Lisdexamfetamine Dimesylate 2-year Safety Study in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Lisdexamfetamine Dimesylate 2-year Safety Study in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD) (NCT01328756), a na phase 4 study. The primary outcome is Number of Participants With All Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs.

2. Clinical Question

The clinical question is primarily about the safety experience recorded during treatment and shortly after treatment ended. Treatment-emergent events were defined as events that started or worsened from the day of the first dose through 3 days after treatment cessation. The primary outcome’s timeframe extends from baseline to 3 days after the last dose, for up to 2 years.

The record also lists secondary measures concerning ADHD symptoms and clinical global ratings: change from baseline in the ADHD Rating Scale-IV total score at the last on-treatment assessment, and participant counts for Clinical Global Impression-Improvement and Clinical Global Impression-Severity of Illness at that assessment. These measures do not change the central limitation of the design: without a concurrent comparator, observed changes or event counts cannot isolate what would have happened under another treatment condition.

3. Trial Design

This was a Phase 4, open-label, multicentre safety study of lisdexamfetamine dimesylate in children and adolescents with ADHD. The registry lists a single-group model, no masking, and allocation as not applicable. The listed intervention is lisdexamfetamine dimesylate. No comparator arm is described, so the study is not a randomized treatment comparison.

The registry reports enrollment of 314. The safety population was defined as participants who took at least 1 dose of study medication; the adverse-event risk denominators are also reported as 314. The primary observation period ran from baseline through 3 days after the last dose, with treatment lasting up to 2 years. The study status is completed. Its recorded start date is 2011-07-07 and its primary completion date is 2014-09-30.

The record identifies Shire as the sponsor. It also notes that the study changed to Phase 3 in Poland to permit a study with investigational medication in that country, while the study number remained SPD489-404. This country-specific note does not make the overall registry design a controlled comparison.

The study’s stated purpose was to further evaluate long-term effects in children and adolescents. The registry does not report the protocol’s detailed visit schedule, dose-adjustment procedures, eligibility criteria, or statistical analysis plan. The design supports a description of events observed among treated participants, but it does not establish how event rates would compare with an untreated group or another therapy.

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: If participants from previous SDP489 studies had a gap of more than 7 days before participation in this study, they were required to have baseline Attention-Deficit/Hyperactivity Disorder (ADHD) total score of at least 28, to be enrolled. Of 348 participants screened, 314 participants were enrolled and treated.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population included all participants who took at least 1 dose of Lisdexamfetamine dimesylate during this study.

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 Number of Participants With All Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs, measured over Baseline up to 3 days after the last dose of study treatment (up to 2 years).

The primary endpoint is the number of participants with treatment-emergent adverse events (TEAEs) and serious TEAEs. An adverse event was defined as an untoward medical occurrence in a participant who received study drug, regardless of whether it was considered causally related to the drug. Both serious and non-serious events count as adverse events.

For this study, an event was treatment-emergent if it began or worsened between the participant’s first dose and 3 days after treatment cessation. The timeframe is baseline through 3 days after the last dose, for up to 2 years. A serious adverse event was defined by outcomes such as death, initial or prolonged inpatient hospitalization, a life-threatening experience, persistent or significant disability or incapacity, or congenital anomaly; an event could also be considered serious for another significant reason.

Counting participants with events is useful in a safety study because it describes how many people experienced events meeting the endpoint definition during the observation period. It is a descriptive measure: it does not by itself establish that treatment caused an event. Nor does a participant count convey the full pattern of event timing, duration, recurrence, or severity. The registry record does not report those details for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level event measure: a participant either met the definition for an event during the stated window or did not. The registry reports participant counts for the all-TEAE and serious-TEAE categories. For a binary outcome, such counts describe the number of participants with the event; a proportion can also be useful when the relevant denominator is available. The posted figures include a risk denominator of 314 for each category, but no additional calculation is needed to interpret the reported counts.

In general, a confidence interval describes the uncertainty around an estimate and the range of values reasonably compatible with the data under the method used. It can help distinguish a precisely estimated frequency from one with substantial uncertainty. The registry record does not report a confidence interval for the primary outcome, so its precision cannot be assessed from an interval in this record. The absence of a reported interval does not mean that the event count is exact as an estimate for other populations; it is the observed count in this study.

