A Relative Bioavailability Study of SSP-004184AQ (Magnesium Salt) and SSP-004184SS (Disodium Salt): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Relative Bioavailability Study of SSP-004184AQ (Magnesium Salt) and SSP-004184SS (Disodium Salt) (NCT01905540), a randomized phase 1 study. The primary outcome is Area Under the Steady-state Plasma Concentration-time Curve (AUClast) of SSP-004184 After One Dose.

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, open-label, three-period crossover study of relative bioavailability. It compared the pharmacokinetics of SSP-004184AQ, the magnesium salt, with SSP-004184SS, the disodium salt. The registry describes both single-dose and two-dose regimens, as well as two doses of SSP-004184 free acid in the official title. The listed interventions are SSP-004184AQ and SSP-004184SS; the registry record does not provide arm-level outcome results for the free-acid regimen in the registry record reported for this analysis.

The single-dose regimens were oral capsules given once on Day 1: SSP-004184AQ at 40 mg/kg and SSP-004184SS at 21.8 mg/kg. In the two-dose regimens, each formulation was given twice, 12 hours apart on Day 1. The study enrolled 28 healthy subjects. The primary pharmacokinetic outcome is reported for 28 subjects in each single-dose arm, while the two-dose endpoint summaries use smaller arm-specific analysis counts. These are reported outcome counts, not a statement about the number who completed every period.

Randomization assigns treatment sequences, while a crossover design allows participants to receive different regimens across periods. This can make within-participant comparisons informative because each participant may contribute observations under more than one regimen. The sequence assignments, period-specific participation, washout details, and statistical method used to account for the crossover are not reported in the registry record. The study was open-label, meaning masking was not used. It is recorded as completed, with a start date of 2013-08-05 and primary completion date of 2013-09-20.

The registry describes pharmacokinetic sampling before dosing and at multiple post-dose times through 120 hours. Sampling schedules differed by period, with additional sampling times listed in Period 3. This study design focuses on comparing exposure under the tested formulations and regimens in healthy adults; it does not directly test clinical outcomes in people with a disease.

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.

Period 1

Period 2

Period 3

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic Set: All subjects who had taken at least 1 dose of investigational product, had at least 1 post-dose safety assessment, and for whom the primary pharmacokinetic data were considered sufficient and interpretable.

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: Safety Set: All enrolled subjects who had taken at least 1 dose of investigational product and had at least 1 post-dose safety assessment (defined as treatment emergent adverse events \[TEAEs\], physical examination findings, clinical laboratory test results, vital sign measurements, and 12-lead ECG readings).

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Steady-state Plasma Concentration-time Curve (AUClast) of SSP-004184 After One Dose, measured over Periods 1 & 2: Within 30 min pre-dose, and Post-dose 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 48, 72, 96, and 120 hrs. Period 3: Within 30 min pre-dose, and Post-dose 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 12.5, 13, 13.5, 14, 14.5, 16, 20, 24, 48, 72, 96, and 120 hrs..

The primary endpoint was the area under the steady-state plasma concentration-time curve to the last quantifiable concentration, AUClast, for SSP-004184 after one dose. It is reported as a mean with standard deviation, in ng*h/mL. The registry defines AUC 0-last as the area under the plasma concentration-versus-time curve from time 0 to the time of the last quantifiable concentration. In general, an area-under-the-curve measure combines concentration and time to describe the amount and duration of measured drug exposure in plasma.

This endpoint is used in a relative bioavailability study because comparing exposure after different formulations can help characterize how much drug reaches the measured plasma compartment over time. AUClast captures exposure across the observed concentration profile, rather than focusing on a single measurement. Its interpretation depends on the sampling schedule and on which concentrations remain quantifiable. The registry lists samples from pre-dose through 120 hours for the primary endpoint, with the specified sampling times differing by period.

The endpoint is a pharmacokinetic measure. It does not, by itself, establish a difference in symptom relief, disease outcomes, long-term safety, or clinical benefit. The registry record describes the primary measure and population but does not report a clinical threshold for an important exposure difference.

7. Results Posted in the Registry

• SSP-004184SS (Single Dose): mean 164,340 versus 261,902 on control; difference -97,562 (95% CI -128,563 to -66,560), standardized effect d = -1.65; 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.

