading to study-drug discontinuation. These are different reporting concepts. In general, “treatment-emergent” refers to timing after treatment starts, whereas “suspected to be related” involves an attribution judgment. Neither label alone proves that treatment caused an event. The detailed definitions and event-assessment procedures are not reported in the registry record.
Serious adverse events are a safety classification, not a measure of how likely an event is to have been caused by treatment. Deaths may also be reported within serious-event categories, but whether and how the posted death count overlaps with the serious-event count is not specified. The categories must not be assumed to be independent or mutually exclusive.
What do design and analysis labels imply?
Open-label means, as a general design term, that treatment is not masked from participants and study personnel. Lack of masking can affect reporting or assessment in some settings, although the registry record does not establish that such effects occurred in this study. The record’s stated descriptive approach means the reported purpose is to summarize safety observations, not to test a comparative hypothesis.
The registry record does not report a statistical analysis plan, a sample-size justification, interim analyses for this study, or methods for adjusting estimates for participant characteristics. A planning illustration based on an observed effect, if used elsewhere, is not observed power and would not convert this single-group safety study into a comparative analysis. No trial-specific planning rationale or comparative effect estimate for this study is reported in the registry record.
For a fuller statistical interpretation, important details would include the precise endpoint definitions, handling of missing safety observations, exposure time for each participant, rules for coding and grouping events, and methods for calculating any event percentages. Those details are not reported in the registry record. Without them, the posted counts remain useful descriptive information, but their scope should be kept to the recorded categories and study population.
10. Multiplicity, Missing Data and Analysis Populations
The registry record describes one primary safety outcome and states that only descriptive analysis was done. It lists no analyses in the record. No statistical testing plan, multiplicity adjustment, or prespecified hierarchy for multiple safety outcomes is reported. Multiplicity is the general issue that arises when several outcomes or hypotheses are examined: more opportunities to identify an apparently unusual result can affect the interpretation of formal statistical tests. Since no inferential tests are listed, the registry record does not allow assessment of how such testing issues were handled.
Several safety concepts appear in the primary description, including angioedema, adverse events suspected to be related to LCZ696, adverse events leading to discontinuation, serious adverse events, death, blood pressure, and heart rate. The record does not specify whether these were treated as separate endpoints, grouped outcomes, or descriptive assessments within a common analysis plan. The number of analyses is listed as zero, so no multiplicity-adjusted results are available to interpret.
Missing-data handling is not reported in the registry record. The safety population is defined as enrolled participants who received at least one dose, but that definition does not explain how incomplete follow-up, missing measurements, or participants with unknown event status were treated. The record also does not report exposure time for each participant or whether observation time varied across participants, beyond the stated timeframe extending to 30 days after the last dose, up to 30 months.
The registry record does not describe separate analysis populations beyond its definition of the Safety Set. It does not report whether all outcome assessments used that same population or how the at-risk counts were determined. These gaps do not invalidate the reported descriptive counts, but they limit independent assessment of the denominators, missingness, and scope of each safety summary.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| LCZ696 | 555 | 1980 | 28.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| LCZ696 | 186 of 1980 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| LCZ696 | 352 of 1980 |
Most frequent serious adverse event terms
| Event term | Organ system | LCZ696 |
|---|---|---|
| Cardiac failure | Cardiac disorders | 144 of 1980 |
| Pneumonia | Infections and infestations | 47 of 1980 |
| Cardiac failure chronic | Cardiac disorders | 32 of 1980 |
| Ventricular tachycardia | Cardiac disorders | 31 of 1980 |
| Cardiac failure acute | Cardiac disorders | 21 of 1980 |
| Cardiac failure congestive | Cardiac disorders | 20 of 1980 |
| Acute kidney injury | Renal and urinary disorders | 18 of 1980 |
| Hypotension | Vascular disorders | 18 of 1980 |
| Myocardial infarction | Cardiac disorders | 16 of 1980 |
| Sudden cardiac death | General disorders | 15 of 1980 |
Most frequent non-serious adverse event terms
| Event term | Organ system | LCZ696 |
|---|---|---|
| Hypotension | Vascular disorders | 252 of 1980 |
| Hyperkalaemia | Metabolism and nutrition disorders | 118 of 1980 |
Serious events with the highest arm-level rate: cardiac failure (7.3%), pneumonia (2.4%), cardiac failure chronic (1.6%), ventricular tachycardia (1.6%), cardiac failure acute (1.1%).
The registry lists 555 participants with a serious adverse event among 1980 at risk for serious adverse events. It separately lists 352 participants with an other adverse event among 1980 at risk for other adverse events, and 186 deaths. These are counts in the posted safety record; they are not estimates of excess risk compared with a control group. No controlled comparison is reported.
The selected serious-event terms and their posted percentages are Cardiac failure, 7.3%; Pneumonia, 2.4%; Cardiac failure chronic, 1.6%; Ventricular tachycardia, 1.6%; Cardiac failure acute, 1.1%; and Cardiac failure congestive, 1.0%. The registry record does not explain the percentage calculation details alongside these terms, nor does it state whether event categories overlap. The listed percentages should not be added together or read as mutually exclusive shares.
The death count may overlap with the serious adverse-event count, but the registry record does not specify the relationship. Similarly, the other-adverse-event count should not automatically be treated as disjoint from the serious-event count. These figures describe reporting categories, not unique participant totals across categories.
The listed outcome timeframe is from the first dose to 30 days after the last dose, up to 30 months. The counts do not indicate that each participant had an identical duration of follow-up. They should be interpreted as safety observations within the study’s stated reporting framework, not as proof of causation or as a forecast for other populations.
