Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score (NCT03386539), a randomized phase 3 study. The primary outcome is EFFICACY: MATE-3 Score.

2. Clinical Question

The trial was designed to compare the regimens on this composite score and to assess whether the regimen comparison differed for other transplant outcomes, including patient and allograft survival and freedom from selected events. The registry record reports an intention-to-treat primary population and a score carried forward for participants lost to follow-up or withdrawing consent. It does not report the numbers of participants affected by that rule. The clinical question is therefore about a group-level score comparison under the stated analysis approach, not about a guarantee that either regimen prevents an individual complication.

3. Trial Design

The registry record identifies this as a phase III, randomized, single-masked, parallel-group trial sponsored by Boston Children's Hospital. The study is titled as a comparison of everolimus with low-dose tacrolimus against tacrolimus with mycophenolate mofetil in pediatric heart transplant recipients. The brief summary describes recruitment at 25 centers, starting at 6 months post-transplant, with follow-up for 2.5 years. The registered enrollment is 211; the brief summary describes an intended enrollment of 210. The record does not explain this difference.

The primary outcome was assessed at 30 months post-randomization. The registry lists the study as completed, with a primary completion date of 2023-04-17 and a start date of 2018-01-29. The comparison was organized around two parallel treatment groups rather than a crossover between regimens. The masking designation is single, but who was masked and how masking was maintained are not reported in the registry record.

The primary analysis population is described as intention to treat. The record says the last MATE-3 score was carried forward for participants lost to follow-up or withdrawing consent. It does not report the original sample-size justification or the statistical assumptions used when designing the trial. The prespecified statistical plan, details of any interim analyses, and the approach to multiplicity are not reported in the registry record. These missing design details limit how fully the posted result can be connected to the original 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: Participants were assessed for eligibility according to inclusion and exclusion criteria and asked to provide informed consent. All eligible participants were randomized.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intention to treat population; participants who were lost to follow-up or withdrew consent had their last MATE 3 score carried forward.

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: All patients randomized are included in this table.

6. Primary Endpoint

The registry lists the primary outcome as EFFICACY: MATE-3 Score, measured over 30 months post-randomization.

The primary endpoint was the MATE-3 score at 30 months post-randomization. The registry describes MATE-3 as a validated score ranging from 0 to 12, formed by adding subscores for cardiac allograft vasculopathy, chronic kidney disease, and biopsy-proven acute cellular rejection. It is intended to represent the cumulative burden of these three major adverse transplant events. A higher score represents a worse outcome.

A composite score can capture several clinically important outcomes in one measure. That can be useful when the question concerns overall burden across different complications rather than any single event alone. However, a composite score also combines components that may differ in frequency, severity, and clinical meaning. A group-level difference in the combined score does not by itself establish which component contributed most, or whether every component moved in the same direction.

The registry reports the mean and standard deviation for each group and names the intention-to-treat population. For participants lost to follow-up or withdrawing consent, the last MATE-3 score was carried forward. The numbers of such participants and the component-specific results contributing to the composite are not reported in the registry record. Consequently, the score comparison describes the recorded composite outcome under that missing-data rule; it does not replace separate assessment of the component outcomes.

7. Results Posted in the Registry

• Tacrolimus/Mycophenolate Mofetil: mean 1.30 versus 0.90 on control; difference 0.40 (95% CI -0.24 to 1.04), standardized effect d = 0.17; z-test p = 0.218.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Efficacy: Overall Patient Survival

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Tacrolimus/Mycophenolate Mofetil: 2.9% (3/104) versus 2.8% (3/107) on control; risk difference 0.1 percentage points (95% CI -4.4 to 4.6), risk ratio 1.03 (0.21–4.98); unadjusted two-proportion z-test p = 0.972.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Tacrolimus/Mycophenolate Mofetil and the control. The interval gives the range of effects that remain compatible with the data.

Efficacy: Overall Allograft Survival

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Tacrolimus/Mycophenolate Mofetil: 4.8% (5/104) versus 3.7% (4/107) on control; risk difference 1.1 percentage points (95% CI -4.4 to 6.5), risk ratio 1.29 (0.36–4.66); unadjusted two-proportion z-test p = 0.701.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Tacrolimus/Mycophenolate Mofetil and the control. The interval gives the range of effects that remain compatible with the data.

