Assess the Safety and Pharmacokinetics of Ascending, Multiple Oral Doses of SPD489 in Adults With Schizophrenia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Assess the Safety and Pharmacokinetics of Ascending, Multiple Oral Doses of SPD489 in Adults With Schizophrenia (NCT01457339), a randomized phase 1 study. The primary outcome is Change From Baseline in Systolic Blood Pressure at Day 5: 50 mg.

2. Clinical Question

3. Trial Design

This completed Phase 1 study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of ascending multiple oral doses of SPD489 in clinically stable adults with schizophrenia. The brief summary specifies that participants were maintained on a stable dose of antipsychotic medication. The registry record identifies schizophrenia as the condition and lists SPD489 (lisdexamfetamine dimesylate) and placebo as the interventions.

Allocation is recorded as randomized, masking as double, and the model as parallel. These labels indicate the stated design features, but the registry record does not describe the randomization procedure, the concealment process, or how masking was maintained. Arm descriptions are blank, so details about the sequence of dose assignments, duration at each dose, and participant flow between dose groups are not reported in the registry record.

Enrollment is recorded as 31. The study began on 2011-10-21, had a primary completion date of 2012-01-20, and is recorded as completed. The sponsor is Shire. The primary outcome concerns systolic blood pressure change from baseline at Day 5 for 50 mg, with placebo as the comparator. Other listed outcomes include pharmacokinetic measures such as area under the steady-state plasma concentration-time curve and maximum plasma concentration at specified doses.

The primary result uses the Safety Set, defined in the registry record as participants who took at least one dose of investigational product and had at least one post-dose safety assessment. For this endpoint, the posted group sizes are 7 for placebo and 24 for SPD489 50 mg. The registry record does not give a detailed participant-flow account or explain how those endpoint groups relate to exposure across the ascending-dose study.

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 (50 mg)

Period 2 (70 mg)

Period 3 (100 mg)

Reasons for not completing this period:

Period 4 (150 mg)

Analysis population for the primary outcome, as defined in the registry: Safety Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Systolic Blood Pressure at Day 5: 50 mg, measured over Baseline and day 5.

The primary endpoint is change from baseline in systolic blood pressure at Day 5, measured in mmHg, for the 50 mg SPD489 dose and placebo. Change from baseline expresses the difference between a participant’s starting measurement and the measurement at the specified follow-up time. The posted summaries are group means, accompanied by standard deviations.

Blood pressure is a safety measure relevant to monitoring during drug exposure. The registry description says measurements were taken with an automated device, ideally using the same device, arm, and position throughout the study. Participants were seated for at least 5 minutes before measurement. Readings were taken in triplicate, in succession, with the cuff fully deflated between readings; the description says the triplicate readings were expected to be completed within a 5-6 minute period.

Triplicate readings can help characterize a measurement session, while consistent positioning and equipment can reduce avoidable measurement variation. The registry record does not explain how the triplicate readings were combined into the endpoint value, or how missing baseline or Day 5 readings were handled. The endpoint is a short-term physiological measure. It does not directly measure schizophrenia symptoms, functioning, or longer-term safety.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: systolic blood pressure change is measured on a numeric scale in mmHg. The registry identifies the reported parameter as a mean and the measure of dispersion as a standard deviation. A mean describes the central value of the group’s changes; a standard deviation describes how dispersed individual observations are around that mean. The standard deviation does not indicate the uncertainty of the group mean or of a treatment contrast.

What do the group summaries establish?

The posted values establish the mean change and standard deviation for each listed group. They allow a descriptive reading of how the groups’ observed changes are distributed around their respective means. They do not establish the size or precision of a placebo-adjusted effect. To answer that comparative question, an analysis would need to estimate the contrast between groups and report its uncertainty. Such an estimate is not reported in the registry record.

A confidence interval is a statistical range constructed by a specified method to express uncertainty around an estimate. It is useful because it shows which effect sizes are compatible with the observed data under that method. No confidence interval for the primary between-group comparison is reported. A p-value, which evaluates data against a specified null hypothesis under an analysis model, is also not reported. Without these inferential results, the posted summaries should be interpreted descriptively rather than as evidence that a comparison met a significance criterion.

Why do group sizes and variation matter?

The primary endpoint groups have sizes of 7 for placebo and 24 for SPD489 50 mg. The amount of information available for estimating a group mean depends on both the number of observations and their variability. Greater variability generally makes a mean less precise, while a smaller group generally contains less information than a larger group, all else being equal. These general principles do not supply a missing confidence interval or test result for this study.

