Role of Levothyroxine Supplementation in Delayed Recovery Following Cardiac Surgery: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Role of Levothyroxine Supplementation in Delayed Recovery Following Cardiac Surgery (NCT06660823), a randomized phase 3 study. The primary outcome is Change in Glasgow Coma Scale (GCS) From Intervention Initiation to ICU Discharge (Δ).

2. Clinical Question

3. Trial Design

The registry describes a phase 3, randomized, double-masked, parallel-group trial sponsored by Ain Shams University. It enrolled 70 participants and is marked completed. The registry dates the study start as 2024-11-30 and primary completion as 2025-06-15. The posted primary and secondary summaries divide the participants evenly between Group A and Group B, with 35 participants in each arm.

Group A was assigned levothyroxine, described as L-thyroxine administered via Ryle at 25 to 50 ug/day according to BMI. Group B was assigned an inert starch placebo tablet. The registry identifies the overall intervention as oral levothyroxine supplementation and the design as parallel, meaning participants were assigned to one of the two groups rather than receiving both interventions in sequence. Specific details of allocation concealment, how randomization was generated, and how masking was maintained are not reported in the registry record.

The primary endpoint was change in total Glasgow Coma Scale score from intervention initiation to ICU discharge. Intervention initiation was defined as 48 hours postoperatively; discharge was assessed up to 1 month postoperatively, with the record also specifying within 28 days after baseline. The registry lists secondary outcomes covering mechanical ventilation, ICU and hospital stay, inotropic support, left ventricular ejection fraction, and new-onset supraventricular arrhythmia. Numerical summaries are posted for three secondary outcomes. The original sample-size justification, recruitment targets by arm, and details of the planned statistical analysis are not reported in the registry record.

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.

Overall 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.

6. Primary Endpoint

The registry lists the primary outcome as Change in Glasgow Coma Scale (GCS) From Intervention Initiation to ICU Discharge (Δ), measured over From intervention initiation (48 hours postoperatively) to ICU discharge, up to 1 month postoperatively. (i.e., within 28 days after baseline)..

The primary endpoint is the change in total Glasgow Coma Scale (GCS) score from intervention initiation to ICU discharge. The registry defines the starting assessment as 48 hours after surgery and before the intervention. The endpoint is assessed through ICU discharge, up to 1 month postoperatively, with the timeframe further specified as within 28 days after baseline.

The GCS combines eye, verbal, and motor responses into a total score ranging from 3, the worst score, to 15, the best score. The registry explains that higher totals indicate better neurological function. Measuring change focuses on the difference between the post-operative starting assessment and the later ICU-discharge assessment, rather than the discharge score alone. In principle, this can describe how the recorded level of consciousness changes over the interval; it does not by itself identify why a change occurred.

The posted primary summaries are means and standard deviations of change scores by group. The levothyroxine group mean change was 6.65 (SD 3.6), and the placebo group mean change was 2.69 (SD 0.64). The registry does not post the underlying individual scores, baseline distributions, or details of how participants with an unavailable discharge assessment were handled. Those omissions limit assessment of the endpoint beyond the group summaries.

7. Results Posted in the Registry

• Group A (Study Group): mean 6.65 versus 2.69 on control; difference 3.96 (95% CI 2.75 to 5.17), standardized effect d = 1.53; z-test p = <0.001.

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.

Total Duration of Mechanical Ventilation

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Group A (Study Group): mean 130.40 versus 142.14 on control; difference -11.74 (95% CI -40.33 to 16.85), standardized effect d = -0.19; z-test p = 0.421.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group A (Study Group) and the control. The interval gives the range of effects that remain compatible with the data.

Duration of Intensive Care Unit (ICU) Stay

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Group A (Study Group): mean 9.03 versus 7.51 on control; difference 1.52 (95% CI -0.37 to 3.41), standardized effect d = 0.38; z-test p = 0.115.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group A (Study Group) and the control. The interval gives the range of effects that remain compatible with the data.

Total Hospital Stay Stay.

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Group A (Study Group): mean 13.06 versus 10.29 on control; difference 2.77 (95% CI 0.89 to 4.65), standardized effect d = 0.69; z-test p = 0.004.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Group A (Study Group) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes broaden the assessment beyond the primary change in GCS. The registry names six secondary outcomes, covering mechanical ventilation, duration of ICU and hospital stay, inotropic support, change in left ventricular ejection fraction, and new-onset supraventricular arrhythmia. Numerical group summaries and comparisons are posted for mechanical ventilation duration, ICU stay, and hospital stay; numerical results for the other listed outcomes are not reported in the registry record.