Efficacy: Freedom From CKD Event

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Tacrolimus/Mycophenolate Mofetil: 95.2% (99/104) versus 98.1% (105/107) on control; risk difference -2.9 percentage points (95% CI -7.8 to 1.9), risk ratio 0.97 (0.92–1.02); unadjusted two-proportion z-test p = 0.233.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Tacrolimus/Mycophenolate Mofetil and the control. The interval gives the range of effects that remain compatible with the data.

The registry record lists secondary outcomes spanning patient survival, allograft survival, kidney function, freedom from selected events, a composite failure outcome, and quality of life. Among the numerical secondary results described in detail, the pattern is not a clear, consistent separation across outcomes: the posted survival counts are close, and the freedom-from-chronic-kidney-disease-event results also do not establish a statistically clear difference in the reported comparisons. These secondary measures address distinct aspects of post-transplant outcomes rather than repeating the MATE-3 composite.

Secondary results provide context for the primary score, but they do not determine what the MATE-3 result means. An individual secondary outcome can move differently from a composite because it measures a different event, uses a different time frame, or captures only one component. The registry record lists 31 secondary outcomes, alongside 33 outcome measures and 34 analyses. The number of outcomes makes it especially important not to treat an isolated result as a definitive answer.

When many comparisons are made, the chance of observing an apparently unusual result by chance increases unless the analysis accounts for multiplicity. The registry record does not report whether or how multiplicity was addressed. For that reason, unadjusted secondary results generally carry less weight than a clearly prespecified primary analysis, especially when considered individually. The secondary findings are best treated as supporting context and as evidence requiring cautious interpretation, not as independent confirmation of a broad treatment advantage.

The full numerical results and analysis details for every listed secondary outcome are not reported in the registry record. As a result, an overall pattern can be described only at a broad level; it cannot establish that every secondary endpoint had a similar result or that any one component explains the primary score.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Efficacy: Overall Patient Survival
• Efficacy: Overall Allograft Survival
• Efficacy: Change in Kidney Function
• Efficacy: Freedom From CKD Event
• Efficacy: Freedom From CAV Event
• Efficacy: Freedom From BP-ACR Event
• Efficacy: Freedom From Composite Failure
• Efficacy: EuroQOL EQ-5D Y (Youth Version)

9. Statistical Interpretation

10. Statistical Methods Explained

The registry reports group means and standard deviations for the primary continuous outcome, alongside a sponsor-reported rank-based comparison. The unadjusted recalculation uses the posted summary statistics to estimate a difference between arithmetic means. These approaches answer related but not identical statistical questions. The sponsor-reported analysis should be understood on its own terms rather than as a direct restatement of the mean comparison.

What does a mean difference describe?

A mean summarizes the average score in a group. A mean difference compares those averages, with the order of subtraction determining its sign. In the recalculation, the comparison is tacrolimus/mycophenolate mofetil minus everolimus/low-dose tacrolimus. Since higher MATE-3 scores indicate worse outcomes, a positive value in that direction means the observed average score is higher in the comparator group. A mean difference does not describe every participant's outcome, nor does it show how the score's three components contributed.

Standard deviation describes the spread of individual scores around a group mean. It is not the same as the standard error, which describes the uncertainty in an estimated group mean. The groups' reported standard deviations provide context for the variability in scores, while a confidence interval for the mean difference addresses uncertainty in the between-group estimate.

Why is the sponsor's rank-based method different?

A Wilcoxon rank sum test compares the ordering of observations after converting them to ranks, rather than relying only on the arithmetic means. The registry names a zero-inflated version of this test, which is relevant when an outcome has a concentration of observations at zero. In general, zero inflation can make a method that explicitly accounts for many zero values more appropriate than an analysis that treats the outcome as if values were distributed evenly around a mean. That is a general statistical explanation; the registry record does not report the number of zero scores or the detailed implementation of the sponsor's test.

The sponsor reports a net mean difference from this analysis. A rank-based test and a simple mean-based recalculation can yield estimates with different meanings, even when applied to the same underlying outcome. Thus, their estimates and p-values should not be compared as though they were alternate calculations of one identical quantity. The sponsor's reported analysis is the analysis identified in the registry record; the recalculation is a simple, unadjusted comparison based on the posted summary statistics.

What do p-values contribute?

A p-value measures how unusual the observed data, or data more extreme, would be under a specified null model. It is not the probability that the null hypothesis is true, nor a measure of the clinical importance of a result. The sponsor reports p = 0.16 for the primary analysis, while the unadjusted recalculation reports p = 0.218. The difference reflects the distinct analysis methods and estimands; the values should not be read as competing versions of precisely the same test.

