Study of Oral ALXN1840 at 2 Dose Strengths in Healthy Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Oral ALXN1840 at 2 Dose Strengths in Healthy Adults (NCT05303324), a randomized phase 1 study. The primary outcome is Maximum Observed (Plasma) Concentration (Cmax) of Total Molybdenum.

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, open-label, two-way crossover study of single-dose pharmacokinetics in healthy adults. The registry record lists 48 participants as enrolled and the study status as completed. The record gives a start date of 2019-07-04 and a primary completion date of 2019-10-09.

Each participant was assigned to one of two treatment sequences. In Sequence 1 (AB), Treatment A, the single enteric-coated tablet, was given in Period 1, followed by Treatment B, three enteric-coated tablets, in Period 2. In Sequence 2 (BA), the order was reversed: Treatment B in Period 1 and Treatment A in Period 2. Participants received one dose in each period under fasted conditions. The treatment descriptions state that participants were discharged following the 240-hour post-dose period.

A crossover design gives each participant exposure to both treatments, with treatment order randomized across sequences. In general, this can make within-participant comparisons informative because a participant can serve as their own reference. Interpretation of crossover results can also depend on period effects, treatment sequence, and whether effects from the earlier period carry into the later period. The registry record does not report a washout duration or the methods used to assess these issues.

The study was open-label, meaning treatment assignment was not masked. The endpoint was based on measured plasma concentrations, with samples analyzed by inductively coupled plasma-mass spectroscopy. The registry record does not describe blinding of laboratory personnel, the randomization procedure, or the allocation ratio. It also does not report the trial's original sample-size justification or detailed statistical 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 randomized to 1 of 2 treatment sequences (A-B) or (B-A) in a crossover study design during 2 dosing periods. Participants were scheduled to receive either treatment A or B on Day 1 of each dosing period. There was a washout of at least 14 days between the dosing periods.

Treatment Period 1

Treatment Period 2

Analysis population for the primary outcome, as defined in the registry: The Pharmacokinetic Population included all participants who had sufficient plasma samples to enable the calculation of PK parameters of at least the area under the plasma concentration versus time curve (AUC) for at least 1 Treatment Period. Participants were grouped by period for each treatment for this analysis.

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: The Safety Population included all participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed (Plasma) Concentration (Cmax) of Total Molybdenum, measured over Up to 240 hours postdose.

The primary endpoint was maximum observed plasma concentration of total molybdenum, abbreviated Cmax in the registry title, measured up to 240 hours after dosing. Cmax is the highest measured concentration in the sampling period. It describes the peak observed concentration rather than the total concentration exposure across time. The record gives nanograms per milliliter as the unit and reports the endpoint as a mean with standard deviation.

The study measured plasma total molybdenum as a surrogate for ALXN1840. Whole blood samples were collected for measurement of plasma total molybdenum concentrations using inductively coupled plasma-mass spectroscopy. A surrogate is a measurable quantity used in place of a substance that is not directly represented by the reported concentration measure. The registry record does not provide a separate validation analysis for this surrogate in these results.

Pharmacokinetic measures such as Cmax are used to describe how concentrations behave after a dose. Comparing the Cmax distributions after the two tablet presentations addresses whether the observed peak concentrations differed in this study. It does not, by itself, describe every aspect of exposure, such as the full concentration-time profile, nor does it establish a clinical effect. The record lists other outcome measures, but the primary result is the maximum observed concentration.

7. Results Posted in the Registry

• ALXN1840 Treatment B: mean 174.27 versus 173.10 on control; difference 1.17 (95% CI -27.21 to 29.55), standardized effect d = 0.02; z-test p = 0.936.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a continuous endpoint summarized by means and standard deviations. For a continuous measure, a mean describes the arithmetic average of observed values, while a standard deviation describes how spread out individual measurements are around that average. The mean is not a value that every participant experienced. The standard deviation is not a confidence interval for the mean and does not describe the precision of the treatment comparison on its own.

What does the mean difference represent?

The posted comparison is expressed as Treatment B minus Treatment A. A positive estimate means the Treatment B mean is higher in the direction of the subtraction; a negative estimate would mean it is lower. The reported estimate is 1.17 nanograms per milliliter. This is an unadjusted recalculation from the posted means and summary information. It is not a model-based treatment estimate from a crossover analysis.

