Study of Atomoxetine and OROS Methylphenidate to Treat Children and Adolescents Ages 6-17 With ADHD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Atomoxetine and OROS Methylphenidate to Treat Children and Adolescents Ages 6-17 With ADHD (NCT00585910), a na phase 4 study. The primary outcome is Attention Deficit Hyperactivity Disorder Rating Scale (ADHD RS).

2. Clinical Question

3. Trial Design

This completed Phase 4 study enrolled 94 participants and evaluated atomoxetine and OROS methylphenidate together as a treatment approach for ADHD in children and adolescents ages 6-17. The registry lists Massachusetts General Hospital as the sponsor. The study is described as a single-group design with no masking and no randomized allocation. Its treatment period was 7 weeks.

Atomoxetine was initiated and maintained for 4 weeks. Participants described as partial responders then had OROS methylphenidate added for the final 3 weeks. Thus, the combination treatment was not assigned to all participants at the outset; it followed an assessment of response to atomoxetine. The record does not give a more detailed definition of partial response, nor does it report the criteria used to decide who received the added medication.

The study began in 2004-01, had primary completion in 2007-12, and is listed as completed. Those dates describe the study record and do not provide details about when individual outcomes were measured beyond the stated endpoint timeframe. Allocation is listed as NA, and the record explicitly cautions that the groups are not a like-for-like control comparison. The 94 participants enrolled should not be treated as the number in either adverse-event group: the registry lists 72 at risk in the ATMX Only group and 50 at risk in the ATMX and OROS MPH group for adverse-event reporting. The record does not explain the relationship between these counts or provide a participant flow description.

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: Some reasons as to why subjects were excluded from the trial before baselining include: being found ineligible, withdrawing consent, and being lost to follow-up.

Atomoxetine (ATMX) Alone

ATMX + Osmotic-Release Methylphenidate

Analysis population for the primary outcome, as defined in the registry: All analyses were intent to treat, with last observation carried forward.

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 Attention Deficit Hyperactivity Disorder Rating Scale (ADHD RS), measured over 7 weeks.

The primary endpoint was the Attention Deficit Hyperactivity Disorder Rating Scale (ADHD RS), a continuous measure of ADHD symptoms. The registry reports scores in units on a scale, with a best score of 0, indicating no ADHD symptoms, and a worst possible score of 54. The outcome was change from baseline to endpoint, defined as week 7 or the last observation carried forward.

A symptom rating scale can provide a structured way to quantify symptom severity and assess how scores change over time. Analyzing change within participants makes each participant's baseline score the reference for interpreting their endpoint score. In general, a change estimate describes the direction and magnitude of movement on the scale; its precision depends on information such as variability and the number of observed participants. The registry record does not report the mean change, its standard deviation, a confidence interval, or a p-value, so the amount and precision of change are not available.

The record says that change scores were analyzed using paired t-tests and nonparametric Wilcoxon sign-rank tests. It does not report their results. The ADHD Rating Scale is identified as the primary outcome, while Clinical Global Impressions - Level of Severity for ADHD and other psychiatric disorders is listed as a secondary outcome. No outcome values for either measure are reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record describes a continuous primary measure and paired analyses of change from baseline to endpoint. It states that paired t-tests and nonparametric Wilcoxon sign-rank tests were used. The registry record does not provide numerical results for either test, nor does it report a confidence interval for the change estimate.

What does a paired t-test assess?

In general, a paired t-test evaluates the average within-participant difference between two measurements, such as a baseline score and an endpoint score. Pairing matters because the two measurements come from the same participant rather than from independent groups. The test uses the distribution of participant-level differences; a central assumption is that those differences are adequately modeled by a normal distribution for the intended inference. This is a general explanation of the method, not a claim that the assumption was checked in this study. The registry record does not report diagnostic checks or details of assumption assessment.

Here, the stated endpoint was week 7 or the last observation carried forward. A paired analysis can use participants with both a baseline value and an endpoint value, but the registry does not state how many participants contributed to the primary analysis or report the observed paired differences. It therefore does not show how much information supported the test or how variable those differences were.

What does the Wilcoxon sign-rank test add?

In general, the Wilcoxon sign-rank test is a nonparametric paired procedure that uses the signs and ranks of within-participant differences rather than relying on the same normal-distribution model as the paired t-test. It can provide a complementary analysis when the distribution of differences is not well represented by a normal model. Interpreting it as a test of a central location typically relies on assumptions about the shape of the difference distribution. The registry record calls the procedure a nonparametric Wilcoxon sign-rank test but does not report its test statistic, p-value, or any diagnostics.

Using both procedures can offer different views of the same paired data, but their results are not interchangeable measures of effect. A p-value alone, even if reported, would not describe the size or practical meaning of a score change. An estimate of change and an interval expressing uncertainty would be important for understanding magnitude and precision. Neither is reported in the registry record.