In general, a hypothesis test evaluates how compatible observed data are with a specified statistical model or null hypothesis. A p-value is not a measure of clinical importance and does not establish causation. The record does not report a primary-outcome hypothesis test or a comparator-based test. Since this is a single-group study, there is no randomized between-group contrast for the primary endpoint to test.

Event counts can be clinically informative, but they do not describe all aspects of safety. A participant may experience more than one event, while the primary outcome is expressed as the number of participants with events. The record does not provide the total number of events, participant-level event histories, time to first event, or event duration. Consequently, the participant counts should not be interpreted as counts of every event episode.

The serious-event definition is based on specified outcomes and other reasons an event could be judged significant. That definition is distinct from whether the event was considered related to treatment. The record explicitly defines adverse events without regard to a possible causal relationship. A listed event term is therefore evidence that the term was recorded, not proof of a treatment effect.

The registry identifies the safety population as all participants who took at least 1 dose. This population definition is relevant because safety outcomes are generally described among people exposed to the study medication. The record does not report the number of participants who discontinued, the amount of follow-up for each participant, or how incomplete safety observations were handled. Those omissions limit interpretation of the time available to observe events.

The study is open-label and has no masking. In general, awareness of treatment can affect reporting, assessment, and decisions to investigate or classify events. A single-group design also cannot separate events occurring during treatment from events that might have occurred without treatment. These design features do not invalidate the descriptive counts; they limit the causal and comparative claims that can be made from them.

The registry also includes planning illustrations based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. These are planning assumptions, not the design of this single-group study. The illustrations are not observed power and are not evidence that the trial was planned or analyzed with a concurrent control. For time-to-event outcomes, the described illustrations concern total events using the Schoenfeld method; other illustrations are expressed as participants per arm. The specific statistical plan for the trial is not reported in the registry record.

General statistical caution is especially important when translating a descriptive finding into a broader claim. Estimates from a study population can vary because of sampling variation, outcome definitions, follow-up, and population characteristics. A comparative design and clearly reported analysis can address some questions that a single-group count cannot. The registry record does not provide a comparative estimate, adjustment strategy, interim-analysis details, or a sample-size justification for this study.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures and 1 analysis. It identifies a primary safety outcome and lists secondary outcomes involving ADHD Rating Scale-IV total-score change and Clinical Global Impression ratings at the last on-treatment assessment. The record does not report a multiplicity strategy, such as whether or how statistical testing across outcomes was controlled. Because the numerical secondary results and their inferential analyses are not included in the available record, their statistical interpretation cannot be assessed.

Multiplicity is a general concern when many outcomes or comparisons are tested: the chance of at least one apparently notable result can increase as the number of tests grows. A prespecified hierarchy or adjustment can help address that issue, but the registry record does not report such an approach. The existence of several listed outcomes alone does not establish that formal tests were performed for all of them.

The primary endpoint is defined for the safety population, consisting of participants who took at least 1 dose. The adverse-event denominators are reported as 314. The record does not report a separate account of missing outcome data, reasons for incomplete follow-up, imputation methods, or sensitivity analyses. It also does not describe how participants with differing observation periods were handled analytically.

These omissions matter because missing follow-up can affect what events are observed, while multiple outcomes can complicate interpretation of isolated findings. The registry record does not provide enough information to determine whether missingness or multiplicity materially affected the results. No assumptions about those methods should be inferred from the reported counts alone.

11. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: syncope (1.9%), appendicitis (1.0%), pyelonephritis (0.6%), lymphadenitis (0.3%), arrhythmia (0.3%).

The adverse-event figures are participant counts over the study’s treatment-emergent window, rather than counts of every event episode. The record reports 250 participants with all treatment-emergent adverse events and 28 with serious treatment-emergent adverse events, with a risk denominator of 314 for each category. The serious-event terms are listed with percentages: syncope (1.9%), appendicitis (1.0%), pyelonephritis (0.6%), lymphadenitis (0.3%), arrhythmia (0.3%), and abdominal pain (0.3%).

Serious-event status follows the registry’s definition, including specified outcomes such as hospitalization or a life-threatening experience, as well as other significant reasons. The listed terms do not establish that treatment caused the events. Deaths are not reported in the registry record. The record also does not provide event-level timing, duration, recurrence, or participant-specific follow-up, so the term percentages should not be treated as comparative risks or rates over a uniform period.