Area Under the Steady-state Plasma Concentration-time Curve (AUClast) of SSP-004184 After Two Doses

• 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:
  • SSP-004184SS (2 Doses): mean 294,187 versus 545,957 on control; difference -251,770 (95% CI -365,620 to -137,920), standardized effect d = -1.79; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for SSP-004184SS (2 Doses) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUCinf) of SSP-004184 After Two Doses

• 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:
  • SSP-004184SS (2 Doses): mean 294,758 versus 546,114 on control; difference -251,356 (95% CI -368,363 to -134,348), standardized effect d = -1.69; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for SSP-004184SS (2 Doses) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The numerical secondary comparisons available for the two-dose AUC measures follow the same general direction as the primary result: the posted SSP-004184SS means are lower than the corresponding SSP-004184AQ means. Both available unadjusted mean-difference intervals lie below zero, and both reported unadjusted p-values are < 0.001. This directional consistency supports the description of a recurring exposure pattern across the reported AUC summaries, rather than a finding confined to the single-dose endpoint.

The secondary endpoints address exposure after two doses, whereas the primary endpoint addresses exposure after one dose. They therefore provide related but not identical pharmacokinetic information. The registry also lists maximum plasma concentration after two doses as a secondary outcome, but its numerical results are not reported in the registry record. No inference about that endpoint can be made from the available numerical comparisons.

Secondary results generally carry less confirmatory weight when many outcomes are examined without a reported multiplicity strategy. Each additional test creates another opportunity for a chance finding, and interpreting several unadjusted p-values as if they formed one prespecified confirmatory test can overstate evidence. The registry record does not report an adjustment method, testing hierarchy, or whether these secondary outcomes were designated as confirmatory. The posted unadjusted results are therefore best treated as supportive and exploratory.

The two-dose analyses also have endpoint-specific reported analysis counts, and the available recalculations use group summaries rather than individual-level crossover data. These considerations affect how much weight to place on consistency across endpoints. The secondary pattern is relevant to describing the pharmacokinetic findings, but it does not establish clinical importance or a benefit for patients.

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

• Area Under the Steady-state Plasma Concentration-time Curve (AUClast) of SSP-004184 After Two Doses
• Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUCinf) of SSP-004184 After Two Doses
• Maximum Plasma Concentration (Cmax) of SSP-004184 After Two Doses

9. Statistical Interpretation

10. Statistical Methods Explained

Statistical methods are useful only when the estimand, analysis population, and design are clear. The registry reports the primary outcome as a continuous measure summarized by a mean and standard deviation. It also posts an unadjusted recalculation based on the arm summaries. The sponsor's reported result is a ratio of geometric least-squares means with a 90% confidence interval. The registry record does not state the sponsor's modeling method, the covariance structure, or the adjustment variables, so those details cannot be inferred from the ratio alone.

What does the mean describe?

For a continuous endpoint, the arithmetic mean is the sum-based center of the observed values. The standard deviation describes how spread out individual values are around that mean. Neither measure alone describes the uncertainty in the estimated mean or difference; that is the role of a confidence interval. Pharmacokinetic measures such as AUC often have skewed distributions, which is one reason analyses may use logarithmic transformations and report geometric means or ratios. The registry's sponsor analysis is labeled as a geometric least-squares mean ratio, but its exact model and transformation details are not reported in the registry record.

The primary endpoint summaries give means and standard deviations for both single-dose arms. The posted recalculation uses those summaries to estimate an unadjusted difference in arithmetic means and its interval. This offers a transparent descriptive comparison, but it is not a substitute for the sponsor's analysis. It does not incorporate any participant-level information beyond what can be recovered from the summary statistics.

Why does the crossover design matter?

In a crossover study, treatment assignment is organized across periods, so the same participant may contribute measurements under more than one regimen. A paired comparison can account for the fact that observations from one participant tend to be related. The strength of that relationship is represented by within-participant covariance. Arm means and standard deviations alone do not reveal that covariance. As a result, an unadjusted recalculation from these summaries cannot reproduce a paired or period-adjusted analysis. The record does not report the sequence allocation, model specification, treatment of period or sequence effects, or how within-participant correlation was handled.

This distinction matters when interpreting the recalculated standard error, confidence interval, and p-value. They are descriptive, simple unadjusted recalculations from posted summaries, not a reconstruction of the full trial analysis. Since the registry does not identify the statistical method behind the sponsor's result, the methods cannot be compared in detail. The sponsor's own analysis takes precedence as the trial's reported inferential analysis.

What do the confidence interval and p-value say?

A confidence interval expresses uncertainty about an estimated quantity under the assumptions of the analysis. A narrower interval indicates greater precision for that quantity, while a wider interval indicates less precision. Whether an interval includes zero is relevant for a difference, because zero represents no difference on that scale. A ratio uses a different reference value: equality is represented by one. These reference values are specific to the estimand and should not be mixed across arithmetic differences and geometric ratios.

