Efficacy and Safety Study of WTX101 (ALXN1840) in Adult Wilson Disease Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety Study of WTX101 (ALXN1840) in Adult Wilson Disease Patients (NCT02273596), a na phase 2 study. The primary outcome is Percentage Of Participants With Normalized Concentrations Of NCC.

2. Clinical Question

The study also planned to evaluate safety and a range of other outcomes, including changes in NCC, neurological status, psychiatric status, clinical global impression, and quality of life. These outcomes provide additional ways to describe participants’ status during the study, but the registry record does not report numerical results for them. It lists 23 outcome measures and 0 analyses. The primary question is therefore identifiable from the endpoint description, but the posted record does not give the Week 24 percentage or its confidence interval. Without that result, the magnitude and precision of the primary endpoint estimate cannot be assessed from this record.

3. Trial Design

This was a phase 2, multi-centre, open-label study with a single group. The registry record lists 29 participants as enrolled. The study began on 2014-11-24, had a primary completion date of 2016-10-27, and is recorded as completed. Participants were adults aged 18 and older who were newly diagnosed with Wilson Disease and had NCC concentrations within or above the reference range at enrollment.

The Treatment Period was 24 weeks. ALXN1840 was administered at individualized doses ranging from 15 to 60 mg per day. The dose could be increased or reduced in response to NCC concentrations adjusted for molybdenum plasma concentration; administration could be every other day, once daily, or twice daily. The study description also specifies a planned 36-month Extension Period after the Treatment Period. The registry record does not report results from that extension in the information available for this analysis.

Open-label means the study was not masked: the masking entry is NONE. There was no listed concurrent control group, and the design is recorded as single-group. Consequently, the study can describe outcomes observed among participants receiving ALXN1840, but it cannot establish a randomized contrast against another group. The registry record does not report a protocol-level statistical plan, a sample-size justification, or details of interim analyses. Those features should not be inferred from the phase label or from the listed outcomes.

The primary endpoint was assessed at Week 24, and the population for that endpoint is described as participants who enrolled and received at least 1 dose. The record does not provide a count for that specific analysis population. The safety listing reports 28 participants at risk, which is a distinct reported denominator and should not automatically be treated as the primary endpoint denominator.

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 meeting all inclusion and no exclusion criteria were enrolled into the study and studied as outpatients. Participants enrolled as pre-treated with other de-coppering agents were required to undergo a 48-hour washout from their previous Wilson Disease (WD) treatment just prior to initiation of study treatment. Participants who completed the 24-week treatment period and had favorable safety profiles and WD control were offered the opportunity to participate in the Extension Period.

24-Week Treatment Period

Reasons for not completing this period:

Extension Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who were enrolled and received at least 1 dose of study drug.

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: Participants who were enrolled and received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage Of Participants With Normalized Concentrations Of NCC, measured over Week 24.

The primary endpoint is the percentage of participants with normalized NCC concentrations at Week 24. NCC is a measure of copper not bound to ceruloplasmin. In the registry description, it is calculated by subtracting copper bound to ceruloplasmin from total plasma copper. Post-baseline NCC values were adjusted to account for copper bound in tripartite complexes with ALXN1840 and albumin, and the endpoint also specifies adjustment for molybdenum plasma concentration.

Normalization has a study-specific definition. It includes achieving or maintaining NCC levels in the stated range of 0.8 to 2.3 micromole per liter after adjustment, or reaching a reduction of at least 25% in NCC corrected for molybdenum when NCC was above the normal reference range at enrollment. The endpoint therefore combines a range-based criterion with a reduction criterion for the specified baseline subgroup. It is not simply a report of the average change in NCC.

A percentage endpoint is useful for expressing how many participants meet a defined target, while the accompanying 95% confidence interval is intended to communicate uncertainty around that estimate. The registry record says descriptive statistics are reported, but it does not give the Week 24 percentage or confidence interval. The endpoint definition is available; its observed result and precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint describe?

A percentage endpoint counts participants who satisfy a prespecified definition and relates that count to the relevant analysis population. Here, the definition is tied to NCC at Week 24 and includes two routes to meeting the endpoint, depending on the participant’s baseline NCC status. This approach answers a question about the proportion meeting a target, rather than about the average amount of change across participants.

The definition matters for interpretation. A participant could qualify by achieving or maintaining NCC within the stated adjusted range, or, if baseline NCC was above the normal reference range, by reaching the stated reduction threshold. These criteria do not represent the same measurement in every participant. The registry record does not report how many participants met each route, whether all endpoint data were available, or the final overall percentage.

What does a confidence interval convey?

In general, a confidence interval expresses the uncertainty associated with an estimate under the statistical method used. A narrower interval indicates greater precision than a wider interval, while the interval’s location indicates the range of values compatible with the data and method. A confidence interval is not itself a treatment comparison and does not correct for the absence of a control group.