12. What the Result Does, and Does Not, Mean
The study provides a descriptive account of safety events reported during open-label LCZ696 treatment among eligible participants from PARADIGM-HF. The registry record gives counts for serious adverse events, other adverse events, and deaths, and it identifies selected serious-event terms with percentages. This information can help readers understand what types of events were recorded in the study and the size of the counts within the stated reporting categories.
Those observations do not demonstrate that LCZ696 caused any particular event. A safety event can occur during treatment without being caused by treatment, and the registry’s categories include both events based on timing and events suspected by investigators to be related. The record does not provide a complete event-attribution analysis for the posted counts. Nor does a descriptive event count establish whether an event frequency is higher or lower than it would have been with another treatment or without treatment.
The single-group design is central to interpretation. There is no control group or randomized contrast in this study, so the event counts cannot be used as a direct estimate of comparative safety. The registry record’s description of the parent PARADIGM-HF trial does not supply a comparator for this open-label study. Findings from the parent trial should not be treated as though they were a randomized comparison within this safety record.
The posted results also do not establish that the listed event frequencies apply to all people with chronic heart failure and reduced ejection fraction. The study population was eligible participants from PARADIGM-HF, and the registry does not report enough information to assess how its participants compare with other populations. The stated follow-up window and event definitions also delimit what the counts represent.
Finally, the lack of inferential analyses means the registry record does not quantify statistical uncertainty around the primary safety counts. The counts are informative as descriptive observations, but they do not settle questions of causality, comparative risk, or generalizability. Their meaning is bounded by the study’s single-group design, open-label conduct, specified population, outcome definitions, and reporting period.
13. Why This Trial Matters Statistically
Safety studies answer a different statistical question from efficacy comparisons. A descriptive safety study can catalogue events during treatment, identify categories that warrant careful review, and document the observation period and population. This study’s stated purpose was to collect safety and tolerability data in eligible PARADIGM-HF participants receiving open-label LCZ696. Its record also identifies specific assessments, including angioedema, suspected treatment-related events, discontinuations for adverse events, serious adverse events, blood pressure, and heart rate.
The statistical importance lies partly in recognizing what descriptive evidence can and cannot establish. Counts communicate the observed reporting burden in a cohort, while a comparison group is needed to estimate differences between treatment conditions. Without a comparator, the data cannot separate treatment-associated events from the background experience of the condition or other influences. Clear descriptions of population, timeframe, and event categories are therefore essential to avoid overstating the meaning of safety counts.
This study also illustrates why the analysis population and denominators matter. The safety population is defined by receipt of at least one dose, and the posted event figures list their at-risk counts. For a reader assessing safety evidence, it is important to distinguish the enrolled population, the treated population, the population with available follow-up, and the population included in each outcome summary. The registry record does not report all details needed to reconcile those concepts or assess missing observations.
Finally, descriptive summaries are not a substitute for transparent inferential methods when the aim is to estimate precision or compare treatments. The registry record says that analysis was descriptive only and lists no analyses. That makes the proper statistical conclusion narrower, but clearer: the record documents reported events under the study’s stated conditions, without a controlled estimate of comparative risk.
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 is the single-group, open-label design. With no control group and no randomized comparison, the study cannot estimate how event counts would differ under another treatment or in the absence of LCZ696. The observed events may reflect treatment, underlying illness, other care, or multiple influences. The design does not permit those explanations to be separated through a between-group analysis.
The registry record states that only descriptive analysis was done and lists no analyses. It does not report confidence intervals, statistical tests, or an inferential analysis plan for the primary safety outcome. Therefore, the precision of the event estimates cannot be evaluated from inferential statistics in the record. The record also does not report a sample-size justification for this study, so enrollment should not be interpreted as evidence of a particular power or precision target.
Several operational details are not reported in the registry record. These include detailed definitions and ascertainment procedures for the safety outcomes, the method used to calculate the selected serious-event percentages, how event categories may overlap, and how missing or incomplete safety data were handled. The relationship between deaths and the serious adverse-event count is also not specified. These omissions limit independent assessment of the summaries and preclude combining separate category counts.
The timeframe is described as extending from first dose to 30 days after last dose, up to 30 months, but the record does not give participant-level exposure or follow-up durations. The counts therefore should not be interpreted as exposure-adjusted rates or as if observation time were necessarily identical across participants. The population was eligible participants from PARADIGM-HF, which also limits generalization beyond the study population. Further details on representativeness are not reported in the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Safety and Tolerability During Open-label Treatment With LCZ696 in Patients With CHF and Reduced Ejection Fraction — NCT02226120.
- Registry record last updated 2019-02-20; status last verified 2019-02.
- Results first posted 2019-02-20.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT02226120 is a completed phase 3, multicenter, open-label, single-group study of LCZ696 in eligible participants from PARADIGM-HF with chronic heart failure and reduced ejection fraction. The registry lists enrollment of 1980, a target LCZ696 dose of 200 mg bid, and no masking or randomized allocation.
The primary safety outcome concerns treatment-emergent adverse events, serious adverse events, and deaths. Its stated timeframe is from first dose to 30 days after last dose, up to 30 months. The safety population is defined as enrolled participants who received at least one dose. The registry states that analysis was descriptive only.
Posted safety counts include 555 participants with a serious adverse event among 1980 at risk, 352 with an other adverse event among 1980 at risk, and 186 deaths. Selected serious-event terms are listed with percentages. The record does not report a control-group comparison, inferential analysis, confidence intervals, or details on missing-data handling. The results are descriptive observations from the treated study population, not comparative or causal estimates.