How should the treatment sequence affect comparisons?

The design is listed as single group, with no masking and allocation listed as NA. Atomoxetine was used for 4 weeks; OROS methylphenidate was added during the final 3 weeks for partial responders. In general, a before-and-after change in a single-group study can reflect multiple influences, including the treatment sequence, the passage of time, concurrent care, and measurement variation. Without a randomized control group, a within-participant change does not by itself establish what would have happened without treatment.

The adverse-event categories should not be treated as randomized comparison arms. Eligibility for added OROS methylphenidate depended on partial response after atomoxetine. This creates a systematic difference in treatment history and response status between the listed groups. The registry record explicitly cautions that they are not a like-for-like control comparison, and it does not report an analysis that adjusts for those differences.

What do the planning assumptions mean?

The registry's stated sample-size assumptions describe a planning illustration based on the observed effect, not the study's own design. The illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. These assumptions describe how such planning calculations are framed in general. They do not establish the original enrollment rationale, which is not reported in the registry record, and any resulting sample-size illustration is not observed power. No numerical planning results are available in the record.

For a continuous outcome, over-dispersion means that actual variability is greater than a model or planning assumption allows. In general, greater variability can make an effect harder to estimate precisely and can reduce the ability to distinguish an effect from random variation. This is a general statistical point; the registry record does not report an over-dispersion assessment or evidence of over-dispersion for this outcome.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists the ADHD Rating Scale as the primary outcome and Clinical Global Impressions - Level of Severity for ADHD and other psychiatric disorders as a secondary outcome. It reports two outcome measures and zero analyses. No results for either measure are reported in the registry record. The record does not describe a multiplicity adjustment, a hierarchy for testing outcomes, or a strategy for controlling the chance of false-positive findings across multiple analyses. These details are not reported in the registry record, so it is not possible to determine how multiplicity was handled.

The primary outcome description states that all analyses were intent to treat, with last observation carried forward. In general, last observation carried forward fills an unavailable endpoint value with a participant's last recorded measurement. This approach can retain participants without a week 7 measurement, but it treats the carried-forward value as if it represented endpoint status. If the participant's condition would have changed after the last observation, the imputed value may not reflect the true endpoint. The appropriateness of this method depends on the reasons for missingness and the pattern of change, neither of which is described in the registry record.

The record does not report how many primary outcome measurements were missing, why they were missing, or whether sensitivity analyses assessed alternative assumptions. It also does not give the number of participants included in each outcome analysis. Although the enrollment is 94, and adverse-event denominators are reported separately, those counts do not establish the number with usable paired primary outcome data.

The label intent to treat describes the stated analysis population, but the registry does not give operational details about who was included or how participants without a recorded endpoint were handled beyond the last-observation-carried-forward description. As a result, missing-data risk, analysis-population completeness, and robustness to alternative missing-data assumptions cannot be evaluated from the registry record.

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 1% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists serious adverse events for two treatment categories. In the ATMX Only group, 72 participants were at risk and 0 were recorded as affected by a serious adverse event. In the ATMX and OROS MPH group, 50 were at risk and 0 were recorded as affected. These are the counts posted for the groups; the registry does not provide serious adverse event terms in its list of top serious terms. The absence of listed terms should not be read as additional detail about event types.

For other adverse events, 72 were at risk and 72 were affected in the ATMX Only group; 50 were at risk and 50 were affected in the ATMX and OROS MPH group. These figures indicate that every participant included in each stated denominator was recorded as affected by an other adverse event. The record does not provide the event-level detail needed to distinguish types, severity, duration, or whether participants experienced more than one event.

Deaths are not reported in the registry record. These safety counts are descriptive and do not support a direct causal comparison between the groups. The treatment categories were not randomized or like-for-like: OROS methylphenidate was added for partial responders after atomoxetine. The record does not provide further information about how adverse events were collected or attributed.

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

The record establishes that a short treatment sequence was studied in children and adolescents ages 6-17 with ADHD: atomoxetine for 4 weeks, followed by OROS methylphenidate for the final 3 weeks for participants described as partial responders. The primary measure was change in ADHD Rating Scale score from baseline to week 7 or the last observation carried forward. The registry also identifies a secondary clinical severity measure and provides adverse-event counts for two treatment categories.

What the record does not establish is the size or precision of the primary outcome change. No mean change, standard deviation, confidence interval, or p-value is reported. The stated use of paired t-tests and Wilcoxon sign-rank tests identifies analysis methods, not their results. Without the outcome estimates, the posted record cannot show how scores changed or how uncertain that change was. This absence of results should not be interpreted as evidence of either a favorable or an unfavorable outcome.

