Open-label Extension Study to Evaluate Long-term Safety of Sacubitril/Valsartan in Pediatric Patients With HF: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open-label Extension Study to Evaluate Long-term Safety of Sacubitril/Valsartan in Pediatric Patients With HF (NCT03785405), a na phase 3 study. The primary outcome is Number of Participants With Adverse Events.

2. Clinical Question

3. Trial Design

This was a completed Phase 3, multicenter, open-label extension study of sacubitril/valsartan in pediatric patients with heart failure. The registry lists a single-group model, no masking, and allocation as not applicable. The arm is described as a single arm receiving open-label sacubitril/valsartan; there was no concurrent control arm.

The study was intended for eligible participants who successfully completed Part 2 of the CLCZ696B2319 core study. Its stated purpose was to evaluate long-term safety and tolerability and provide post-trial access to treatment for those participants. This eligibility history matters: the enrolled group consisted of core-study completers who met the extension criteria, rather than a separately selected group of all pediatric patients with heart failure.

The registry records enrollment of 216 participants. The safety population is defined as participants who received at least one dose of open-label study treatment, and the adverse-event results report 215 participants at risk in total. The registry does not explain the difference between these figures.

The recorded study start date is 2019-05-02, and the primary completion date is 2023-12-29. The study status is completed. The primary endpoint timeframe is described as continuing to the end of the study, up to 4,5 years. Further details of visit schedules, treatment duration for individual participants, or follow-up procedures are not reported in the registry record.

Because there is no concurrent control group, the study can describe events occurring during the extension but cannot provide a direct randomized comparison with another treatment or with no treatment. Any causal comparison would require evidence beyond the single-group results posted for this extension.

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: A 36-hour washout after the last dose of study medication taken in the PANORAMA-HF core study (Visit 416) was required for all participants before starting Open Label Extension study medication.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Set (SAF): All participants who received at least one dose of open-label study treatment during the extension open-label study.

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: Baseline Participants are based on the Safety Set (SAF) population, as primary analysis are based on the SAF.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events, measured over to end of study, up to 4,5 years.

The primary endpoint is the number of participants with at least one adverse event. It is a participant-level count: each person is counted as having met the endpoint if at least one event was recorded during the defined observation period. It does not, by itself, describe how many total events occurred, how often they occurred, how long they lasted, or how severe they were.

The endpoint is assessed in the Safety Set, defined in the registry as all participants who received at least one dose of open-label study treatment during the extension. The timeframe runs to the end of the study, up to 4,5 years. A count of participants with any event is a common descriptive way to present safety experience because it indicates how many participants had an event during exposure and follow-up. It does not establish that treatment caused an event.

The adverse-event results also distinguish serious events from other events, but the posted figures do not give a separate overall primary-endpoint count for participants with any adverse event. The serious-event count and the count for other events may involve participants who experienced both categories; the registry does not report their overlap. They therefore should not be added to produce an overall endpoint count.

Definitions and adjudication details for adverse events, including the criteria used to classify seriousness, are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

These results are primarily descriptive. The endpoint is a count of participants with at least one adverse event, and the posted adverse-event figures give counts of participants classified as affected within stated groups. A descriptive count answers how many participants met a recorded event definition in the analyzed group. It is not, on its own, an estimate of a treatment-versus-control contrast.

What does a participant count represent?

For a participant-level endpoint, the unit is the person, not the number of event episodes. A participant who experiences more than one event may still count once for an endpoint defined as having at least one event. Separate event-term or seriousness categories can count the same participant in more than one place. In general, category counts can only be added when the categories are known to be mutually exclusive; the registry does not report whether the serious and other event groups overlap.

The primary endpoint is defined for the Safety Set: participants who received at least one dose of study treatment during the extension. The adverse-event results identify 215 participants at risk in total, while overall enrollment is 216. The registry record does not explain the difference. The distinction is important because a safety count should be interpreted using its stated analysis population and denominator, not automatically using enrollment.

Why is a comparison unavailable?

In general, a randomized control group can help distinguish differences associated with treatment assignment from differences due to participant characteristics, the course of illness, or other factors. This extension has a single open-label group and no concurrent comparator. Its results can describe the events recorded among participants receiving treatment, but they cannot estimate a randomized between-group difference. The registry explicitly notes that the arms are not a like-for-like control comparison.

Open-label status means the study is not masked. In general, knowledge of treatment can influence reporting, observation, or classification of events. The posted record does not describe procedures that might reduce such influences, nor does it report blinded adjudication of events.

How should precision be assessed?