A p-value also does not show whether an observed effect is large enough to matter. That question requires clinical context, including a meaningful-difference threshold, which is not reported in the registry record. A result that does not cross a conventional significance threshold does not demonstrate that the groups are equivalent. Establishing equivalence or noninferiority requires an appropriate design, a prespecified margin, and analysis information that are not reported in the registry record.

Why do confidence intervals matter?

A confidence interval expresses the uncertainty around an estimate under the assumptions of its statistical method. It indicates a range of effect values compatible with the data and method, rather than a guarantee that the true effect lies within that particular interval. For the sponsor analysis, the reported 95% confidence interval ranges from -0.90 to 0.20. For the unadjusted mean comparison, the recalculated interval ranges from -0.236 to 1.036. Both intervals include zero, but they concern different estimands and should be interpreted separately.

Interval width also matters. A wide interval leaves more uncertainty about the size of a difference than a narrow one. Intervals may include effects in opposite directions and still be consistent with the observed data. The clinical relevance of any value within an interval depends on what size of score difference would matter; that threshold is not reported in the registry record.

What is a planning illustration?

Sample-size illustrations use assumptions about a target effect and analysis to estimate the number of participants needed for a chosen probability of detecting that effect if it is present. They are design-planning calculations, not a measure of how much power the completed trial achieved. The displayed calculations use the observed effect as their starting point and include smaller fractions of that effect. Smaller effects are harder to detect and generally require more participants, all else equal. The trial's original sample-size assumptions are not reported in the registry record.

More generally, results depend on outcome definition, missing-data handling, analysis population, and statistical method. The primary population is identified as intention to treat, and the registry describes carrying forward the last score for participants lost to follow-up or withdrawing consent. The extent and consequences of missing data, the full statistical analysis plan, and any sensitivity analyses are not reported in the registry record. Those omissions limit the extent to which the posted result can be independently assessed against the complete planned analysis.

11. Confidence Intervals and Precision

The sponsor-reported primary estimate is a net mean difference of -0.32, with a 95% confidence interval from -0.90 to 0.20. This interval includes zero and values on either side of it. It therefore does not pin down a single direction of difference between regimens. The range also includes differences whose clinical importance cannot be judged without a meaningful-score threshold, which is not reported in the registry record.

The unadjusted recalculation from the posted group means gives a mean difference of 0.4, with a 95% confidence interval from -0.236 to 1.036. That interval also includes zero and allows for a difference in either direction. Its interpretation concerns a simple arithmetic mean contrast, not the sponsor's rank-based net difference. The intervals should not be placed side by side as if they were confidence intervals for exactly the same estimand.

A confidence interval is a way to express uncertainty under a particular statistical method and its assumptions. It is not a range containing 95% of participant scores, and it is not a probability statement that the true effect has a 95% chance of falling inside the reported interval. A narrower interval would indicate greater precision for that estimand, while a wider interval permits a broader range of possible effects.

The group standard deviations, 2.2 and 2.5, describe variation in individual scores. They do not by themselves determine the clinical importance of the difference between group means. Since the record does not report a clinically meaningful threshold, the precision of the estimates can be described statistically but not translated into a definitive judgment about practical importance.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The primary-outcome planning figures are participants per arm, not total events. They are planning illustrations computed using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect used is the stated fraction of the observed effect. These are not the trial's original design assumptions; those are not reported in the registry record.

Using 100% of the observed effect, the illustration gives 544 participants per arm for 80% power and 727 participants per arm for 90% power. Planning for 75% of the observed effect gives 966 participants per arm for 80% power and 1,293 participants per arm for 90% power. Planning for 50% of the observed effect gives 2,173 participants per arm for 80% power and 2,908 participants per arm for 90% power.

In general, 80% power means that a study designed under the stated assumptions would have an 80% probability of detecting the specified effect using the stated test if that effect were present. The 90% column expresses the same idea at a higher target probability. These probabilities are properties of a proposed design under its assumptions, not certainty about what a study will find. Smaller effects need more participants to detect because they are harder to distinguish from random variation. The figures are planning illustrations based on the observed effect, not observed power for the completed trial.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.400; pooled standard deviation σ = 2.353.
2. n = 2 × (1.96 + 0.842)² × 2.353² / 0.400² = 543.0, rounded up to 544 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.4                      # observed difference in means
sigma <- 2.35263264934735                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(3386539)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 544 (80% power), 727 (90% power)
 75% of observed effect: n per arm = 966 (80% power), 1,293 (90% power)
 50% of observed effect: n per arm = 2,173 (80% power), 2,908 (90% power)
power.t.test: 544 
Simulated power at n = 544 per arm: 0.802 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry reports a sponsor analysis of the primary outcome using a zero-inflated Wilcoxon rank sum test. It gives a net mean difference of -0.32, a 95% confidence interval from -0.90 to 0.20, and p = 0.16. The result is rank-based and should be interpreted as the sponsor's reported analysis, not as a simple comparison of arithmetic means.

