Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease (NCT03539952), a randomized phase 3 study. The primary outcome is Serum NCC Concentration.

2. Clinical Question

The clinical question is framed around a laboratory measure of copper in the blood rather than a patient-reported symptom or a clinical event. The registry describes the primary outcome as serum NCC measured by speciation assay, in µg/L. Its description says that the comparative analysis was of the mean difference between groups 24 weeks after randomization, with a non-inferiority margin of -50 µg/L.

The comparison is active-treatment versus active-treatment; the record does not describe a placebo group. The trial was open-label, so participants and study personnel were not masked to treatment assignment. The primary outcome was assessed at Week 36. The posted registry results also include urinary copper excretion and the Clinical Global Impression of Change rating scale, both at Week 36. These measures provide additional information but do not replace the prespecified primary question.

3. Trial Design

The registry identifies NCT03539952, titled “Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease,” as a completed, randomized, open-label, parallel-group phase 3 study sponsored by Orphalan. The listed enrollment is 77. The study began on 2018-09-03, and primary completion is recorded as 2020-08-19. The brief description calls it a multicenter study with penicillamine as the active standard-of-care comparator.

The registry describes a penicillamine arm and a trientine arm. Its intervention listings include treatment periods spanning D1-W12, W12-60, and 60-<W108; arm descriptions identify the randomized treatment during the postrandomization and first extension period. These listings indicate that the study record covers more than the primary Week 36 comparison, but they do not by themselves explain every treatment transition or the rationale for each period.

For the primary outcome at Week 36, the posted group summaries include 25 participants in the penicillamine arm and 26 in the TETA 4HCL arm. The registry labels the primary analysis population ITT. These outcome-specific counts should not be interpreted as a complete account of enrollment or of missing measurements; the record does not report the flow of participants through the analysis.

Random allocation can reduce systematic differences between groups at the start of a trial, while open-label conduct leaves treatment assignment known during follow-up. The record does not report the randomization procedure, concealment details, or measures used to limit assessment bias. It identifies a parallel model but does not report the original sample-size justification or the trial's full statistical analysis plan.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: After enrolment, patients entered a 12-week run-in period. This is referred to the Penicillamine Baseline Period. During this time, all patients received penicillamine, allowing dose adjustments to reach clinical and laboratory stability criteria. At the end of this 12-week period, patients were randomized 1:1 ratio to either continue penicillamine or receive TETA 4HCl if protocol definition of stability were met in addition to an independent assessment from a panel of WD specialists.

Penicillamine Baseline Period (Day1-W12)

Reasons for not completing this period:

Post-randomization Period (Week 12-36)

Reasons for not completing this period:

Extension Post Random. (Week 36-60)

Reasons for not completing this period:

All on TETA 4HCl, From wk 60 Till 108max

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT

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 Serum NCC Concentration, measured over Week 36.

The primary endpoint is serum NCC concentration, measured in µg/L by speciation assay at Week 36. NCC refers to non-ceruloplasmin-bound copper. The registry describes this as the primary efficacy outcome and specifies a comparison of group means 24 weeks after randomization. It also records a non-inferiority margin of -50 µg/L.

A continuous laboratory outcome retains information about the measured amount rather than reducing every participant's result to a category. Comparing group means is one way to summarize the average measured concentration in each treatment group. The standard error reported for each mean describes uncertainty in estimating that group average; it is not the spread of individual participant measurements.

In general, a biomarker endpoint can be useful when the measure is relevant to the biological process under study and can be assessed consistently. Its interpretation is not identical to a direct measure of how participants feel, function, or experience clinical events. The registry's secondary outcomes include urinary copper excretion and a clinical global impression rating, which represent other kinds of information. The record does not explain how the NCC measure was validated for this particular comparison or how changes in NCC relate to longer-term clinical outcomes.

The non-inferiority margin is a prespecified boundary used to frame whether the comparative result is compatible with a sufficiently small disadvantage, under a stated direction and analysis. Evaluating that question requires the sponsor's analysis details and uncertainty interval in relation to the margin. The posted sponsor analysis does not include a confidence interval, so the registry result alone does not show the precision of that reported non-inferiority estimate.

7. Results Posted in the Registry

• TETA 4HCL Arm: mean 58.70 versus 46.50 on control; difference 12.20 (95% CI -3.37 to 27.77), standardized effect d = 0.43; z-test p = 0.124.

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.