In general, a simple difference in means treats the two displayed treatment summaries as the basis for comparison. In a crossover study, both treatment measurements may come from the same participant. Those measurements are usually correlated: participants with relatively high values under one treatment may also tend to have relatively high values under the other. A paired analysis can use the within-participant differences and their variability. The treatment-level means and standard deviations alone do not reveal the standard deviation of those paired differences, so they do not allow the paired uncertainty to be reconstructed without additional information.

Why does the crossover structure matter?

Randomizing the treatment sequence helps distribute the order of treatment exposure across participants. Period effects are differences associated with when a treatment is given, rather than with the treatment itself. Sequence effects are differences associated with assignment to one order rather than the other. Carryover refers generally to an effect of a previous treatment that persists into a later period. These are standard considerations in crossover studies. Whether and how they were assessed is not reported in the registry record.

The registry descriptions show two periods and the two treatment orders, but do not give a washout duration. They also do not report the model, covariates, or testing approach for an adjusted crossover comparison. The result calculated from the posted summary statistics should therefore be distinguished from an analysis that explicitly models participant, period, sequence, or carryover effects. No such model is posted as an analysis record.

How should the p-value be understood?

The unadjusted p-value of 0.936 comes from a simple recalculation based on the posted summary statistics. In general, a p-value is evaluated under a specified null hypothesis and statistical model. It describes the compatibility of the observed data with that model, not the probability that the null hypothesis is true. It also does not show whether an effect is clinically important. The registry record does not report a sponsor analysis for this endpoint, nor does it state the inferential method used for a primary treatment comparison.

The sample-size planning illustration specifies a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Those assumptions describe the planning illustration, not necessarily the original design of this crossover trial. The trial's original sample-size assumptions are not reported in the registry record. The illustration is based on fractions of the observed effect and is not a substitute for a design calculation based on a prespecified target effect and a crossover-specific variance model.

What is the role of variability and over-dispersion?

General statistical context: variability matters because a mean difference is harder to estimate precisely when individual measurements vary substantially. The standard deviations for the posted treatment summaries are 78.1 and 62.96, compared with a mean difference estimate of 1.17. Those summaries suggest considerable spread relative to the estimated difference, but they do not show the within-person variation needed for a paired crossover calculation.

Over-dispersion is a general term for observed variability greater than a statistical model expects. It can make standard errors too small if a model assumes less variability than is present. The registry record does not report an over-dispersion assessment or a model for it. For this endpoint, it is more appropriate to note that participant-level paired data and the analysis specification are not reported than to infer whether over-dispersion occurred.

All inferential values should be read in light of these limitations. The displayed means and standard deviations are descriptive, while the difference, interval, and p-value are unadjusted recalculations from posted summaries. They do not replace a prespecified analysis using the participant-level crossover data.

10. Confidence Intervals and Precision

The estimated unadjusted mean difference between Treatment B and Treatment A was 1.17 nanograms per milliliter. The reported confidence interval extended from -27.21 to 29.55. In general, a confidence interval expresses uncertainty around an estimate under a particular statistical method. A narrower interval indicates more precision than a wider interval, all else being equal. The confidence level and construction method for this interval are not reported in the registry record.

The interval includes zero and spans negative and positive values. Thus, the posted comparison does not precisely distinguish the direction of a mean difference. The interval also includes differences larger in magnitude than the point estimate in both directions. The result should not be described as proof that the treatments yield the same Cmax; a nonzero difference remains compatible with the interval.

The precision calculation is an unadjusted recalculation from the posted treatment summaries. In a crossover design, a paired interval would typically depend on the variability of within-participant differences. That information is not reported, and the registry record does not provide a crossover-adjusted confidence interval. The displayed uncertainty therefore should not be interpreted as a precision estimate that fully uses the paired design.

The standard deviations were 78.1 for Treatment A and 62.96 for Treatment B. They describe the spread of observed values in each treatment summary, not the uncertainty in the difference by themselves. The registry record gives 48 participants for each posted treatment group, but the pharmacokinetic population definition requires sufficient samples for at least one period, and the final population count under that definition is not reported in the registry record.

11. 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.

Read each planning row as a scenario based on a stated fraction of the observed effect. The listed figures are participants per arm, not total events. The planning illustration assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Its effect to detect is the stated fraction of the observed effect. The original trial's sample-size justification and design assumptions are not reported in the registry record.

The 80% power column gives the illustrated number of participants per arm for a design that would have an 80% chance of detecting the specified effect under those planning assumptions, if that effect and model were true. The 90% power column gives the corresponding per-arm planning figure for a 90% chance. These are design targets, not probabilities that the observed result is correct. They are not observed power.