In general, a confidence interval describes the statistical uncertainty around an estimate under a specified model and analysis. A narrower interval indicates greater precision, while a wider interval indicates less precision. No confidence intervals or other uncertainty intervals for the adverse-event counts are reported in the registry record. Without those intervals, the descriptive counts do not quantify the precision of an estimated event rate.

In general, event rates can depend on both the number of participants who experience events and the amount of time each participant is observed. The registry gives a study-level timeframe of up to 4,5 years, but participant-specific follow-up time and exposure-adjusted rates are not reported in the registry record. The counts should not be read as if each participant necessarily had the same duration of observation.

What does the sample-size illustration mean?

The registry’s stated sample-size assumptions describe a planning illustration based on a fraction of an observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For time-to-event outcomes, the stated convention is to give a total event count using the Schoenfeld approach; for other outcomes, the stated convention is participants per arm. Those are general planning assumptions, not evidence that this single-group extension was designed as a two-arm comparison. The record does not provide a sample-size justification for the actual extension, and no calculated illustration values are included in the registry entries.

Such planning illustrations are not observed power. In general, power calculations describe the chance of detecting a specified effect under assumed conditions; they do not establish the probability that a finding is true or that a treatment has a particular effect. The single-group design and absence of a comparative analysis mean that the illustration cannot supply a control-group estimate for this trial.

The registry lists 0 analyses and does not report inferential tests, model specifications, adjustment methods, or a statistical analysis plan. The posted counts are therefore best read as descriptive safety information, with no registry-reported inferential comparison to support stronger conclusions.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Age Group 1", "Age Group 2")
n      <- c(130, 85)
events <- c(111, 78)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Age Group 1  130  111  85.4  78.1  91.0  78.3  90.4  78.3  90.4
ARM  Age Group 2  85  78  91.8  83.8  96.6  84.0  96.0  83.9  95.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 3 outcome measures but reports 0 analyses. Details about a prespecified testing hierarchy, multiplicity adjustment, or prioritization of secondary outcomes are not reported in the registry record. It is therefore not possible to determine whether the outcome measures were intended to support confirmatory testing or how any multiple-testing concerns would have been addressed. No p-values or comparative analyses are posted in the registry record described for this study.

Missing-data methods are not reported in the registry record. The endpoint is based on participants who received at least one dose, but the record does not explain how incomplete follow-up, withdrawal, missed assessments, or event reports with incomplete information were handled. Nor does it state whether participants were followed for different durations or how those differences affected the summaries.

The defined Safety Set includes all participants who received at least one dose of open-label treatment. The adverse-event results report 215 participants at risk overall, compared with enrollment of 216. The reason for this difference and the disposition of the participant not included in the safety count are not reported in the registry record. The reported figures should be interpreted using the specific denominators stated for each result.

Interim analyses, stopping rules, and any statistical procedures for monitoring accumulating safety data are not reported in the registry record. This absence of detail does not establish that such procedures were or were not used; it means their presence and implementation cannot be assessed from the registry information.

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: cardiac failure (11.5%), covid-19 (4.7%), pneumonia (4.7%), dilated cardiomyopathy (3.8%), chest pain (3.8%).

The serious-event figures are participant counts, not counts of every serious-event episode. In the total group, 84 of 215 participants are recorded as affected by serious adverse events. The age-group entries report 59 of 130 for Age Group 1 and 25 of 85 for Age Group 2. The corresponding figures for other adverse events are 150 of 215 overall, 90 of 130 in Age Group 1, and 60 of 85 in Age Group 2.

Serious and other adverse-event categories are presented separately. The registry does not say whether participants could be represented in both categories, so the counts must not be summed to claim a number of unique participants with any event. The primary endpoint is defined as participants with at least one adverse event, but an overall result for that combined endpoint is not separately stated in the registry entries.

The record reports 11 deaths overall. It does not provide cause, timing, treatment relationship, or a breakdown of deaths by age group in the registry record reported. The serious-event terms and their percentages are descriptive listings; the denominator and event-term counting rules are not reported in the registry record. These figures describe what was recorded and do not establish causation.

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

The registry record documents a long-term safety and tolerability extension for eligible pediatric participants who completed the earlier core study. The posted adverse-event figures describe participants recorded with serious and other adverse events during treatment and follow-up in the extension. They also list serious-event terms and report deaths. This is useful descriptive information about the experience captured in this study population.

The design does not establish whether an event occurred because of sacubitril/valsartan. There is no concurrent control group, and the study is open-label. Events may reflect the underlying condition, other influences, treatment, or a combination; the posted single-group counts cannot separate those possibilities. The figures also cannot establish whether the frequency of events differs from that under another treatment or in a comparable untreated group.