The unadjusted recalculation uses the posted group means and standard deviations. It estimates a mean difference of 0.4 for tacrolimus/mycophenolate mofetil minus everolimus/low-dose tacrolimus, with a 95% confidence interval from -0.236 to 1.036 and p = 0.218. The two estimates differ in method and estimand, so their numerical differences do not, by themselves, indicate an error or a contradiction.

The registry record does not flag a discrepancy between the posted summary statistics and the sponsor analysis. The sponsor result is the trial's reported analysis; the recalculation is a supplementary, unadjusted calculation from the posted summaries. Neither analysis provides a precise estimate that excludes zero. The full statistical analysis plan and further details about the sponsor method are not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates several outcomes, time points, or statistical comparisons. With more tests, the possibility of at least one apparently positive result by chance can increase. A prespecified strategy may control that issue, for example by prioritizing a primary endpoint or adjusting inference across selected comparisons. The registry record identifies a primary endpoint and lists 31 secondary outcomes, but a multiplicity strategy is not reported in the registry record. It is therefore not possible to determine whether secondary p-values were adjusted or how the family of comparisons was defined.

The primary population is described as intention to treat. The registry says that participants lost to follow-up or withdrawing consent had their last MATE-3 score carried forward. This identifies a missing-data rule for the primary score, but the record does not report how many participants were affected, when their last scores were measured, or sensitivity analyses evaluating the rule. Carrying the last observation forward can make an assumption that the recorded score remains an appropriate substitute for the unobserved later score; whether that assumption is reasonable depends on the circumstances and cannot be assessed from the information reported.

Methods for missing data on secondary outcomes are not reported in the registry record. Nor are the detailed analysis populations for each secondary endpoint, the handling of participants with incomplete outcome data beyond the stated primary rule, or the use of per-protocol analyses. The statistical analysis plan, interim analyses, and original sample-size justification are also not reported in the registry record.

These omissions do not invalidate the posted estimates, but they limit independent assessment of whether each analysis followed its intended plan and how sensitive the results are to analytical choices. The available primary result should therefore be interpreted with the stated intention-to-treat population and score carry-forward rule in mind, while avoiding assumptions about unreported procedures.

16. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: immune system disorders - other, specify (18.3%), lung infection (17.8%), infections and infestations - other, specify (15.9%), dehydration (11.2%), gastrointestinal disorders - other, specify (11.2%).

The registry reports serious adverse events in 76 participants in the everolimus/low-dose tacrolimus group and 60 participants in the tacrolimus/mycophenolate mofetil group. The corresponding group sizes at risk were 107 and 104. Other adverse events were reported in 101 participants and 100 participants, respectively. The record lists 3 deaths in each group.

These figures are counts of participants with reported events, not counts of every event episode. A participant may experience more than one event, and the registry record does not provide enough detail to determine overlap between serious and other adverse-event categories. The leading serious-event terms listed include immune system disorders, lung infection, other infections and infestations, dehydration, gastrointestinal disorders, and upper respiratory infection. Their reported percentages should be read as event-term summaries; detailed definitions and denominators for those percentages are not reported in the registry record.

Adverse-event counts are descriptive. They do not establish that a regimen caused an event or that one regimen has a different safety profile, particularly without further detail on event timing, severity, exposure, and statistical comparisons. The counts should be considered alongside the trial's clinical outcomes and the limitations of the reported safety information.

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

The posted primary results describe the MATE-3 score at 30 months post-randomization for pediatric heart transplant recipients assigned to the two regimens. The average scores were 0.9 in the everolimus/low-dose tacrolimus group and 1.3 in the tacrolimus/mycophenolate mofetil group. Since a higher score represents a worse outcome, the observed means were numerically lower in the former group. The confidence intervals from both the sponsor analysis and the unadjusted recalculation include zero, so the results do not establish a clear difference between the groups.

This does not demonstrate that the regimens are equivalent. A result that does not establish a difference can reflect uncertainty as well as a small underlying difference. Equivalence or noninferiority requires a suitable design and a prespecified margin; such a margin is not reported in the registry record. Nor does the primary score alone show which of its three components contributes to the observed group means.