Across the posted secondary summaries, the estimated group contrasts do not form a uniformly aligned pattern with the primary result. The ventilation and ICU-stay comparisons have confidence intervals that include zero and unadjusted p-values above 0.05. The hospital-stay comparison is in the direction of a longer mean stay in the levothyroxine group, with an interval above zero and an unadjusted p-value of 0.004. These additional endpoints therefore add context, rather than a single consistent picture that simply reinforces the primary contrast.

General statistical interpretation: secondary outcomes can help describe other aspects of the trial, but they are usually less decisive when many outcomes are examined without a reported multiplicity strategy. Unadjusted tests do not account for the number of opportunities to obtain a seemingly notable result. In addition, the registry does not report which secondary analyses, if any, were prespecified as confirmatory or how missing measurements were handled. The secondary results should be considered alongside the primary endpoint, not treated as independent proof of the same underlying effect.

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

• Total Duration of Mechanical Ventilation
• Duration of Intensive Care Unit (ICU) Stay
• Total Hospital Stay Stay.
• Average Inotropic Support Infusion Rate in ICU
• Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to ICU Discharge
• Number of Participants With New-onset Supraventricular Arrhythmia

9. Statistical Interpretation

10. Statistical Methods Explained

The registry presents the primary outcome as a continuous measure: mean change in GCS score. A continuous outcome can take a range of numerical values, and the group mean describes the average observed change. The standard deviation describes the spread of individual scores around that group mean. These are different features: the mean locates the group average, while the standard deviation indicates how varied the observations are within the group. The posted primary means are 6.65 for Group A and 2.69 for Group B, with standard deviations of 3.6 and 0.64, respectively; each group has 35 participants in the summary.

What does the mean difference describe?

The reported mean difference is 3.96, calculated as the levothyroxine-group mean change minus the placebo-group mean change. A positive value means the posted average change was higher in the levothyroxine group. The comparison is a difference in group averages, not a statement that every participant had a higher score or that the groups were identical in other respects. A mean difference also retains the outcome’s original scale, so this contrast is expressed in GCS points.

What do the standard deviation and standardized effect add?

The registry also reports a pooled standard deviation of 2.585 and a standardized effect estimate, d=1.532. General statistical interpretation: a standardized effect expresses a difference relative to the variability used to standardize it, whereas the mean difference remains in the original outcome units. Standardization can help describe the size of a contrast in relation to the spread of scores, but it does not replace the scale-specific result or explain whether a difference matters clinically. The record does not report a clinical threshold for interpreting GCS change.

How should the confidence interval and p-value be read?

A confidence interval gives a range of values compatible with the estimate under the statistical method and its assumptions. For the primary mean difference, the reported interval is 2.749 to 5.171. Its width conveys precision: narrower intervals indicate greater precision than wider intervals on the same scale. The unadjusted p-value is <0.001. General statistical interpretation: a p-value measures how unusual data at least as discrepant as those observed would be under a specified null model; it is not the probability that the null hypothesis is true, and it does not measure the probability that the finding will replicate. The registry does not name the statistical test or provide the full model specification, so those details should not be inferred from the posted p-value.

What does “unadjusted” mean?

The reported p-values are unadjusted. General statistical interpretation: when several outcomes or comparisons are examined, each test creates an opportunity to observe a small p-value by chance even if none of the underlying effects is real. Adjustments or a prespecified hierarchy can address some multiplicity concerns. The registry record does not report a multiplicity strategy, and it lists no reported analyses. Accordingly, the primary p-value should be understood as an unadjusted result, not as evidence that a family of tests was controlled for multiple comparisons.

Why can variability matter?

General statistical interpretation: greater variation within groups can make estimates less precise, because a fixed group size then provides less information about the underlying group means. The posted primary standard deviations differ between arms, with 3.6 in Group A and 0.64 in Group B. A summary-based comparison can be sensitive to the assumptions used to calculate its standard error and interval, especially when group spreads differ. The record does not identify the exact test, whether assumptions were checked, or whether an alternative method was considered. No conclusion about those choices can be drawn from the reported summaries alone.

The registry supplies an unadjusted comparison and interval for the primary endpoint, but it does not report the original statistical analysis plan, covariate adjustment, analysis population, missing-data method, or handling of protocol deviations. Those details matter because they determine which participants and measurements contribute to an estimate and how uncertainty is calculated. The posted means and comparison remain useful descriptions of the recorded results, but a full evaluation of the analysis requires details not reported in the registry record.

11. Confidence Intervals and Precision

The primary mean difference is 3.96 GCS points, with a 95% confidence interval from 2.749 to 5.171. The interval is entirely above zero, indicating that the range of values compatible with this calculation does not include a zero mean difference. The unadjusted p-value is <0.001. These statistics describe the evidence and precision for the posted group contrast under the method’s assumptions; they do not account for every possible source of uncertainty in the trial.