In this endpoint, the standard deviations are 9.543 for placebo and 11.51 for SPD489 50 mg. They reflect observed within-group dispersion, not the precision of the between-group contrast. A contrast’s uncertainty would also depend on the analysis method, the handling of missing observations, and any model adjustments. Those details are not reported in the registry record.

What does a general comparison model do?

For a continuous outcome in a randomized parallel-group study, a basic comparison might estimate a difference in group means. More complex methods can adjust for baseline values or other prespecified factors. These approaches answer somewhat different questions and can produce different estimates, especially when baseline values differ between groups. The registry record does not report the method used for a primary between-group test or whether the primary result was adjusted for baseline.

Baseline adjustment can improve precision when it is planned and appropriate, but it should not be assumed from a change-from-baseline endpoint alone. Reporting change from baseline does not show whether a model compared changes directly, adjusted for baseline measurements, or used another method. The analysis approach is not reported in the registry record.

What role do planning calculations play?

Planning illustrations based on an observed effect are not observed power and do not provide evidence that the study was adequately powered for its clinical or safety objectives. Their interpretation depends on stated assumptions, including the target effect and allocation. The registry record describes planning assumptions using a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects expressed as fractions of the observed effect. Such illustrations are prospective planning aids, not a substitute for the results of an inferential analysis.

The registry record does not report the trial’s own sample-size justification. It also does not report an inferential analysis count for the posted outcome summaries. Accordingly, no conclusion about the original design’s power or the operating characteristics of its analysis should be drawn from the descriptive endpoint values.

Why does measurement procedure matter?

Blood pressure can vary with posture, equipment, and measurement conditions. The registry’s description of a seated rest, repeated readings, and efforts to use the same device, arm, and position indicates attention to standardized measurement. Repeated measurements can reduce the influence of a single unusually high or low reading, depending on how they are combined. The record does not specify the exact derivation of the endpoint from the triplicate readings, so the averaging or selection procedure should not be inferred.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Placebo", "SPD489 (Lisdexamfetamine Dimesylate)(50 mg)")
n   <- c(7, 24)
m   <- c(-0.14, 8.94)
sp  <- c(9.543, 11.51)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Placebo  7  -0.140  9.543  -8.966  8.686
CARM  SPD489 (Lisdexamfetamine Dimesylate)(50 mg)  24  8.940  11.510  4.080  13.800

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 84 outcome measures and records 66 secondary outcomes as posted. A study with multiple outcomes or dose-specific assessments can raise a multiplicity question: when many hypotheses are tested, the chance of at least one nominally notable result can increase. Whether and how that issue was addressed depends on the analysis plan. A multiplicity adjustment or testing hierarchy is not reported in the registry record, so it is not possible to determine how the primary and secondary outcomes were interpreted jointly.

The record lists zero analyses for the results summarized in the registry record, and the primary continuous endpoint is flagged as lacking values or being not estimable for a two-arm comparison. The displayed group summaries are still interpretable descriptively, but they do not supply a reported inferential comparison. The analysis population beyond the Safety Set definition is not reported in the registry record.

Missing-data procedures are also not reported in the registry record. It does not explain whether any endpoint measurements were missing, whether participants were excluded from the Day 5 summary, or how missing baseline or follow-up values were handled. The endpoint group sizes therefore should be read as the reported counts for these summaries, not as evidence about the reason for inclusion or exclusion.

The Safety Set is defined as participants who took at least one dose and had at least one post-dose safety assessment. That population definition supports safety monitoring but does not establish that every participant contributed to every outcome. The record does not describe imputation, sensitivity analyses, or another approach to assess the effect of missing data.

12. 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 serious adverse event summaries list 0 affected participants in the placebo group, which had 7 at risk, and 0 in each listed SPD489 dose group. The listed dose groups are 50 mg, 70 mg, 100 mg, 150 mg, 200 mg, and 250 mg; the record also includes an all-doses group. The number at risk differs across the dose-specific groups, as recorded in the registry.

These figures describe the recorded serious adverse event counts for the listed groups. They do not show that the risk of a serious event is zero in a broader population, nor do they establish equivalence or absence of harm. A study of this size and duration may not be informative about uncommon or delayed events, and the registry record does not report a statistical comparison of serious adverse event rates.

Deaths are not given as zero; they are not reported in the registry record. The record also lists no serious adverse event terms. Non-serious adverse events are separately summarized in the record, but those counts should not be confused with the serious-event figures. Interpretation should remain limited to the recorded observation period and groups.

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

The primary result provides a descriptive account of systolic blood pressure change from baseline to Day 5 in the placebo and SPD489 50 mg groups. It reports the group means and their standard deviations, giving a sense of the central changes and within-group variability. The result does not report a placebo-adjusted estimate with a confidence interval or a p-value.