The primary endpoint is the number of participants with at least one adverse event, but the registry entries do not give a distinct overall count for that endpoint. Serious events and other events are reported separately, and overlap is not described. The serious-event counts therefore should not be combined to reconstruct the endpoint. The analysis population is defined by treatment exposure, and the record does not explain the difference between total enrollment of 216 and 215 participants at risk in the total safety results.

The reported timeframe extends to the end of the study, up to 4,5 years, but the registry does not provide individual follow-up durations or exposure-adjusted summaries. The results therefore do not show how event occurrence varied with time on treatment. Confidence intervals, inferential comparisons, and the analysis procedures are also not reported in the registry record. Consequently, the counts do not quantify comparative effects or their statistical precision.

The appropriate interpretation is limited to the descriptive safety experience recorded among participants included in this extension. It should not be extended to all pediatric patients with heart failure, to people who did not meet the extension eligibility criteria, or to a causal conclusion about treatment.

14. Why This Trial Matters Statistically

Statistically, this study illustrates why design determines what a result can answer. The extension has a single open-label group and measures adverse events among participants who received treatment. It can report how many participants in that defined safety population were recorded with events, but it cannot estimate a randomized treatment contrast without a concurrent control group.

The endpoint also highlights the difference between an event count and an event rate. A participant-level count indicates whether a person had at least one event, while repeated events and time at risk require additional information. Although the registry gives an overall timeframe of up to 4,5 years, it does not provide participant-specific follow-up or exposure-adjusted rates. The posted counts alone therefore do not describe event frequency per unit of treatment exposure.

Population definitions are equally important. Enrollment is 216, whereas the total safety results report 215 participants at risk. Because the Safety Set includes participants who received at least one dose, the analysis denominator is not automatically the same as enrollment. The reason for the difference is not reported in the registry record, making transparent reporting of analysis populations essential to interpreting even straightforward safety summaries.

Finally, the record lists 0 analyses and does not report uncertainty intervals or inferential methods. Descriptive counts can convey the observed burden of recorded events, but without information on precision, comparison groups, and analysis procedures they cannot answer whether event occurrence differs from another setting. This distinction between documenting safety experience and estimating comparative effects is central to reading extension-study results responsibly.

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.

Several limitations are specific to the registry information for this extension. The study is single-group and open-label, with no concurrent control. The results therefore describe events in the treated extension population but cannot separate treatment-associated effects from the underlying condition, other exposures, or other influences. The registry itself cautions that the arms are not a like-for-like control comparison.

The study population is restricted to eligible participants who completed Part 2 of the earlier core study. The posted experience may not represent pediatric patients with heart failure who did not complete that study or who were not eligible for the extension. The registry does not provide enough detail to assess how selection into the extension affects the reported counts.

The record reports enrollment of 216 and a total safety group of 215 participants at risk, but does not explain the difference. It does not report individual follow-up duration, exposure-adjusted event rates, event definitions, seriousness-classification procedures, missing-data handling, or the overlap between serious and other adverse-event categories. The overall primary endpoint count is not separately stated in the registry entries.

The serious-event term percentages are listed without a stated denominator or counting rules. The death count lacks detail about timing, causes, or relationship to treatment. The registry also does not report confidence intervals, inferential analyses, a statistical analysis plan, multiplicity procedures, or interim monitoring methods. These omissions limit assessment of precision and of how completely the posted results capture safety over time; they do not establish that unreported procedures were absent.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Open-label Extension Study to Evaluate Long-term Safety of Sacubitril/Valsartan in Pediatric Patients With HF — NCT03785405.
• Registry record last updated 2025-05-16; status last verified 2025-05.
• Results first posted 2024-07-16.
• 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

NCT03785405 is a completed Phase 3, multicenter, open-label, single-group extension study of sacubitril/valsartan in pediatric patients with heart failure due to systemic left ventricle systolic dysfunction. It was intended for eligible participants who completed Part 2 of the CLCZ696B2319 core study, with the stated purposes of evaluating long-term safety and tolerability and providing post-trial access.

The registry reports enrollment of 216 and defines the Safety Set as participants who received at least one dose of treatment. The total adverse-event results list 215 participants at risk. The primary endpoint is the number of participants with at least one adverse event through the end of the study, up to 4,5 years. The posted safety counts include 84 participants with serious adverse events, 150 with other adverse events, and 11 deaths overall; these categories do not establish a causal treatment effect.

There is no concurrent comparator, and the registry lists 0 analyses. The reason for the enrollment and safety-population difference, inferential methods, and further details of missing data and event classification are not reported in the registry record.