General statistical interpretation: a confidence interval is not a range containing a fixed proportion of individual participant outcomes. It is a range of plausible values for the population parameter under a repeated-sampling framework and the assumptions used to construct it. The interval’s width reflects sampling uncertainty, but not uncertainty from unreported methods, measurement limitations, selection, missing observations, or other systematic problems. The registry does not report the interval method or full analysis model.

The two arm standard deviations are 3.6 and 0.64, so the recorded spread of change scores differs between groups. This matters when considering how a mean-difference interval was obtained. The pooled standard deviation is 2.585, but the record does not give details about assumption checks or sensitivity analyses. The estimate and interval should therefore be read as a summary of the posted analysis rather than as a guarantee that all relevant sources of variation have been captured.

Precision also differs from clinical importance. The registry defines the direction of better GCS function, but it does not provide a threshold for a meaningful change. Consequently, the interval can describe the statistical range for the group contrast, but it cannot by itself determine the practical importance of that contrast.

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 planning figures are participants per arm for the continuous-outcome comparisons. They are not total events. The planning illustration uses the observed effect or a stated fraction of it, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The original trial’s own design assumptions and sample-size justification are not reported in the registry record.

The 80% power column indicates the estimated participants per arm under those planning assumptions for a design with an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column gives the corresponding planning figure for a 90% chance. These are planning concepts, not guarantees for a future study; realized power depends on the true effect, variability, analysis, and other design features.

The rows use 100%, 75%, and 50% of the observed effect. Smaller assumed effects require more participants per arm to achieve the same target power under the stated assumptions. The figures are illustrations calculated from the observed effect, not the trial’s original design rationale. This is not observed power.

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 = 3.960; pooled standard deviation σ = 2.585.
2. n = 2 × (1.96 + 0.842)² × 2.585² / 3.960² = 6.7, rounded up to 7 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 <- 3.96                      # observed difference in means
sigma <- 2.58549801779077                     # 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(6660823)
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 = 7 (80% power), 9 (90% power)
 75% of observed effect: n per arm = 12 (80% power), 16 (90% power)
 50% of observed effect: n per arm = 27 (80% power), 36 (90% power)
power.t.test: 7.8 
Simulated power at n = 7 per arm: 0.755 (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. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and six secondary outcomes. It posts comparison results for the primary outcome and numerical summaries for three secondary outcomes, while the other listed secondary outcomes lack numerical results in the registry record. The registry reports no analyses in its analysis listing. It does not describe a hierarchy for testing outcomes, a family-wise error approach, a false-discovery procedure, or any other method for addressing multiplicity. The posted p-values are unadjusted.

General statistical interpretation: multiplicity arises when several hypotheses are tested. Without a prespecified strategy, a small p-value among multiple tests can be less persuasive than the same p-value for a single planned primary test, because the chance of at least one low result can increase with the number of tests. The registry identifies a primary endpoint, which helps distinguish it from the secondary outcomes, but the record does not explain whether testing was restricted to a prespecified sequence or whether any correction was used. Therefore, the unadjusted secondary findings deserve cautious interpretation.

Missing-data methods are not reported in the registry record. The record does not state how many participants contributed to each endpoint, whether all randomized participants were included, how unavailable GCS assessments were handled, or whether any imputation or sensitivity analysis was used. The posted arm summaries give n=35 for each primary and displayed secondary outcome, but those counts alone do not describe the analysis population or establish how missing observations were addressed.

The record also does not report intention-to-treat or per-protocol analyses, treatment-adherence summaries, exclusions after randomization, or covariate-adjusted analyses. These details affect how the estimated group contrast should be interpreted. Their absence does not establish that a particular method was or was not used; it means the relevant information is not reported in the registry record.

15. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: arrhythmias (37.1%).

The registry reports serious adverse events affecting 1 of 35 participants in Group A and 13 of 35 in Group B. Other adverse events are recorded as affecting 0 of 35 participants in each group. Death counts are listed separately as 5 in Group A and 16 in Group B. The serious-event term identified as the top serious term is Arrhythmias, reported as 37.1%.

These are counts as recorded, not adjusted comparisons. The registry does not provide an inferential comparison for these safety figures, nor does it report event-level timing, severity criteria, attribution to study treatment, or whether the death counts overlap with the serious adverse event counts. The 37.1% figure is reported for Arrhythmias, but the record does not specify a group-specific denominator in that listing. The figures should therefore be read descriptively and should not be taken on their own to establish why an event occurred or whether the treatment caused it.

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

The primary result describes a larger mean increase in GCS score for the levothyroxine group than for the placebo group over the interval from intervention initiation to ICU discharge. The reported difference is 3.96 points, with a 95% confidence interval from 2.749 to 5.171 and an unadjusted p-value of <0.001. Because higher GCS scores indicate better neurological function, the direction of the recorded mean contrast favors a greater average increase in the levothyroxine group on this measure.