The primary endpoint specifies a 95% confidence interval, but its bounds are not reported in the registry record. The interval’s width and location therefore cannot be assessed. No interval should be reconstructed without the relevant result and analysis details. In a single-group study, even a precisely estimated percentage would describe the study group; precision alone would not establish what would have occurred under another treatment or without treatment.

Why does the endpoint adjust NCC?

The endpoint description distinguishes the NCC calculation from later adjustments. NCC is calculated by subtracting copper bound to ceruloplasmin from total plasma copper. The record says post-baseline values were adjusted to account for copper bound in tripartite complexes with ALXN1840 and albumin, and the primary endpoint refers to NCC adjusted for molybdenum plasma concentration. These are features of the measure’s definition in this study. The registry record does not provide further laboratory or modeling details, so additional assumptions about the adjustment procedure are not warranted.

How should the design shape statistical interpretation?

A single-group study has no listed concurrent group against which to estimate a treatment contrast. Its descriptive statistics can characterize outcomes among the participants observed, but cannot by themselves separate intervention effects from other influences on outcomes. Open-label conduct also means masking was NONE. The registry record does not report whether outcome assessors were masked or whether any other bias-reduction procedures were used.

The phase 2 designation and enrollment count do not establish the rationale for the sample size. A sample-size justification and the trial’s own statistical analysis plan are not reported in the registry record. Any sample-size planning illustration based on the observed effect is not evidence of the trial’s original design rationale and is not observed power. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect defined as a fraction of the observed effect. Those assumptions describe an illustration, not this single-group study’s reported analysis; the registry record does not provide an observed primary effect.

Why can over-dispersion matter in general?

In general, over-dispersion occurs when observed variability is greater than a statistical model assumes. If a model does not allow enough variability, its uncertainty estimates may be too small and its confidence intervals too narrow. The registry record does not identify an over-dispersion model or report that over-dispersion was assessed for this endpoint. This general consideration should not be mistaken for a description of the analysis used in this study.

What analysis details are missing?

The record states that descriptive statistics are reported for the primary endpoint, but it does not specify the calculation method for the confidence interval, the handling of missing Week 24 observations, or any sensitivity analysis. It also does not report an interim-analysis plan, adjustment for multiple outcomes, or a detailed account of analysis populations beyond the primary population definition. No such methods should be inferred from the listed endpoint or study design.

10. Exact Estimates for Each Arm

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

R code and output

arm    <- c("ALXN1840")
n      <- c(28)
events <- c(24)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  ALXN1840  28  24  85.7  67.3  96.0  68.5  94.3  68.3  94.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 23 outcome measures, including the primary endpoint and secondary outcomes covering NCC, time to normalization, neurological and psychiatric status, clinical global impression, and quality of life. It also lists 0 analyses. The record does not report how the number of outcomes was considered in the statistical plan or whether any multiplicity adjustment was used.

In general, evaluating many outcomes can increase the chance that at least one result appears notable by chance when each is tested separately. A multiplicity strategy can define how to interpret a family of tests, but no such strategy is reported. The listed outcomes alone do not show which tests, if any, were performed or how their results were handled.

Missing-data methods are not reported in the registry record. The primary endpoint population is described as participants who enrolled and received at least 1 dose, but the record does not state the number with an evaluable Week 24 measurement, how missing observations were treated, or whether any imputation or sensitivity analyses were used. The enrollment count of 29 and the safety at-risk count of 28 do not establish the primary analysis denominator.

The record also does not report a detailed analysis-population definition beyond the stated primary population, nor an interim-analysis plan or the protocol-level statistical analysis plan. These omissions limit assessment of how the endpoint was analyzed and how robust its estimate would be to missing observations or alternative analysis choices. Because the numerical primary result is not reported either, its statistical uncertainty and any relationship to secondary findings cannot be evaluated from the registry record.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: agranulocytosis (3.6%), neutropenia (3.6%), hepato-lenticular degeneration (3.6%), dysphagia (3.6%), gait disturbance (3.6%).

The safety listing reports 28 participants at risk for ALXN1840. Among them, 11 were affected by serious adverse events, and 26 were affected by other adverse events. The record reports 0 deaths. These are counts of participants, not a comparison between treatment groups; the study had a single group and no listed control.

The listed serious adverse event terms are Agranulocytosis, Neutropenia, Hepato-lenticular degeneration, Dysphagia, Gait disturbance, and Alanine aminotransferase increased. Each term is reported at 3.6%. These term-specific percentages should not be added together or treated as the overall proportion with serious adverse events: a participant may contribute to more than one event term, and the record does not provide participant-level overlap.

Adverse event counts describe events recorded during the study, not necessarily events caused by the study drug. The registry record does not provide a causal assessment for each event term or a comparison rate from another group. The safety figures should therefore be read as descriptive observations among the participants at risk, not as comparative evidence.