For 100% of the observed effect, the illustration lists 57,697 participants per arm for 80% power and 77,240 for 90% power. For 75% of the observed effect, it lists 102,573 and 137,316 participants per arm. For 50% of the observed effect, it lists 230,788 and 308,960 participants per arm. The general pattern is that smaller effects require more participants to detect under the same assumptions, and a higher target power also requires more participants.

These are planning illustrations calculated from the observed effect, not an explanation of how the study's enrollment of 48 was originally selected. They rely on a two-arm normal-approximation setup and do not describe a crossover-specific paired analysis. The figures should be read as illustrative rather than as recommendations or as evidence that the completed study had any particular power.

12. 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 = 1.170; pooled standard deviation σ = 70.932.
2. n = 2 × (1.96 + 0.842)² × 70.932² / 1.170² = 57,697.0, rounded up to 57,697 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 <- 1.17000000000002                      # observed difference in means
sigma <- 70.9322054499929                     # 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(5303324)
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 = 57,697 (80% power), 77,240 (90% power)
 75% of observed effect: n per arm = 102,573 (80% power), 137,316 (90% power)
 50% of observed effect: n per arm = 230,788 (80% power), 308,960 (90% power)
power.t.test: 57697.9 
Simulated power at n = 57,697 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.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists three outcome measures and one posted secondary outcome: the number of participants with a treatment-emergent adverse event. It lists no analysis records. The primary endpoint discussed is maximum observed plasma concentration of total molybdenum. The multiplicity strategy for testing multiple endpoints, time points, or treatment contrasts is not reported in the registry record.

Multiplicity arises generally when several statistical hypotheses are tested. If each is considered separately, the chance of at least one apparently unusual result can increase across the set of tests. Statistical plans may address this through a hierarchy, adjustment, or another prespecified strategy. The record does not describe whether such an approach was planned or used. The p-value discussed for the primary comparison is unadjusted and should not be treated as a multiplicity-adjusted result.

The stated pharmacokinetic population included participants who had sufficient plasma samples to calculate pharmacokinetic parameters for at least one treatment period. The record does not state how many participants met that criterion for the primary endpoint, how many had data for both periods, or how missing samples were handled. Missing-data rules, exclusions, imputation, and sensitivity analyses are not reported in the registry record.

These details matter especially for a crossover comparison. If a participant contributes data in only one period, that person may not contribute a complete within-participant comparison. The handling of incomplete periods can affect which observations enter a paired analysis. Because the analysis population counts and missing-data methods are not reported, the displayed treatment group counts should not be assumed to represent a complete paired dataset.

The registry also does not report a prespecified analysis plan, adjustment for period or sequence, or criteria for outlier handling. Those omissions do not demonstrate that the study team did not use such methods; they mean the methods are not reported in the registry record. As a result, the posted summaries support descriptive interpretation, while the precise inferential approach cannot be independently characterized from the record.

14. 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 non-serious adverse event terms

The registry record reports serious adverse events by treatment and period. In Period 1, 0 of 25 participants at risk had a serious adverse event with Treatment A, and 0 of 23 at risk had one with Treatment B. In Period 2, the corresponding counts were 0 of 23 for Treatment A and 0 of 25 for Treatment B. No deaths were reported in the listed groups.

These are period-specific counts in a crossover study, in which participants received both treatments in different periods. They should not be added across periods to create a count of unique participants, because an individual may contribute to more than one period. The record also reports other treatment-emergent adverse events, but serious-event counts are the focus of this summary.

Zero reported serious events in these groups is a description of the posted observations, not evidence that an event is impossible or that the treatments have equivalent safety. The record does not provide a treatment-level inferential comparison of serious adverse events. Interpretation is limited to the reported counts and the study population and exposure described.

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

The posted pharmacokinetic summaries show mean maximum observed plasma total molybdenum concentrations of 173.1 nanograms per milliliter for the single-tablet Treatment A and 174.3 for the three-tablet Treatment B. The unadjusted difference estimate was 1.17, with a confidence interval from -27.21 to 29.55 and an unadjusted p-value of 0.936. These results describe the recorded summary values; they do not establish that the treatments are identical or that a difference is absent.

The study addressed single-dose pharmacokinetics in healthy adults under fasted conditions. It used total molybdenum as a surrogate measure for ALXN1840 and measured concentrations up to 240 hours after dosing. Its findings cannot, on the basis of the posted information, be extended to repeated dosing, other populations, or clinical outcomes. No clinical efficacy endpoint is reported in the primary result.