24-hour Urinary Copper Excretion (UCE)

• 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 errors.
• Result:
  • Penicillamine: mean 510.80 versus 274.50 on control; difference 236.30 (95% CI 106.88 to 365.72), standardized effect d = 0.98; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Penicillamine than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Clinical Global Impression of Change (CGIC) Rating Scale

• 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 errors.
• Result:
  • TETA 4HCL: mean 3.90 versus 4.10 on control; difference -0.20 (95% CI -0.42 to 0.02), standardized effect d = -0.55; z-test p = 0.074.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between TETA 4HCL and the control. The interval gives the range of effects that remain compatible with the data.

The registry reports two secondary outcomes at Week 36: 24-hour urinary copper excretion and the Clinical Global Impression of Change rating scale. Their recalculated comparisons have different patterns: the urinary copper comparison has an interval entirely above zero and an unadjusted p-value below 0.001, while the clinical impression comparison has an interval that includes zero and an unadjusted p-value of 0.074. These are unadjusted summaries and should be interpreted as supporting context rather than as replacements for the primary endpoint.

The secondary measures do not all describe the same construct. Urinary copper excretion is a laboratory measure, whereas the clinical global impression is a rating scale. Their results therefore cannot be combined into a single conclusion about treatment effects. The primary endpoint remains serum NCC, and secondary results do not resolve the limitations in the sponsor's posted non-inferiority analysis.

Unadjusted secondary tests carry less weight because considering multiple outcomes can increase the chance of seeing a nominally notable result by chance. The registry does not report a multiplicity adjustment or identify a hierarchy for interpreting these outcomes. In general, secondary findings are most informative when treated as complementary evidence and interpreted with attention to their measurement, precision, and prespecified status. The record does not establish that either secondary result was intended as confirmatory evidence.

The participant counts also differ across the posted secondary summaries, and the record does not explain the analysis-set differences or the availability of each measure. That makes it important not to infer that every outcome was observed for the same participants or handled in the same way. Together, the secondary findings describe additional Week 36 measurements, but their statistical certainty and relationship to the primary question remain limited by the information reported in the registry.

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

• 24-hour Urinary Copper Excretion (UCE)
• Clinical Global Impression of Change (CGIC) Rating Scale

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each measurement is a serum NCC concentration in µg/L. A mean summarizes the central level of a continuous measure within a group. The registry gives a mean and standard error for each primary-outcome group. In general, the standard error describes the uncertainty of an estimated mean, whereas a standard deviation describes variation among individual observations. The posted primary summaries use standard errors, not standard deviations.

What does the mean difference represent?

The recalculated comparison subtracts the penicillamine group mean from the TETA 4HCL group mean. On that stated orientation, the estimate of 12.2 µg/L means the posted TETA 4HCL mean is higher than the posted penicillamine mean at Week 36. The confidence interval runs from -3.365 to 27.77 µg/L. Because the interval includes zero, the recalculated summaries do not rule out no mean difference at the conventional two-sided 5% level. This statement concerns the unadjusted recalculation; it is not a conclusion about the sponsor's separate non-inferiority analysis.

A confidence interval combines an estimate with a range of values reasonably compatible with the data and the calculation's assumptions. It is not a range containing a known proportion of individual participant values. A wider interval indicates less precision about the comparative estimate; an interval that crosses zero can reflect uncertainty about whether the average contrast is positive or negative. The interval should be considered together with the estimate, the endpoint, and the analysis that produced it.

How should the p-value be read?

The unadjusted p-value is 0.124. In general, a p-value describes how unusual the observed data, or more extreme data, would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, nor is it a measure of clinical importance. Because this p-value is unadjusted, it does not account for testing multiple outcomes or comparisons. It also does not answer the non-inferiority question by itself: that assessment depends on the direction of the contrast, the margin, and the relevant confidence interval from the planned analysis.

What is different about non-inferiority?

In a non-inferiority design, the objective is not simply to show that two group means differ. The analysis asks whether the data exclude an unacceptable loss relative to a prespecified margin. The registry lists -50 µg/L as the margin and reports a sponsor analysis of mean difference in final values of -9.2. However, the reported result has no confidence limits or p-value, and the registry does not provide the method or direction convention for that analysis. Without those details, the sponsor's non-inferiority inference cannot be independently evaluated from the posted result. A recalculated ordinary difference test is not a replacement for the planned non-inferiority analysis.

Why do the recalculated and reported results need to stay separate?