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

The record establishes that this was an open-label, single-group phase 2 study in adults newly diagnosed with Wilson Disease, with a 24-week Treatment Period and a Week 24 primary endpoint focused on normalized NCC concentrations. It also gives the endpoint’s definition, the intended population, and selected safety counts. These details help clarify what the study set out to describe and how the primary outcome was defined.

The record does not report the numerical primary endpoint result or its 95% confidence interval. It therefore does not show what percentage met the endpoint definition or how precisely that percentage was estimated. Although the registry lists secondary outcome measures, it does not report numerical findings for those outcomes in the record used for this analysis. The presence of an outcome in the registry is not evidence of a particular result.

Even if a single-group endpoint percentage were available, it would describe outcomes in the observed study group rather than a randomized comparison. The absence of a comparator limits conclusions about differences relative to another treatment or no treatment. Open-label conduct is another design feature relevant to interpretation, while the registry record does not report additional masking details or procedures that might address bias.

The safety counts likewise describe participants in the study group. They do not establish whether an event was caused by ALXN1840, and they do not quantify how event rates compare with another group. Taken together, the registry record supports a careful account of the study’s design and reported safety experience, but it does not support a conclusion about the size of the primary endpoint result or a comparative treatment effect.

14. Why This Trial Matters Statistically

This study illustrates why an endpoint definition and an endpoint result are different kinds of information. The registry describes a specific Week 24 definition for normalized NCC, including adjustment for molybdenum plasma concentration and criteria that depend on baseline NCC. That definition identifies what the investigators intended to count. Without the numerical percentage and confidence interval, readers cannot assess the observed frequency or its precision.

The design also makes the distinction between description and comparison central. A single-group, open-label study can provide descriptive observations among participants receiving ALXN1840, but it does not provide a concurrent control contrast. A numerical result, if reported, would need to be interpreted in that design context rather than as a randomized estimate of treatment difference.

The record also shows why denominators need to be tied to their purpose. The study enrolled 29 participants, the primary endpoint population is defined by receiving at least 1 dose, and the safety entry identifies 28 participants at risk. The record does not give the number analyzed for the primary endpoint. Treating these counts as interchangeable would obscure which participants contributed to each result.

Finally, the registry lists many outcome measures but does not report analyses or numerical endpoint findings in the record. Without the analysis plan, missing-data methods, or multiplicity approach, readers cannot fully assess how the listed outcomes were handled. These are not minor details: they shape how uncertainty and the breadth of the reported findings should be understood.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several trial-specific limitations follow from the registry information. The study is single-group and open-label, with no listed comparator. This prevents a like-for-like comparison and limits causal interpretation of any changes observed during treatment. The record does not report masking of outcome assessors or other methods that might reduce bias.

The principal limitation for interpreting the primary endpoint is that its Week 24 result and 95% confidence interval are not reported in the registry record. The record describes the endpoint definition and says descriptive statistics are reported, but it does not give the estimate. The number of participants included in the primary endpoint analysis is also not reported. Although 29 participants were enrolled and 28 were listed as at risk for safety, neither count should be assumed to be the primary endpoint denominator.

The registry lists 23 outcome measures and 0 analyses. Numerical results for the listed secondary outcomes are not available in the record, and multiplicity handling is not reported. Missing-data methods, sensitivity analyses, an interim-analysis plan, a detailed statistical analysis plan, and a sample-size justification are also not reported. These gaps prevent assessment of the analysis decisions and the robustness of endpoint estimates.

The study description includes a planned 36-month Extension Period, but extension results are not reported in the record used. The six serious adverse event terms and their percentages are available, along with overall affected-participant counts, but no comparison group or event-level causal assessment is reported. These limitations constrain both efficacy interpretation and comparative safety assessment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy and Safety Study of WTX101 (ALXN1840) in Adult Wilson Disease Patients — NCT02273596.
• Registry record last updated 2021-09-29; status last verified 2021-09.
• Results first posted 2021-09-29.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT02273596 is a completed phase 2, multi-centre, open-label, single-group study of ALXN1840 in adults newly diagnosed with Wilson Disease. The registry lists 29 participants enrolled. The Treatment Period lasted 24 weeks, with individualized doses from 15 to 60 mg per day, followed by a planned 36-month Extension Period.

The primary endpoint was the percentage of participants with normalized NCC concentrations at Week 24. The registry record describes its definition and states that descriptive statistics were reported, but the numerical result and 95% confidence interval are not reported in the registry record. It lists 23 outcome measures and 0 analyses.

The safety entry lists 28 participants at risk, 11 affected by serious adverse events, 26 affected by other adverse events, and 0 deaths. These are descriptive figures from a single-group study, not comparative treatment estimates.