A p-value measures how compatible the observed data are with a specified null hypothesis under the test assumptions. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The recalculated p-values are unadjusted. The registry record does not report whether the sponsor used a one- or two-sided test, the sponsor's p-value, or a prespecified testing hierarchy for the outcomes.

Why can over-dispersion matter?

General statistical explanation: when observations vary more than a model expects, standard errors can be too small if the extra variability is ignored. This can make intervals too narrow and tests appear more decisive than warranted. Pharmacokinetic exposure data can vary substantially between people, and repeated observations from the same person are also related. An analysis should reflect the design and variability structure. The registry record does not provide enough detail to assess whether or how the sponsor addressed these features. This is a general point about model checking, not a claim that this study's analysis had over-dispersion.

There is no posted sample-size justification or original power calculation in the registry record. The planning illustrations use observed effect estimates and stated planning assumptions, so they should be read as hypothetical design calculations rather than evidence about what the original design intended. They do not correct for the crossover structure unless that is explicitly part of the stated method; the planning assumptions describe a normal approximation with equal allocation, not a reconstruction of the trial's original design.

Finally, the Pharmacokinetic Set definition narrows the primary analysis population to subjects with dosing, a post-dose safety assessment, and sufficient interpretable primary pharmacokinetic data. The record does not detail how many subjects were excluded from a particular endpoint beyond the posted arm counts, why observations might have been unavailable, or how missing measurements were handled. Those omissions limit independent assessment of the analysis.

11. Confidence Intervals and Precision

The primary unadjusted mean-difference estimate for SSP-004184SS relative to SSP-004184AQ is -97560.0 ng*h/mL, with a 95% confidence interval from -128600.0 to -66560.0. The interval lies below zero, indicating that the posted summary data are compatible with a lower arithmetic mean for SSP-004184SS on this scale. The interval also shows uncertainty around the estimated size of that difference; it does not identify a single exact underlying difference.

Confidence intervals are informative about precision, not clinical importance. A confidence interval is constructed so that, over repeated comparable studies under the model assumptions, intervals generated by the method would cover the target quantity at the stated rate. It is not a probability statement about this particular interval after it has been calculated. The width reflects both variability and information in the data, as well as the method used to estimate uncertainty.

The sponsor's reported geometric least-squares mean ratio is 1.244, with a 90% confidence interval from 1.081 to 1.430. Its ratio scale and confidence level differ from those of the unadjusted arithmetic difference. The intervals therefore answer different statistical questions and should not be compared as if they were estimates of the same quantity. The sponsor's analysis method is not reported, which prevents a more detailed assessment of its precision calculation.

The two-dose endpoint summaries also have confidence intervals, with the posted unadjusted difference intervals on the negative side of zero. Their interpretation remains limited by the small reported endpoint analysis counts and the fact that the recalculation does not use participant-level crossover information. Precision in the reported sample is not the same as assurance that the estimate will be reproduced in another study. The record does not report a prespecified threshold for an exposure difference that would be considered important.

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 80% power and participants per arm for 90% power. They are not total event counts: the outcomes are continuous measures, and the planning display reports participants per arm. The calculations use the observed effect as a reference and then consider planning for 100%, 75%, or 50% of that observed effect. As the assumed effect gets smaller, more participants are needed to distinguish it from no difference with the same target power.

The stated planning 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. These assumptions describe the planning illustrations, not the trial's original design assumptions; those original assumptions are not reported in the registry record.

In plain terms, the 80% power column gives the estimated participants per arm under the stated assumptions for a design intended to have an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column describes the corresponding planning target with a greater chance of detection, usually requiring more participants under otherwise comparable assumptions. The displayed counts are rounded planning outputs, not observed trial outcomes. These estimates are not observed power.

Because the calculations are based on the observed effect, they are sensitive to the size of that estimate and should not be treated as a reliable guarantee for a future trial. They also use the stated simplified assumptions and do not establish that the original crossover design was planned this way. The figures are best read as illustrations of how sample-size requirements change when the target effect is reduced, rather than as a retrospective judgment about the adequacy of enrollment.

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 = -97561.900; pooled standard deviation σ = 59183.315.
2. n = 2 × (1.96 + 0.842)² × 59183.315² / -97561.900² = 5.8, rounded up to 6 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 <- -97561.9                      # observed difference in means
sigma <- 59183.3154330255                     # 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(1905540)
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 = 6 (80% power), 8 (90% power)
 75% of observed effect: n per arm = 11 (80% power), 14 (90% power)
 50% of observed effect: n per arm = 24 (80% power), 31 (90% power)
power.t.test: 6.9 
Simulated power at n = 6 per arm: 0.732 (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 sponsor's posted primary analysis reports a ratio of geometric least-squares means of 1.244, with a 90% confidence interval from 1.081 to 1.430. This is the sponsor's reported analysis of the primary comparison. The registry does not give the model or method used to obtain it, and no sponsor p-value is reported.