The recalculation uses posted group means, standard errors, and group sizes to produce a simple unadjusted comparison. The sponsor's result is described as a mean difference in final values. The registry does not state whether this sponsor analysis used adjustment, a different estimand, or a different direction convention. Nor does it report the sponsor's analysis method. A difference in displayed estimates cannot therefore be explained by assuming a particular model or data handling. The two results answer only what their stated summaries permit.

For continuous outcomes, the usual summary-based comparison relies on assumptions about the sampling distribution and the quality of the reported means and standard errors. In general, the normal approximation can be useful for inference on group means, but it does not make the calculation immune to influential observations, skewed measurements, or departures from the underlying analysis assumptions. The registry does not provide participant-level distributions or diagnostics for the primary endpoint.

Group-level summaries also limit what can be checked. They do not allow an independent review of covariate balance, outcome distributions, outliers, or the handling of missing observations. The primary endpoint population is identified as ITT, but the record does not describe the exact analysis set, how participants with unavailable Week 36 measurements were treated, or whether any imputation was used. These are relevant to interpreting both the estimate and its uncertainty.

The same general issues apply to secondary continuous outcomes. Their means and standard errors support descriptive and unadjusted comparisons, but no adjustment for multiple comparisons is reported. General statistical practice treats exploratory or unadjusted findings as less definitive when several outcomes are considered, because the chance of at least one apparently notable result can increase as the number of tests grows. The registry does not report a multiplicity strategy, so the secondary p-values should not be treated as confirmatory evidence.

11. Confidence Intervals and Precision

The recalculated primary mean difference is 12.2 µg/L, with a 95% confidence interval from -3.365 to 27.77 µg/L. This interval expresses uncertainty around the unadjusted comparison based on the posted summary statistics. It includes zero and also includes values on either side of zero. Thus, the estimate is not precise enough to establish a direction of difference with confidence under this calculation.

The interval is not a statement about where individual NCC results fall. It concerns the uncertainty in the estimated difference between group means. The registry reports standard errors of 5.69 for the penicillamine mean and 5.54 for the TETA 4HCL mean, with outcome counts of 25 and 26, respectively. Those group summaries support a recalculation, but they do not reveal the raw outcome distributions or whether there were influential observations.

The primary outcome description gives a non-inferiority margin of -50 µg/L. The posted sponsor analysis reports -9.2 for mean difference in final values but does not include a confidence interval. As a result, its precision relative to the margin cannot be read from the posted sponsor estimate. The recalculated confidence interval belongs to a distinct, unadjusted comparison and should not be used as if it were the sponsor's non-inferiority interval.

Precision is also distinct from importance. A confidence interval can help show which effect sizes remain compatible with the data under the analysis assumptions, but it does not determine whether those effects matter clinically. The registry does not report a threshold for a clinically meaningful difference in NCC, nor does it provide enough detail to connect the observed laboratory contrast to clinical outcomes.

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, not total participants or total events. They illustrate how sample size changes when planning around different fractions of the observed effect. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The trial's own original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column represents the number of participants per arm in a hypothetical design that would have an 80% chance of detecting the stated effect under those planning assumptions, if that effect and the assumptions were correct. The 90% power column uses a higher chance of detection and therefore requires more participants per arm for the same effect. These are planning illustrations, not a description of the completed trial's design.

The planning rows use 100%, 75%, and 50% of the observed effect. As the assumed effect becomes smaller, more participants per arm are needed to distinguish it from random variation. For example, for the primary outcome, planning for 100% of the observed effect gives 85 participants per arm for 80% power and 114 for 90% power; planning for 50% gives 340 and 454, respectively. The intermediate row is planning for 75% of the observed effect.

These figures are not observed power. They do not tell whether the completed trial was adequately powered for its original objective, since the original planning effect, analysis assumptions, and target power are not reported. Nor should the observed effect be assumed to be the true effect: estimates from a study can be uncertain, and planning from an observed estimate can give an unstable basis for future studies.

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 = 12.200; pooled standard deviation σ = 28.347.
2. n = 2 × (1.96 + 0.842)² × 28.347² / 12.200² = 84.8, rounded up to 85 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 <- 12.2                      # observed difference in means
sigma <- 28.3474074688336                     # 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(3539952)
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 = 85 (80% power), 114 (90% power)
 75% of observed effect: n per arm = 151 (80% power), 202 (90% power)
 50% of observed effect: n per arm = 340 (80% power), 454 (90% power)
power.t.test: 85.7 
Simulated power at n = 85 per arm: 0.792 (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's sponsor-reported primary analysis is a mean difference in final values of -9.2 for the two groups. It is labeled as a non-inferiority analysis, but the record does not include its confidence interval, p-value, method, or direction convention. Those omissions limit independent interpretation: the point estimate alone does not show how precisely the sponsor estimated the contrast or how it related to the stated -50 µg/L margin.