It therefore does not establish whether a between-group difference is statistically distinguishable from chance under a specified analysis, and it does not quantify the precision of such a difference. A missing inferential result is not evidence that the groups are equal. Likewise, the observed group summaries alone do not establish that the drug caused the observed changes; causal interpretation of a randomized comparison depends on the actual comparative analysis and its assumptions.

The endpoint concerns short-term systolic blood pressure, not symptom response, quality of life, or longer-term outcomes. Although the study was designed to examine safety, tolerability, pharmacokinetics, and pharmacodynamics, the listed aims do not establish what the study found for those domains. Numerical results for the other listed outcomes are not reported in the registry record in the registry record for this analysis.

The serious adverse event summaries report no affected participants in the listed groups, but the record does not report deaths as zero. These observations do not rule out uncommon events or establish safety beyond the observed groups and study period. The registry record’s description should be treated as a bounded summary of this Phase 1 study, not as a broad clinical recommendation or a definitive assessment of treatment effects.

14. Why This Trial Matters Statistically

This trial illustrates the distinction between reporting group summaries and reporting a comparative analysis. Means and standard deviations are useful descriptions, but they do not answer how precisely the groups differ. A numerical treatment contrast with an uncertainty interval would make that distinction explicit; the registry record does not report such an estimate for the primary endpoint.

The endpoint also highlights the importance of matching the statistical interpretation to the study question. Systolic blood pressure is a safety measure, and the primary result concerns a short-term change at Day 5 for the 50 mg group and placebo. It should not be interpreted as a measure of clinical benefit or as a summary of every dose studied.

Ascending-dose studies can include multiple dose-specific outcomes, which makes transparent reporting of the analysis population, outcome definitions, missing-data handling, and multiplicity strategy especially relevant. The record lists many outcomes and dose-specific pharmacokinetic measures, but does not report the analysis plan or the method for handling multiplicity. Those omissions constrain how confidently the results can be interpreted across outcomes.

The study’s Phase 1 scope matters as well. Its stated focus is safety, tolerability, pharmacokinetics, and pharmacodynamics in clinically stable adults with schizophrenia who were maintained on antipsychotic medication. This is a focused setting, and the primary blood pressure summary should be understood within that context. Statistical transparency helps readers distinguish what the posted data describe from conclusions that would require additional analyses or evidence.

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.

The primary endpoint result is descriptive: the registry record reports means, standard deviations, and group sizes but not a confidence interval, p-value, or stated between-group estimate. The record also does not identify the statistical model used for the primary comparison, whether the analysis adjusted for baseline blood pressure, or whether another adjustment was made.

Details needed to understand the endpoint’s derivation are limited. The record describes triplicate blood pressure measurements but does not state how those readings were combined into a participant-level value. It also does not report how missing baseline or Day 5 measurements were handled, whether any observations were excluded, or whether sensitivity analyses were conducted.

Participant flow and dose exposure are not described in the arm descriptions. The endpoint reports 7 participants for placebo and 24 for SPD489 50 mg, while dose-specific safety groups have different recorded numbers at risk. The registry record does not explain these patterns or give enough detail to reconstruct participants’ dose histories. The stated Safety Set definition is available, but further analysis-population details are not reported.

The record lists numerous outcome measures, yet the analysis plan, multiplicity approach, and sample-size justification are not reported. It does not give numerical results for the other listed outcomes in the registry record for this analysis. Deaths are not reported as zero. These reporting gaps limit conclusions about comparative effects, other safety outcomes, and the wider pattern of results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Assess the Safety and Pharmacokinetics of Ascending, Multiple Oral Doses of SPD489 in Adults With Schizophrenia — NCT01457339.
• Registry record last updated 2021-06-03; status last verified 2021-05.
• Results first posted 2013-01-21.
• 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

NCT01457339 is a completed, randomized, double-blind, placebo-controlled, parallel-group Phase 1 study sponsored by Shire. It examined ascending multiple oral doses of SPD489 in clinically stable adults with schizophrenia who were maintained on a stable dose of antipsychotic medication. Enrollment is recorded as 31.

The primary outcome is change from baseline in systolic blood pressure at Day 5 for SPD489 50 mg and placebo. The posted group means are 8.94 mmHg for SPD489 50 mg and -0.14 mmHg for placebo; the corresponding standard deviations are 11.51 and 9.543. A comparative confidence interval and p-value are not reported in the registry record. Serious adverse event counts are recorded as 0 affected participants in each listed group; deaths are not reported in the registry record.