The simple recalculation instead compares the posted arithmetic means and reports a mean difference of -97560.0 ng*h/mL, with a 95% confidence interval from -128600.0 to -66560.0 and p < 0.001. These results differ in scale, summary measure, and confidence level. A ratio of geometric least-squares means is not directly interchangeable with an unadjusted arithmetic mean difference. In addition, a recalculation from arm summaries cannot account for participant-level covariance in a crossover design.

The recalculation is useful as a transparent check of the direction and broad separation in the posted means, but it is not an attempt to replace or reproduce the sponsor's model. The sponsor's own analysis takes precedence for the trial's reported inferential result. The record does not identify a discrepancy between the posted and recalculated results.

15. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity adjustment or a testing hierarchy for the primary and secondary outcomes. Multiplicity arises when several hypotheses are tested: the more tests considered together, the greater the chance that at least one result appears unusual under a collection of null hypotheses. A prespecified strategy can control how results are interpreted across outcomes. Without one reported, the unadjusted secondary p-values should not be read as if each independently confirmed a primary claim.

The primary analysis has a sponsor-reported geometric least-squares mean ratio and confidence interval, but the method, analysis model, and any prespecified decision rule are not reported in the registry record. The registry does not report whether any interim analyses took place or how they would have affected testing. The sample-size justification and original statistical plan are also not reported in the registry record.

The primary Pharmacokinetic Set includes subjects who had taken at least 1 dose, had at least 1 post-dose safety assessment, and whose primary pharmacokinetic data were considered sufficient and interpretable. That definition indicates that the primary analysis was not simply defined as every enrolled subject, but the record does not provide a full accounting of exclusions or reasons for missing endpoint data. The handling of missing concentration measurements, incomplete profiles, values below quantification limits, and other missing data is not reported in the registry record.

Arm-specific outcome counts are available for the posted summaries, including lower counts for the two-dose endpoints than for the single-dose primary endpoint. The registry does not explain the differences in endpoint analysis counts or establish whether missingness was related to treatment, period, tolerability, or data quality. Without those details, the direction and possible influence of missing data cannot be assessed independently.

Other analysis populations, such as a separately defined safety population or a per-protocol population, are not described in the registry record. The crossover sequence and period structure are also not detailed enough to assess how analysis populations were constructed across treatment periods. These gaps matter because population definitions, missing-data handling, and multiplicity procedures all affect the interpretation and reproducibility of pharmacokinetic estimates.

16. Safety Results

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

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The posted serious adverse event counts are zero for each listed regimen group: 0 of 28 for SSP-004184AQ single dose, 0 of 28 for SSP-004184SS single dose, 0 of 12 for SSP-004184AQ two doses, and 0 of 13 for SSP-004184SS two doses. These figures mean that no serious adverse events are listed for the reported at-risk groups during the registry's safety reporting period.

Zero reported serious events in these groups does not demonstrate that serious events are impossible, nor does it establish comparative safety with high precision. Safety interpretation depends on the number of participants exposed, follow-up, event definitions, and completeness of reporting. The study was a Phase 1 investigation in healthy adults, and the reported groups are small.

The registry lists other adverse events as affecting 12 subjects in the SSP-004184AQ single-dose group, 11 in the SSP-004184SS single-dose group, 5 in the SSP-004184AQ two-dose group, and 5 in the SSP-004184SS two-dose group. These are counts for other adverse events, not serious adverse events. Death counts are not reported in the registry record. The record does not provide event-term details in the registry record for this interpretation, so the counts should not be used to infer the nature or severity of those events.

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

The main statistical result is a difference in measured plasma exposure after the tested single-dose formulations. The posted arithmetic mean for SSP-004184AQ is higher than the posted mean for SSP-004184SS, and the unadjusted recalculated difference has a confidence interval below zero. The sponsor's reported analysis uses a geometric least-squares mean ratio and also reports an interval that does not include its equality reference value. These are pharmacokinetic comparisons, not clinical outcome comparisons.

Relative bioavailability studies describe how exposure compares across formulations under specified study conditions. The observed AUC difference may be relevant to formulation development and to understanding pharmacokinetics, but it does not by itself show whether a change in exposure improves or worsens a clinical outcome. The registry record does not report an exposure target, clinically meaningful threshold, or link between the observed AUC values and therapeutic response.