The separate recalculation from posted group means gives a mean difference of 12.2 µg/L when expressed as TETA 4HCL minus penicillamine, with a 95% confidence interval from -3.365 to 27.77 µg/L and an unadjusted p-value of 0.124. This calculation is not the sponsor's reported non-inferiority result. Its direction is explicitly defined from the posted arm means, while the record does not document the sponsor's direction convention or whether its analysis used a different method or estimand.

The registry does not provide enough information to reconcile the two estimates or to identify the reason for their differing signs. The recalculated comparison is useful as a transparent, unadjusted check of the posted summaries, but it should not override the sponsor's planned analysis or be presented as a reproduction of it. The sponsor result also cannot be fully assessed without its uncertainty interval and analysis details.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures and posts the primary serum NCC result alongside two secondary outcomes. It reports one primary analysis. It does not report a multiplicity procedure, such as an adjustment to the significance threshold or a prespecified testing hierarchy. When multiple outcomes are tested, unadjusted p-values do not account for the increased opportunity to obtain a seemingly unusual result by chance. This makes the secondary comparisons less conclusive unless their confirmatory status and multiplicity plan are known.

The primary outcome is labeled as using an ITT population. That label identifies the intended analysis population at a high level, but the record does not explain how the analysis set was defined in practice. It does not report how missing Week 36 measurements were handled, whether any imputation was used, whether participants were analyzed according to their randomized assignments, or whether sensitivity analyses were conducted. These details matter because missing outcome data can affect the estimated group means and the validity of the comparison.

The primary outcome counts and the enrollment figure are not identical descriptions of the study: enrollment is listed as 77, while the posted Week 36 primary summaries include 25 and 26 participants. The registry does not provide a participant flow account or explain these outcome-specific counts. No conclusion about the reasons for unavailable measurements should be inferred from the summaries alone.

The registry record also does not report the trial's complete statistical analysis plan, the randomization method, baseline-adjustment strategy, or the original sample-size assumptions. It gives a non-inferiority margin but does not post the sponsor analysis's confidence interval or p-value. Without these details, readers cannot fully assess the primary inferential procedure, the handling of incomplete data, or how conclusions were protected against multiplicity.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: colitis (4.3%), multiple organ dysfunction syndrome (4.3%), arteriosclerosis coronary artery (4.3%), atrial fibrillation (3.8%), cholangiocarcinoma (3.7%).

The registry posts serious and other adverse-event counts across treatment-period groups. For serious events, the D1-W12 penicillamine group lists 1 affected participant among 27 at risk, and the corresponding TETA 4HCl group lists 1 among 26. In W12-W36, the penicillamine group lists 3 among 27 and the TETA4HCl group lists 0 among 26. Later period-specific entries also report counts, including 3 serious events among 23 at risk in the W60-108 TETA4HCl group, where 1 death is listed; the other listed period groups report zero deaths.

These are period-specific figures, not a single participant-level comparison across the full trial. The registry does not explain whether the same participant could contribute to more than one period, nor does it provide a detailed account of event ascertainment, exposure time, or causal attribution. Counts should not be added across periods to create an overall total. The posted serious-event terms include colitis, multiple organ dysfunction syndrome, coronary artery arteriosclerosis, atrial fibrillation, cholangiocarcinoma, and hepatic cancer, with the registry listing 4.3%, 4.3%, 4.3%, 3.8%, 3.7%, and 3.7%, respectively. These figures describe reported events and do not establish that treatment caused them.

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

The posted primary data describe mean serum NCC concentrations at Week 36 in the randomized penicillamine and TETA 4HCL groups. The simple recalculation estimates a mean difference of 12.2 µg/L, with a 95% confidence interval from -3.365 to 27.77 µg/L. That interval includes zero, so the recalculated comparison is not precise enough to establish a clear group difference in either direction. It does not prove the treatments are equal.

The registry identifies the study as a non-inferiority trial and states a margin of -50 µg/L. However, the sponsor's posted estimate of -9.2 has no confidence interval, p-value, or analysis details. The registry record therefore does not allow a complete independent assessment of the sponsor's non-inferiority conclusion. The unadjusted recalculation should not be substituted for the sponsor's inferential analysis.