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

The results describe adverse events recorded among participants who received lisdexamfetamine dimesylate in this open-label, single-group study. The registry reports participant counts for all treatment-emergent adverse events and serious treatment-emergent adverse events, along with percentages for selected serious-event terms. This is useful descriptive safety information for the study population and its stated observation period.

The results do not establish whether the medication caused any particular event. The event definition did not require a suspected causal relationship, and there was no concurrent control group to show how often similar events occurred under another condition. The study also cannot establish that event frequency was higher or lower than it would have been without treatment.

The counts do not by themselves characterize the number of event episodes, their timing, duration, severity beyond the serious-event classification, or the length of each participant’s follow-up. The registry record does not report a confidence interval for the primary counts or a time-adjusted event rate. These limits mean the figures should be understood as recorded participant counts, not as complete estimates of comparative risk or long-term population risk.

The study’s secondary outcomes concern symptom ratings and global clinical impressions, but their numerical results are not reported in the registry record. The safety figures therefore do not answer whether ADHD symptoms changed during treatment. Nor do they establish the balance of benefits and harms relative to other treatment options. Such comparative conclusions would require evidence and analyses not reported in this record.

13. Why This Trial Matters Statistically

This study illustrates why the design determines the questions a result can answer. A long-term, single-group safety study can document events observed during treatment and provide a description of the treated population’s experience. It cannot, by itself, distinguish treatment-associated events from events that would occur in the absence of treatment or under another therapy.

It also highlights the difference between a participant count and an event rate. The primary outcome counts participants meeting an event definition, while the follow-up window may extend up to 2 years. Without reported person-time or participant-level observation durations, the counts do not standardize exposure time. That distinction is important when interpreting safety data from studies with extended follow-up.

The study’s endpoint definition is another key statistical feature. Treatment-emergent events are identified by when they start or worsen, not by a determination that treatment caused them. Seriousness is classified using specified consequences and other significant reasons. Keeping timing, seriousness, and causality conceptually separate helps prevent overinterpretation of event listings.

Finally, the registry record demonstrates why statistical planning illustrations must be kept separate from observed study design. The described planning assumptions concern a hypothetical two-arm framework, whereas this study is recorded as single-group with allocation not applicable. Such illustrations do not imply that a control arm existed or that the trial had a particular power for its observed safety counts.

14. 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 principal limitation is the absence of a concurrent comparator. With a single group and no masking, the study can describe events reported during treatment but cannot provide a randomized estimate of treatment effects or comparative safety. The registry’s definition of an adverse event explicitly does not depend on a causal relationship, so event counts should not be attributed to the medication solely because they occurred during the study.

Follow-up could extend up to 2 years, but the registry record does not report participant-specific time under observation or a time-to-event analysis for the primary outcome. The counts therefore do not account for possible variation in follow-up duration. The record also does not report event recurrence, duration, or a complete event-level summary.

The registry record does not report confidence intervals or inferential tests for the primary counts, or explain missing-data handling. It also does not report a multiplicity strategy for the listed outcomes. The specific statistical analysis plan, sample-size justification, and interim-analysis details are not reported in the registry record.

Numerical results for the listed secondary measures are not reported in the registry record. The serious-event terms and percentages are descriptive, and deaths are not reported in the registry record. These limitations constrain both the precision of interpretation and the range of conclusions that can be drawn from the posted safety results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Lisdexamfetamine Dimesylate 2-year Safety Study in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD) — NCT01328756.
• Registry record last updated 2021-06-10; status last verified 2021-05.
• Results first posted 2015-08-06.
• 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.

18. Record Summary

The registry record describes NCT01328756, a completed Phase 4, open-label, multicentre, single-group safety study of lisdexamfetamine dimesylate in children and adolescents with ADHD. Enrollment is reported as 314. The recorded start date is 2011-07-07, and the primary completion date is 2014-09-30. The planned treatment period was up to 2 years.

The primary endpoint counts participants with treatment-emergent adverse events and serious treatment-emergent adverse events. The posted counts are 250 and 28, respectively, with a risk denominator of 314 for each. The record lists secondary symptom and global-rating outcomes, but their numerical results are not reported in the registry record. No concurrent comparator is listed, and the record does not report a primary-outcome confidence interval or comparative test.