The sequential, response-dependent design also limits what can be concluded about the contribution of OROS methylphenidate. Those who received it had first received atomoxetine and were classified as partial responders. The registry identifies no randomized comparator, and it cautions that the groups are not like-for-like. Any difference between the groups could reflect differences in treatment history and response status, as well as other factors; the record does not provide a comparative analysis capable of separating these influences.

The safety figures describe counts of participants affected in the listed categories. They do not provide a detailed account of event type or severity, and the record does not report deaths. Descriptive counts from non-randomized groups cannot establish that one treatment caused more or fewer events than another.

Overall, the registry record documents a study design, outcome definitions, selected analysis methods, and adverse-event counts. It does not provide enough outcome information to quantify the primary result, judge its precision, or attribute change to a particular component of the treatment sequence.

13. Why This Trial Matters Statistically

This study is statistically informative as an example of why design and outcome reporting must be read together. The primary question is framed around within-participant change in a continuous symptom score, and the record names paired t-tests and a nonparametric paired test. Those methods can address change over time within participants, but the presence of a statistical method does not substitute for reporting an estimate and its uncertainty. Without those results, readers cannot assess magnitude, precision, or the relationship between the findings and the stated clinical question.

The response-dependent sequence is another important statistical feature. OROS methylphenidate was added only for participants described as partial responders to atomoxetine. Consequently, the two adverse-event categories do not represent exchangeable groups created by random allocation. Their labels describe different treatment histories, and a simple comparison would be confounded by the selection process. The registry's explicit warning against treating them as a like-for-like comparison is central to interpreting the record.

The record also illustrates how analysis decisions affect interpretation. Intent-to-treat analyses with last observation carried forward are stated, but the missing-data counts, reasons, and sensitivity analyses are not reported. This prevents readers from evaluating whether missing measurements could have materially changed the result. Reporting the number analyzed, outcome estimates, uncertainty intervals, and robustness checks would make the evidence easier to assess.

Finally, the planning assumptions must be kept distinct from observed findings. A planning illustration based on an observed effect is not the trial's original design justification, and a sample-size calculation is not observed power. The record does not report its original sample-size rationale. The main statistical lesson is that transparent estimates, uncertainty, and analysis-population details are needed to make a registry entry interpretable, particularly when the treatment groups arise from a response-guided sequence rather than randomization.

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 most important limitation for interpretation is that the registry record does not report primary outcome results. Although it identifies the ADHD Rating Scale, the endpoint timing, and paired analyses, it gives no change estimate, dispersion, confidence interval, or p-value. The stated statistical methods therefore cannot be evaluated against their reported findings.

The single-group, unmasked design has no randomized comparator. The treatment sequence also makes the ATMX Only and ATMX and OROS MPH categories different by design: the combination followed partial response to atomoxetine. This limits causal interpretation and precludes treating the categories as equivalent comparison groups. The registry explicitly notes that they are not a like-for-like control comparison.

The record does not define partial response, explain how that determination was made, or describe the number of participants who moved into each treatment category. Enrollment is 94, while the adverse-event record lists 72 and 50 at risk in the two categories. A participant flow account and an explanation of these denominators are not reported in the registry record. The number contributing to the primary analysis is also not reported.

Missing-data assessment is limited. Last observation carried forward is specified, but counts and reasons for missing values, patterns of missingness, and sensitivity analyses are not reported. The registry does not describe diagnostic checks for the paired t-test or provide enough results to evaluate the Wilcoxon sign-rank analysis. Multiplicity handling is not reported despite the listing of primary and secondary outcome measures.

Safety information is also limited to participant counts. Event terms and further detail on severity, timing, and recurrence are not reported, and deaths are not reported in the registry record. These limitations concern what can be interpreted from the registry record and do not establish what the full study documentation may contain.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Atomoxetine and OROS Methylphenidate to Treat Children and Adolescents Ages 6-17 With ADHD — NCT00585910.
• Registry record last updated 2012-11-14; status last verified 2012-11.
• Results first posted 2010-05-10.
• 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 a completed Phase 4, single-group study of atomoxetine and OROS methylphenidate in children and adolescents ages 6-17 with ADHD. Enrollment was 94. Atomoxetine was used for 4 weeks, with OROS methylphenidate added for the final 3 weeks for participants described as partial responders. The primary outcome was baseline-to-endpoint change in ADHD Rating Scale score, with endpoint at week 7 or the last observation carried forward. Paired t-tests and Wilcoxon sign-rank tests are stated, and analyses are described as intent to treat with last observation carried forward.

Primary outcome values and inferential results are not reported in the registry record. The record lists Clinical Global Impressions - Level of Severity as a secondary outcome, two outcome measures, and zero analyses. Serious adverse event counts were 0 affected among 72 at risk in ATMX Only and 0 among 50 at risk in ATMX and OROS MPH. Other adverse events affected 72 of 72 and 50 of 50, respectively. The groups were not randomized or like-for-like comparison groups.