This result does not establish that levothyroxine caused the difference. Randomization is a design feature that can support causal interpretation, but assessing that interpretation also depends on how the study was conducted, how participants were analyzed, whether outcomes were missing, and how the analysis was specified. Important details on these points are not reported in the registry record. The reported estimate also does not show how individual participants changed, or whether the average reflects a similar pattern across the groups.

The result is specific to the GCS change endpoint and its defined assessment interval. It does not directly establish a difference in longer-term neurological function, and the registry does not provide a clinical threshold for interpreting the magnitude of change. The posted secondary outcomes offer additional measures of care and recovery, but their results are not uniformly aligned with the primary contrast, and the unadjusted secondary comparisons carry multiplicity concerns.

The registry’s safety counts should likewise be interpreted descriptively. Event totals do not by themselves establish causation, and the record lacks details on attribution, event timing, and overlap between serious events and deaths. Taken together, the posted data provide a statistical description of the recorded outcomes, but the registry information is not sufficient to settle questions about clinical importance, mechanisms, broader applicability, or treatment-related safety.

17. Why This Trial Matters Statistically

This trial is statistically notable because its primary endpoint is a change score, not a single end-of-study measurement. A change score depends on measurements at the starting and ending assessments, so interpretation hinges on the timing and completeness of both. The record specifies intervention initiation at 48 hours postoperatively and ICU discharge as the endpoint, giving readers a defined interval, while leaving baseline distributions and missing-data procedures unreported.

The group summaries also have notably different standard deviations: 3.6 in the levothyroxine group and 0.64 in the placebo group. General statistical interpretation: differences in variability can matter for standard errors and confidence intervals, and make it useful to know which method was used and whether assumptions were assessed. The registry gives an interval and p-value but does not identify the test or report assumption checks.

The trial reports a clear primary contrast in its posted summary, while the secondary endpoints show a less uniform pattern. This illustrates why an endpoint hierarchy and multiplicity plan matter: one primary result and several secondary tests do not carry identical interpretive weight, particularly when the secondary p-values are unadjusted. The record does not report a multiplicity strategy.

Finally, the planning illustrations are distinct from evidence about the original design. They show how sample requirements would change under stated assumptions and different fractions of the observed effect, but the trial’s own sample-size rationale is not reported. Keeping that distinction clear prevents post hoc planning calculations from being mistaken for design justification or observed power.

18. 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 posted group summaries do not include individual-level data, so readers cannot assess the distribution of change scores, identify outliers, or examine how starting GCS values relate to subsequent changes. The registry does not report baseline GCS summaries, participant flow, exclusions, missing outcome counts, or missing-data methods. Although the displayed outcome summaries list 35 participants in each arm, this does not establish which analysis population was used or how incomplete assessments were treated.

The statistical test and full model are not reported in the registry record. Nor are covariate adjustments, assumption checks, sensitivity analyses, or a prespecified multiplicity plan. The different arm-level standard deviations for the primary outcome make these analysis details particularly relevant to understanding how the posted interval and p-value were calculated.

The registry identifies the trial as double masked and randomized but does not report how the random sequence was generated, whether allocation was concealed, which people were masked, or how masking was maintained. The primary endpoint is assessed at ICU discharge, with the timeframe limited to the stated postoperative window; longer-term outcomes are not included in the posted primary result. The record also does not report a threshold for clinically important GCS change.

Six secondary outcomes are named, but numerical summaries are posted for only three. The registry does not report explanations for unavailable secondary results, treatment adherence, protocol deviations, or detailed adverse-event definitions and attribution. These are limitations of the available registry information; the record does not establish whether unreported procedures or data were absent from the trial itself.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Role of Levothyroxine Supplementation in Delayed Recovery Following Cardiac Surgery — NCT06660823.
• Registry record last updated 2025-08-17; status last verified 2025-08.
• Results first posted 2025-08-17.
• 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.

22. Record Summary

The registry describes NCT06660823, a completed phase 3 randomized, double-masked, parallel-group trial sponsored by Ain Shams University. It enrolled 70 participants: 35 assigned to levothyroxine and 35 to an inert starch placebo. The primary outcome was change in GCS score from 48 hours postoperatively to ICU discharge.

The posted primary mean difference was 3.96 points in favor of a larger mean change in the levothyroxine group, with a 95% confidence interval of 2.749 to 5.171 and an unadjusted p-value of <0.001. Secondary summaries were posted for three outcomes, with other listed secondary outcomes lacking numerical results. The registry does not report the original sample-size justification, full statistical plan, missing-data methods, or multiplicity approach.