The trial result is not an estimate of an individual's outcome. Group averages and comparisons cannot predict whether a particular participant will experience cardiac allograft vasculopathy, chronic kidney disease, rejection, or another complication. The posted data also do not justify medical advice or a treatment choice.

Interpretation depends on the endpoint definition, analysis method, missing-data rule, and uncertainty. The sponsor's rank-based result and the mean-based recalculation answer related but different statistical questions. The record states that last MATE-3 scores were carried forward for participants lost to follow-up or withdrawing consent, but does not report how many participants this affected or sensitivity analyses. A clinically meaningful score threshold is also not reported. Those limits make the result informative as a trial comparison while leaving important questions about magnitude, component outcomes, and practical importance unresolved.

18. Why This Trial Matters Statistically

This trial addresses a statistical challenge common in clinical research: comparing treatment strategies when the central outcome combines several important but distinct events. MATE-3 brings cardiac allograft vasculopathy, chronic kidney disease, and biopsy-proven acute cellular rejection into one score. That can offer a concise summary of cumulative burden, but it also means that interpretation requires attention to the score's components and to how the composite is constructed.

The posted results also illustrate why an analysis method matters. The sponsor used a zero-inflated Wilcoxon rank sum test, while a simple recalculation from group means estimates an arithmetic mean difference. Those analyses produce related but not identical estimands. Reporting the method and its uncertainty alongside the group summaries helps readers distinguish a rank-based comparison from a direct comparison of averages.

The trial further highlights the importance of precision and planning. The observed mean contrast has an interval that includes zero, and planning illustrations based on smaller target effects require more participants. Such calculations can help readers understand the relationship between effect size and sample size, but they cannot substitute for the original design assumptions, which are not reported in the registry record.

Finally, the number of listed secondary outcomes underscores why prespecification and multiplicity handling matter. A broad collection of outcomes can provide useful context, but isolated unadjusted results deserve caution. These statistical considerations help readers judge what the trial's posted findings support, what remains uncertain, and which aspects require more complete reporting.

19. 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 trial-specific limitations affect interpretation. The registry's registered enrollment is 211, whereas the brief summary describes enrollment of 210; the record does not explain the difference. The masking designation is single, but who was masked and the practical masking procedures are not reported. The primary analysis carries the last MATE-3 score forward for participants lost to follow-up or withdrawing consent, but the number affected and sensitivity analyses are not reported.

The primary endpoint combines three components. The available primary result does not report how each component contributed to the composite score, and the record does not report a threshold for a clinically meaningful MATE-3 difference. The sponsor's rank-based result and the unadjusted mean-based recalculation also target different statistical quantities, which limits direct numerical comparison between them.

The registry lists 31 secondary outcomes and 34 analyses, but the multiplicity strategy is not reported. The full statistical analysis plan, interim-analysis procedures, and original sample-size assumptions are not reported in the registry record. The arm descriptions are truncated, so complete dosing and dose-adjustment details are not available in the record text. Detailed safety-event definitions, timing, and the extent of overlap between event categories are also not reported.

These reporting limits do not show that a particular analysis or procedure was inappropriate. They identify areas where the registry record does not provide enough detail for independent evaluation. The posted findings should be interpreted within the scope of the reported outcome definitions, analyses, and missing-data information.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score — NCT03386539.
• Registry record last updated 2026-07-31; status last verified 2026-04.
• Results first posted 2026-07-31.
• 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.

23. Record Summary

NCT03386539 is a completed phase III randomized, single-masked, parallel-group trial sponsored by Boston Children's Hospital. It compared everolimus with low-dose tacrolimus against tacrolimus with mycophenolate mofetil in pediatric heart transplant recipients. The primary outcome was the MATE-3 score at 30 months post-randomization, a composite of cardiac allograft vasculopathy, chronic kidney disease, and biopsy-proven acute cellular rejection; higher scores indicate worse outcomes.

The group mean scores were 0.9 and 1.3, respectively. The sponsor-reported zero-inflated Wilcoxon analysis gave a net mean difference of -0.32, with a 95% confidence interval from -0.90 to 0.20 and p = 0.16. The unadjusted mean-based recalculation gave a difference of 0.4, with a 95% confidence interval from -0.236 to 1.036 and p = 0.218. These are different analyses and estimands; both intervals include zero. The original sample-size assumptions, multiplicity approach, and detailed missing-data sensitivity analyses are not reported in the registry record.