The crossover structure offers the possibility of comparing the two treatments within the same participants, but the comparison shown is an unadjusted recalculation from treatment-level summary statistics. The registry record does not report the paired analysis, a crossover model, the number of participants with complete data in both periods, or the treatment of missing measurements. Consequently, the result should not be interpreted as a definitive crossover-adjusted estimate.

Safety counts are also descriptive. No serious adverse events or deaths were reported in the listed treatment-period groups, but these counts do not by themselves determine comparative safety. The registry record does not give a formal safety comparison or enough detail to make broader conclusions.

Overall, the record supports a cautious description of observed mean concentrations and their unadjusted uncertainty. It does not support a claim of equivalence, a clinical benefit claim, or a conclusion about how the treatments compare under dosing conditions or populations not studied.

16. Why This Trial Matters Statistically

This trial illustrates the distinction between a study design and the analysis needed to use that design fully. A crossover study exposes participants to both treatments, with the order randomized between sequences. That structure can support efficient within-participant comparisons, but analysis should account for the pairing and relevant period structure. Treatment means and standard deviations alone do not show the variability of paired differences.

The posted unadjusted mean difference is 1.17 nanograms per milliliter, while the interval ranges from -27.21 to 29.55. Reading both the point estimate and its uncertainty matters: the estimate alone can appear exact, while the interval shows that a broad range of differences remains compatible with the reported calculation. The unadjusted p-value does not resolve that uncertainty or establish equivalence.

The endpoint also highlights a recurring distinction in pharmacokinetic reporting. A maximum concentration is one feature of the concentration-time profile, and total molybdenum is identified as a surrogate measure for ALXN1840. The result should be interpreted at that measurement level rather than as a direct clinical outcome.

Finally, the sample-size illustration is based on the observed effect and general two-arm assumptions, while the original design justification is not reported. Such illustrations can show how planning numbers respond to smaller target effects and higher power, but they do not reveal the rationale for the study's enrollment or the achieved precision of a crossover analysis. Transparent reporting of analysis populations, paired methods, missing data, and design assumptions is central to evaluating this kind of result.

17. 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 registry record does not report the numerical dose strengths, so the tablet presentations are distinguishable by the listed tablet counts but not by stated dose amounts. The treatment descriptions identify fasted single-dose administration, but do not report a washout duration. Period and sequence effects, carryover assessment, and the model for the crossover comparison are also not reported.

The posted comparison is an unadjusted recalculation from treatment-level means and standard deviations. It does not incorporate the within-participant covariance that is ordinarily relevant to a paired crossover analysis. The confidence level and calculation method for the interval are not reported in the registry record. The number of participants in the defined pharmacokinetic population, and the number with complete data in both periods, are not reported either.

Further analysis details are absent: handling of missing measurements, outlier rules, multiplicity procedures, and any prespecified statistical analysis plan are not reported in the registry record. No sponsor analysis records are listed. Therefore, the recalculated comparison should not be mistaken for a reported adjusted trial analysis.

The study enrolled healthy adults and examined single-dose pharmacokinetics with total molybdenum as a surrogate. Its results do not directly address repeated treatment, other populations, or clinical outcomes. The sample-size figures are planning illustrations based on the observed effect under stated general assumptions, not the trial's reported original sample-size rationale.

Safety results are presented by period, and the same participants may appear in both periods. The period counts cannot be interpreted as counts of unique participants across the entire study without participant-level information. The registry record does not report a formal comparison of adverse-event rates.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Study of Oral ALXN1840 at 2 Dose Strengths in Healthy Adults — NCT05303324.
• Registry record last updated 2023-08-02; status last verified 2022-09.
• Results first posted 2023-08-02.
• 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.

21. Record Summary

NCT05303324 is a completed Phase 1 randomized, open-label, two-way crossover study of single-dose oral ALXN1840 in healthy adults. The registry record lists 48 participants enrolled. Participants received one enteric-coated tablet and three enteric-coated tablets in opposite orders across two periods, under fasted conditions.

The primary endpoint was maximum observed plasma concentration of total molybdenum, used as a surrogate measure for ALXN1840, up to 240 hours postdose. The posted means were 173.1 for Treatment A and 174.3 for Treatment B, in nanograms per milliliter. The unadjusted recalculated mean difference was 1.17, with an interval from -27.21 to 29.55 and an unadjusted p-value of 0.936.

No serious adverse events or deaths were reported in the listed period-specific groups. The registry record does not report a formal crossover analysis, missing-data approach, or original sample-size justification.