The secondary outcomes add information about urinary copper excretion and a clinical impression rating, but they are unadjusted and their multiplicity plan is not reported. They do not settle the primary question. Likewise, adverse-event counts are presented by treatment period and do not, by themselves, establish whether an event was caused by treatment or provide a complete comparative safety analysis.

Overall, the registry supports a description of the posted group averages and their uncertainty, but not a broad claim about effects on all aspects of Wilson disease or longer-term outcomes. The primary endpoint is a laboratory measurement at a specified follow-up time. The record does not report the relationship between that measurement and later clinical outcomes, nor enough methodological detail to resolve the limits of the posted sponsor analysis.

18. Why This Trial Matters Statistically

This study is statistically notable because it frames an active-treatment comparison as a non-inferiority question. Non-inferiority requires more than finding no statistically significant difference: the analysis must estimate the contrast precisely enough, in the correct direction, to rule out an unacceptable loss relative to the margin. The registry records a margin but does not post the sponsor analysis's confidence interval, leaving a key part of that assessment unavailable in the record.

The case also illustrates why recalculations from summary statistics must be separated from a trial's planned analysis. The posted group means and standard errors allow a straightforward unadjusted comparison, but the sponsor's reported final-value estimate is not accompanied by the details needed to reproduce or reconcile it. A transparent recalculation is useful for understanding the summaries, yet it cannot establish that the sponsor used the same endpoint definition, analysis set, or method.

Open-label conduct, incomplete reporting of missing-data handling, and the absence of a reported multiplicity strategy all influence how confidently results can be interpreted. The secondary measures broaden the range of outcomes described, but without a prespecified hierarchy or adjustment, they should not be treated as independent confirmation of the primary question.

The trial therefore provides a useful example of the distinction between an estimate, its precision, and the conclusion a design is intended to support. Readers need the effect estimate and uncertainty, the direction and margin, and the analysis methods to evaluate a non-inferiority claim. When some of those elements are not reported, the correct statistical interpretation is correspondingly limited.

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 limitations are specific to the registry information for this trial. Although the study is described as randomized and open-label, the randomization procedure and allocation concealment are not reported. The record also does not describe blinding of outcome assessment. These omissions limit assessment of how assignment and measurement were protected from bias.

The primary outcome is identified as ITT, but the record does not describe the exact analysis population, missing-data methods, or sensitivity analyses. It provides no participant flow explanation for the difference between enrollment and the Week 36 outcome counts. It is therefore not possible to determine from the registry whether missing measurements could have influenced the reported summaries.

The sponsor's non-inferiority result is posted as -9.2 without an uncertainty interval, p-value, method, or direction convention. The stated margin is -50 µg/L, but the missing analysis details prevent a full evaluation of the reported inferential result. The simple recalculation from group summaries is not a substitute for the sponsor analysis.

The record does not report the original sample-size calculation, its target effect, or its statistical assumptions. Nor does it report adjustment for multiple secondary outcomes. The safety results are separated into treatment periods, and the registry does not explain how period exposure, repeated events, or event attribution were handled. These limitations concern what can be concluded from the record and should not be taken as evidence that any particular methodological choice was made.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease — NCT03539952.
• Registry record last updated 2025-07-02; status last verified 2025-06.
• Results first posted 2023-04-20.
• 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.

23. Record Summary

NCT03539952 is a completed, randomized, open-label, parallel-group phase 3 study of TETA 4HCL and penicillamine in Wilson disease, sponsored by Orphalan. The registry lists enrollment of 77 and identifies serum NCC at Week 36 as the primary efficacy outcome in an ITT population. The primary outcome description specifies a mean comparison and a non-inferiority margin of -50 µg/L.

The posted primary group means are 46.5 µg/L for penicillamine and 58.7 µg/L for TETA 4HCL. The unadjusted recalculation gives a mean difference of 12.2 µg/L, with a 95% confidence interval from -3.365 to 27.77 µg/L and p = 0.124. The sponsor-reported final-value mean difference is -9.2, without a posted confidence interval or p-value.

Two secondary outcomes and period-specific adverse-event counts are also reported. The registry does not provide the full statistical plan, original sample-size assumptions, missing-data methods, or a multiplicity strategy. These gaps limit independent evaluation of the sponsor's non-inferiority analysis and the weight that can be placed on secondary findings.