The results also do not establish that one formulation is safer than the other. No serious adverse events are listed for the reported groups, but the study's scope and size limit what can be concluded about uncommon events or longer-term safety. The registry does not report death counts in the registry entries, and the other adverse event counts are not accompanied by event terms.

The findings apply to the healthy adult subjects and dosing regimens studied. They should not be assumed to describe people with a disease, different dosing schedules, repeated use beyond the stated regimens, or other populations not included in the record. The registry record does not report clinical efficacy outcomes. Accordingly, the result supports a statement about measured exposure under the study conditions, not a recommendation about treatment or a conclusion about patient benefit.

18. Why This Trial Matters Statistically

This trial illustrates why the choice of statistical scale matters. An arithmetic mean difference and a geometric least-squares mean ratio may describe related data, but they answer different questions and have different reference values. The sponsor's analysis and the unadjusted recalculation should therefore be read as distinct summaries rather than as competing versions of the same numerical estimate.

It also illustrates a limitation of registry-level summary data in a crossover study. A crossover can support within-participant comparisons, but the arm-level means and standard deviations do not show the correlation between measurements from the same participant across periods. Without participant-level data or a fully reported model, an independent recalculation cannot reproduce the crossover analysis. The distinction between descriptive re-analysis and the trial's sponsor analysis is important for transparent interpretation.

Finally, statistical evidence is not the same as clinical importance. The primary interval and p-value describe uncertainty and compatibility with a statistical null under the recalculation's assumptions. They do not define a meaningful exposure threshold, predict clinical outcomes, or establish benefit. The registry's secondary results suggest a consistent direction among the reported AUC comparisons, but the absence of a reported multiplicity strategy means those results have less confirmatory force.

For biostatisticians and clinical researchers, the record is a compact example of how design, estimand, analysis population, multiplicity, and reporting detail shape interpretation. It shows why a numerical result should be paired with an account of what was measured, how the estimate was obtained, and what the evidence cannot establish.

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.

The registry record does not report the sponsor's statistical model, crossover sequence details, period or sequence adjustments, or the method used to account for within-participant correlation. This prevents independent reproduction of the sponsor's geometric least-squares mean ratio and limits interpretation of the unadjusted recalculation, which relies on arm-level summaries rather than paired participant data.

The primary endpoint population is defined, but the record does not give a complete explanation of the endpoint-specific analysis counts or reasons for missing or uninterpretable pharmacokinetic data. Missing-data handling, treatment of incomplete concentration profiles, and decisions about quantifiable concentrations are not reported in the registry record. These details can matter for AUC estimates.

The study was open-label and enrolled healthy adults. The registry does not report masking, and none was used. The available results concern pharmacokinetic measurements under specific dosing regimens; clinical efficacy outcomes and a clinically meaningful exposure threshold are not reported. Generalization beyond the study population and regimens is therefore limited.

The registry lists three secondary outcomes, but numerical results are available in the registry record for two secondary AUC measures; numerical results for maximum plasma concentration are not reported in the registry record. A multiplicity approach and confirmatory hierarchy are also not reported. The secondary findings should consequently be interpreted as supportive rather than definitive.

Finally, the sponsor's analysis is reported as a ratio with a 90% confidence interval, while the simple recalculation is an arithmetic mean difference with a 95% interval. Because the estimands and confidence levels differ, direct numerical comparison is inappropriate. The record does not report the original sample-size justification or full analysis plan, limiting evaluation of whether the analyses followed prespecified decisions.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Relative Bioavailability Study of SSP-004184AQ (Magnesium Salt) and SSP-004184SS (Disodium Salt) — NCT01905540.
• Registry record last updated 2021-07-19; status last verified 2021-06.
• Results first posted 2014-12-24.
• 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

NCT01905540 is a completed Phase 1 randomized, open-label, three-period crossover relative bioavailability study sponsored by Shire. It enrolled 28 healthy adults and compared the pharmacokinetics of SSP-004184AQ, the magnesium salt, and SSP-004184SS, the disodium salt. The primary endpoint was AUClast after one dose, reported as a mean and standard deviation.

The posted single-dose means were 261900.0 ng*h/mL for SSP-004184AQ and 164300.0 ng*h/mL for SSP-004184SS. The sponsor reported a geometric least-squares mean ratio of 1.244 with a 90% confidence interval from 1.081 to 1.430. The unadjusted recalculation gives a mean difference of -97560.0 ng*h/mL, with a 95% confidence interval from -128600.0 to -66560.0.

The reported data describe relative pharmacokinetic exposure, not clinical benefit. Details of the sponsor's model, multiplicity procedures, and missing-data handling are not reported in the registry record.